European Journal of Medicinal Chemistry (v.44, #5)

Antifungal unsaturated cyclic Mannich ketones and amino alcohols: Study of mechanism of action by Béla Kocsis; Ildikó Kustos; Ferenc Kilár; Adrien Nyul; Péter B. Jakus; Szilárd Kerekes; Victor Villarreal; László Prókai; Tamás Lóránd (1823-1829).
The antifungal activity of some known unsaturated Mannich ketones and their amino alcohols has been reported and the mechanism of antifungal action has been studied. The inhibition of the fungal ergosterol, chitin, protein synthesis and pseudohypha formation was investigated. According to our results, Mannich ketones can influence the development of pseudohyphae of Candida albicans strains. In addition, they are able to induce significant changes in the protein composition of this fungal strain. Some of our Mannich ketones have shown inhibitory effect on the fungal chitin synthase enzyme. QSAR studies were also carried out.The antifungal activity and the mechanism of action of some unsaturated Mannich ketones were investigated studying the inhibition of the fungal ergosterol, chitin, protein synthesis and pseudohypha formation.Display Omitted
Keywords: Mannich ketone; Antifungal activity; Protein synthesis; Pseudohypha; Chitin synthase; QSAR;

Synthesis and biological evaluation of 4,5-diphenyloxazolone derivatives on route towards selective COX-2 inhibitors by Yasemin Dündar; Serdar Ünlü; Erden Banoğlu; Antonio Entrena; Gabriele Costantino; Maria-Teresa Nunez; Francisco Ledo; M. Fethi Şahin; Ningur Noyanalpan (1830-1837).
A series of 3-unsubstituted/substituted-4,5-diphenyl-2-oxo-3H-1,3-oxazole derivatives were prepared as selective cyclooxygenase-2 (COX-2) inhibitors. Among the synthesized compounds, 4-(4-phenyl-3-methyl-2-oxo-3H-1,3-oxazol-5-yl)benzensulfonamide (compound 6) showed selective COX-2 inhibition with a selectivity index of >50 (IC50COX-1 = >100 μm, IC50COX-2 = 2 μm) in purified enzyme (PE) assay. Compound 6 also exhibited selective COX-2 inhibition in human whole blood assay. Molecular docking studies showed that 6 can be docked into the COX-2 binding site thus providing the molecular basis for its activity.A series of 3-unsubstituted/substituted-4,5-diphenyl-2-oxo-3H-1,3-oxazole derivatives were prepared and evaluated for their inhibitory properties of cyclooxygenase-2 (COX-2).Display Omitted
Keywords: 4,5-Diphenyloxazolone; Cyclooxygenase inhibition; COX-1; COX-2; Docking;

The voltage-gated potassium channel Kv1.3 constitutes an attractive pharmacological target for the treatment of effector memory T cell-mediated autoimmune diseases such as multiple sclerosis and psoriasis. Using 5-methoxypsoralen (5-MOP, 1), a compound isolated from Ruta graveolens, as a template we previously synthesized 5-(4-phenoxybutoxy)psoralen (PAP-1, 2) which inhibits Kv1.3 with an IC50 of 2 nM. Since PAP-1 is more than 1000-fold more potent than 5-MOP, we here investigated whether attaching a 4-phenoxybutoxy side chain to other heterocyclic systems would also produce potent Kv1.3 blockers. While 4-phenoxybutoxy-substituted quinolines, quinazolines and phenanthrenes were inactive, 4-phenoxybutoxy-substituted quinolinones, furoquinolines, coumarins or furochromones inhibited Kv1.3 with IC50s of 150 nM to 10 μM in whole-cell patch-clamp experiments. Our most potent new compound is 4-(4-phenoxybutoxy)-7H-furo[3,2-g]chromene-7-thione (73, IC50 17 nM), in which the carbonyl oxygen of PAP-1 is replaced by sulfur. Taken together, our results demonstrate that the psoralen system is a crucial part of the pharmacophore of phenoxyalkoxypsoralen-type Kv1.3 blockers. We here investigated whether attaching a 4-phenoxybutoxy side chain to various heterocyclic systems would produce Kv1.3 channel blockers as potent as the 5-(4-phenoxybutoxy)psoralen PAP-1 (IC50 2 nM).Display Omitted
Keywords: Kv1.3; Voltage-gated potassium channel; PAP-1; Immunosuppression;

Hansch analysis of substituted benzoic acid benzylidene/furan-2-yl-methylene hydrazides as antimicrobial agents by Pradeep Kumar; Balasubramanian Narasimhan; Deepika Sharma; Vikramjeet Judge; Rakesh Narang (1853-1863).
A series of substituted hydrazide derivatives have been synthesized and screened for their in vitro antimicrobial activities against five representative microorganisms. The results of antimicrobial study indicated that the presence of electron withdrawing groups on the benzoic acid moiety improved antimicrobial activity. Further, the presence of heterocyclic ring furan does not improve the antimicrobial activity of substituted hydrazides. To understand the relationship between physicochemical parameters and antimicrobial activity of substituted hydrazide derivatives, QSAR investigation was performed by the development of one-target and multi-target models. The multi-target model was found to be effective in describing the antimicrobial activity of substituted hydrazides in comparison to the one-target models. Further, it indicated the importance of the topological parameter, valence third order molecular connectivity index (3 χ v) and the electronic parameter, energy of highest occupied molecular orbital (HOMO) in describing the antimicrobial activity of substituted hydrazides.Display Omitted
Keywords: Substituted hydrazides; Antibacterial activity; Antifungal activity; QSAR;

The structure of Rimonabant in the solid state and in solution: An experimental and theoretical study by Ibon Alkorta; Mario Alvarado; José Elguero; Santiago García-Granda; Pilar Goya; María Luisa Jimeno; Laura Menéndez-Taboada (1864-1869).
The X-ray molecular structure of Rimonabant methanol solvate has been determined together with the 1H, 13C and 15N NMR spectra in acetone solution. B3YP/6-311++G(d,p) calculations have been performed out to determine two minimum energy conformations, on these geometries GIAO calculations were carried out to obtain the corresponding absolute shieldings that were compared with the experimental chemical shifts.The X-ray molecular structure of Rimonabant methanol solvate has been determined together with its 1H, 13C and 15N NMR spectra in acetone solution. B3YP/6-311++G(d,p) calculations have been also been performed.Display Omitted
Keywords: Rimonabant; X-ray structure; 1H NMR; 13C NMR; 15N NMR; DFT calculations; GIAO calculations;

Gallium(III) complexes of 2-pyridineformamide thiosemicarbazones: Cytotoxic activity against malignant glioblastoma by Isolda C. Mendes; Marcela A. Soares; Raquel G. dos Santos; Carlos Pinheiro; Heloisa Beraldo (1870-1877).
The gallium(III) complexes [Ga(2Am4DH)2]NO3 (1), [Ga(2Am4Me)2]NO3 (2) and [Ga(2Am4Et)2]NO3 (3) were prepared with 2-pyridineformamide thiosemicarbazone (H2Am4DH) and its N(4)-methyl (H2Am4Me) and N(4)-ethyl (H2Am4Et) derivatives. The thiosemicarbazones were cytotoxic against malignant RT2 glioblastoma cells (expressing p53 protein) with IC50 values in the 7.3–360 μM range, and against malignant T98 glioblastoma cells (expressing mutant p53 protein) with IC50 values in the 3.6–143 μM range. Coordination to gallium strongly increased the cytotoxic potential in complexes 2 and 3, which showed IC50 values in the 0.81–9.57 μM range against RT2 cells and in the 3.6–11.30 μM range against T98 cells, and were 20-fold more potent than cisplatin. All thiosemicarbazones and gallium complexes were able to induce cell death by apoptosis.Display Omitted
Keywords: Thiosemicarbazones; Gallium complexes; Glioblastoma; Cytotoxicity;

Some water-soluble polymer–copper(II) complexes, [Cu(phen)(l-phe)(BPEI)]ClO4·4H2O (phen = 1,10-phenanthroline, l-phe =  l-phenylalanine, and BPEI = branched polyethyleneimine), with various amounts of copper(II) chelates in the polymer chain, were prepared by ligand substitution method in water–ethanol medium and characterized by infra-red, UV–visible, EPR spectral and elemental analysis methods. Binding of these complexes with calf thymus DNA (CT DNA) has been investigated by absorption spectroscopy, emission spectroscopy and gel electrophoresis techniques. The experimental results indicate that the amount of copper(II) chelate content in the polymer backbone have marked effect on the binding affinity to CT DNA. Interactions like electrostatic interaction, van der Waals interaction, hydrogen bonding and/or partial intercalation binding modes exist in this system. A sample of polymer–copper(II) complex was tested for its antibacterial and antifungal activity against certain human pathogenic organisms and it was found to have good antibacterial and antifungal activities.Polymer–copper(II) complex samples (containing 1,10-phenanthroline and l-phenylalanine ligand) with varying amounts of copper(II) complex content in the polymer chain were prepared and characterized. DNA binding properties of these samples have been carried out using different physico-chemical methods. A sample of this polymer–copper(II) complex was tested for its antimicrobial activity.Display Omitted
Keywords: Polymer–metal complex; DNA binding; Antibacterial activity; Antifungal activity;

Cationic surfactants from lysine: Synthesis, micellization and biological evaluation by Lourdes Pérez; Aurora Pinazo; M. Teresa García; Marina Lozano; Angeles Manresa; Marta Angelet; M. Pilar Vinardell; Montse Mitjans; Ramon Pons; M. Rosa Infante (1884-1892).
Biocompatible cationic surfactants from the amino acid lysine (hydrochloride salts of Nɛ-lauroyl lysine methyl ester, Nɛ-myristoyl lysine methyl ester and Nɛ-palmitoyl lysine methyl ester) have been prepared in high yields by lysine acylation in ɛ position with three natural saturated fatty acids. The micellization process of these surfactants has been studied using the PGSE-NMR technique. The compounds were tested as antimicrobial agents against Gram-positive and Gram-negative bacteria. The surfactants show moderate antimicrobial activity against the Gram-positive bacteria but Gram-negative bacteria are resistant to these surfactants in the concentration range tested. The haemolytic activity is considerably lower than those reported for other cationic Nα-acyl amino acid analogues. The acute toxicity against Daphnia magna and biodegradability was studied. The toxicity is clearly lower than that reported for conventional cationic surfactants from quaternary ammonium and the three surfactants from lysine can be classified as ready biodegradable surfactants.Cationic Nɛ-acyl lysine methyl ester surfactants were prepared using classical synthetic methods. We were evaluated for such physicochemical properties as critical micellar concentration and also such biological properties as antimicrobial activity, ecotoxicity, biodegradation and haemolytic activity.Display Omitted
Keywords: Lysine; Surfactants; Haemolysis; Antimicrobial properties;

Synthesis of novel 3-(aryl)benzothieno[2,3-c]pyran-1-ones from Sonogashira products and intramolecular cyclization: Antitumoral activity evaluation by Maria-João R.P. Queiroz; Ricardo C. Calhelha; Luís A. Vale-Silva; Eugénia Pinto; M. São-José Nascimento (1893-1899).
Several novel 3-(aryl)benzothieno[2,3-c]pyran-1-ones (tricyclic lactones) were prepared either by a tandem one-pot Sonogashira coupling and intramolecular cyclization, reacting the 3-bromobenzo[b]thiophene-2-carboxylic acid with arylacetylenes, or by Sonogashira coupling of the methyl 3-bromobenzo[b]thiophene-2-carboxylate or the methyl 3-bromo-6-methoxybenzo[b]thiophene-2-carboxylate with arylacetylenes followed by an electrophilic intramolecular cyclization using iodine or TFA in two separate steps. The Sonogashira products and the tricyclic lactones obtained were evaluated for their capacity to inhibit the in vitro growth of three human tumor cell lines, MCF-7 (breast adenocarcinoma), NCI-H460 (non-small cell lung cancer) and SF-268 (CNS cancer). Most of the compounds showed a high growth inhibitory effect on all the tested cell lines, with GI50 values in the μM range. A structure–activity relationship was established for the Sonogashira products and for the tricyclic lactones, namely related to the presence and position of substituents (OMe and/or F) in the benzothiophene moiety or in the phenyl ring.A series of novel 3-(aryl)benzothieno[2,3-c]pyran-1-ones were prepared from intramolecular cyclization of arylalkynyl compounds and both types were tested in vitro for their antitumoral activity using three human tumor cell lines.Display Omitted
Keywords: Benzo[b]thiophenes; Sonogashira coupling; Intramolecular lactonization; Benzothieno[2,3-c]pyran-1-ones; Antitumor activity;

Design, synthesis, and evaluation of biphenyl-4-yl-acrylohydroxamic acid derivatives as histone deacetylase (HDAC) inhibitors by Sabrina Dallavalle; Raffaella Cincinelli; Raffaella Nannei; Lucio Merlini; Gabriella Morini; Sergio Penco; Claudio Pisano; Loredana Vesci; Marcella Barbarino; Valentina Zuco; Michelandrea De Cesare; Franco Zunino (1900-1912).
A series of hydroxamic acid-based histone deacetylase (HDAC) inhibitors were designed on the basis of a model of the HDAC2 binding site and synthesized. They are characterized by a cinnamic spacer, capped with a substituted phenyl group. Modifications of the spacer are also reported. In an in vitro assay with the isoenzyme HDAC2, a good correlation of the activity with the docking energy was found. In human ovarian carcinoma IGROV-1 cells, selected compounds produced significant acetylation of p53 and α-tubulin. Most compounds showed an antiproliferative activity comparable to that of SAHA. At equitoxic concentrations, the tested compounds were more effective than SAHA in inducing apoptotic cell death. Compounds selected for in vivo evaluation exhibited a significant antitumor activity on three tumor models at well tolerated doses, thus suggesting a good therapeutic index.A new series of HDAC inhibitors showed HDAC2 inhibition and antiproliferative activity on a panel of human tumor cell lines, as well as in vivo activity on three tumor models.Display Omitted
Keywords: Histone deacetylase; Antiproliferative activity; Synthesis;

Design, synthesis, and biological evaluation of novel triazole derivatives as inhibitors of cytochrome P450 14α-demethylase by Xiaoyun Chai; Jun Zhang; Honggang Hu; Shichong Yu; Qingyan Sun; Zhigang Dan; Yuanying Jiang; Qiuye Wu (1913-1920).
Based on the results of computational docking to the active site of the cytochrome P450 14α-demethylase (CYP51), a series of 1-(1H-1,2,4-triazole-1-yl)-2-(2,4-difluorophenyl)-3-substituted-2-propanols as analogs of fluconazole were designed, synthesized, and evaluated as antifungal agents. The MIC80 values indicate that compounds 1an exhibited higher activity against nearly all fungi tested except Aspergillus fumigatus than fluconazole, while compounds 2af, 3af showed no activity or only moderate activity against all fungi tested. Noticeably, the MIC value of compounds 1a, 1b and 1g is 64 times lower than that of fluconazole against Microsporum gypseum in vitro. And compounds 1a, 1b and 2b showed 128 times higher activity (with the MIC80 value of 0.0039 μg/mL) than that of fluconazole against Candida albicans and also showed higher activity than that of the other positive controls. Computational docking experiments indicated that the inhibition of CYP51 involves a coordination bond with iron of the heme group, the hydrophilic H-bonding region, the hydrophobic region, and the narrow hydrophobic cleft. In addition, the activity of the compounds would be enhanced when the side chains were shorter.A number of novel triazole derivatives have been designed, synthesized, and studied with molecular docking to get the insight of structural requirements for better enzyme inhibition.▪
Keywords: Triazole; Synthesis; Antifungal activity; CYP51; Molecular docking;

Novel trans-dichloridoplatinum(II) complexes with 3- and 4-acetylpyridine: Synthesis, characterization, DFT calculations and cytotoxicity by Gordana M. Rakić; Sanja Grgurić-Šipka; Goran N. Kaluđerović; Santiago Gómez-Ruiz; Snežana K. Bjelogrlić; Siniša S. Radulović; Živoslav Lj. Tešić (1921-1925).
Novel complexes of platinum(II) with 3- (1) or 4-acetylpyridine (2) have been synthesized and characterized by elemental analyses, IR, 1H and 13C NMR spectroscopy. Single crystal X-ray diffraction revealed the trans geometry of complex 2. DFT calculations confirm formation of trans isomers for both complexes. The complexes have been tested for their cytotoxicity against HeLa (human cervical cancer), U2OS (human osteosarcoma), U2OScisR (human osteosarcoma cisplatin resistant), B16 (murine melanoma), MDA-453, MDA-361, and MCF-7 (human breast cancer), LS-174 (human colon cancer) and FemX (human melanoma) cell lines. The most promising compound trans-dichloridobis(4-acetylpyridine)platinum(II) (2) overcomes cisplatin resistance of U2OScisR cells after 48 h of drug exposure.Novel complexes of platinum(II) with 3- (1) or 4-acetylpyridine (2) have been tested for their cytotoxicity against HeLa, U2OS, U2OScisR, B16, MDA-453, MDA-361, MCF-7, LS-174 and FemX cells. The most promising compound 2 overcomes cisplatin resistance of U2OScisR cells in 48 h.Display Omitted
Keywords: Platinum(II); Antitumoral activity; DFT; X-ray;

The study compares GRIND-based 3D-QSAR and CoMFA [A. Cavalli, E. Poluzzi, F. De Ponti, M. Recanatini, J. Med. Chem, 45(2002), 3844–53] to investigate a biological topic dominated by hydrophobic interactions, e.g. hERG K+ channel blocking activity.As expected, models are found by both methods and there is a fine agreement between statistical and graphical results as well. However, a closer inspection revealed that failures in the prediction of hERG blocking activity for lipophilic compounds were registered for both methods. The study explores the reasons for these failures which are strongly dependent on the chosen method, and gives some suggestions to handle with these topics.Display Omitted
Keywords: 3D-QSAR; ALMOND; hERG; GRIND; Molecular modelling;

Design and synthesis of new N-(fluorenyl-9-methoxycarbonyl) (Fmoc)-dipeptides as anti-inflammatory agents by Chiao-Ting Yen; Tsong-Long Hwang; Yang-Chang Wu; Pei-Wen Hsieh (1933-1940).
Twenty-four new dipeptide analogs (124) of aurantiamide acetate were designed, synthesized, and assayed for effects on superoxide anion generation and elastase release by human neutrophils in response to fMLP/CB. Among them, seven N-(fluorenyl-9-methoxycarbonyl) (Fmoc)-dipeptides (6, 9, 12, 14, 17, 18 and 20) showed potent inhibitory effects. Compounds 9 and 18 showed the most selective effects against human neutrophil elastase release, with IC50 values of 0.8 ± 0.1 and 1.7 ± 0.6 μM, respectively, and were 130-fold more potent than phenylmethylsulfonyl fluoride (PMSF), the positive control, in this anti-inflammatory assay. These two compounds could be developed as new lead anti-inflammatory agents.Twenty-six Fmoc-based dipeptides were designed and synthesized. Among them, compounds 9 and 18 showed potent inhibitory effect on human neutrophils elastase release, with IC50 values of 0.8 ± 0.1 and 1.7 ± 0.6 μM, respectively.Display Omitted
Keywords: Fmoc-based dipeptides; Aurantiamide derivatives; Anti-inflammatory agents;

A series of naphthalene and non-naphthalene derivatives (n  = 42) having cytochrome P450 2A6 and 2A5 inhibitory activities, reported by Rahnasto et al., were subjected to QSAR and QAAR studies. The analyses were performed using electronic, spatial, shape and thermodynamic descriptors to develop quantitative models for prediction of the inhibitory activities and to explore importance of different descriptors for the responses. The data set was divided into training and test sets (with test set size being approximately 25% of the full data set size) based on K-means clustering applied on the standardized descriptor matrix. Genetic function approximation (GFA) and genetic partial least-squares (G/PLS) were used as chemometric tools for modeling, and the derived equations were of acceptable statistical and prediction (both internal and external) qualities although different equations varied in quality in a wide range (R 2: 0.561–0.898, R a 2: 0.508–0.870, Q 2: 0.495–0.814, R pred 2: 0.615–0.914, r 2: 0.679–0.905, r 0 2: 0.639–0.904, r m 2: 0.494–0.876). In the case of CYP2A5 inhibition, the GFA derived QSAR model is better than the G/PLS derived model considering both internal and external validations. In the case of CYP2A6 inhibitory potency data, the GFA derived QSAR model is better than the G/PLS model considering internal validation whereas the latter is better in external validation (which is more important) than the former. The model development process was subjected to randomization test at 90% confidence level by taking into account the whole pool of descriptors, while the developed models were also subjected to randomization test (99% confidence level) for validation. Based on the randomization test results, GFA models are found to be superior to the G/PLS models. Among the parameters, which were found important in modeling both the responses, were different Jurs descriptors, electronic descriptors (like Sr, Apol), steric descriptors (like shadow indices, Molref), shape descriptors (like COSV, Fo) and lipophilicity descriptors. This indicates that the CYP2A5 and CYP2A6 inhibition of these compounds is related to charge distribution, surface area, electronic, hydrophobic and spatial properties of the molecules.A series of naphthalene and non-naphthalene derivatives (n  = 42) having cytochrome P450 2A6 and 2A5 inhibitory activities have been subjected to QSAR and QAAR studies.Display Omitted
Keywords: QSAR; QAAR; Cytochrome P450 enzymes; GFA; G/PLS;

QSAR model for predicting radical scavenging activity of di(hetero)arylamines derivatives of benzo[b]thiophenes by Rui M.V. Abreu; Isabel C.F.R. Ferreira; Maria João R.P. Queiroz (1952-1958).
A QSAR study was developed in order to model the antioxidant activity, specifically the radical scavenger activity (RSA), of 26 di(hetero)arylamines' derivatives of benzo[b]thiophenes. The QSAR model was constructed, using the partial least squares projection of latent structures (PLS) method, and its robustness and predictability were verified by internal and external cross-validation methods. A total of 4 molecular descriptors, belonging to RDF (Radial Distribution Function) descriptors (RDF020e and RDF045e) and 2D-autocorrelation descriptors (GATS8p and MATS5e) were selected to build the QSAR model. RDF descriptors seem to relate the presence of electronegative atoms at the inner atmosphere of the compounds to increase RSA. 2D-Autocorrelation descriptors associate the presence of polarizable and electronegative pairs of atoms, at specific topological distance, with the RSA of the compounds. Finally this QSAR model proved to be a useful tool in the prediction of radical scavenger activity of congeneric compounds and will be used to guide the synthesis of new diarylamines in our laboratory.A QSAR study was developed in order to model the antioxidant activity, specifically the radical scavenger activity, of 26 compounds belonging to 3 classes of di(hetero)arylamines' derivatives of benzo[b]thiophenes.▪
Keywords: Benzo[b]thiophenes; Di(hetero)arylamines; Antioxidants; QSAR; PLS;

Synthesis, pharmacological evaluation and docking studies of new sulindac analogues by Nelilma C. Romeiro; Ramon D.F. Leite; Lidia M. Lima; Suzana V.S. Cardozo; Ana L.P. de Miranda; Carlos A.M. Fraga; Eliezer J. Barreiro (1959-1971).
This paper describes the synthesis, pharmacological evaluation and docking studies of a series of new sulindac analogues. Overall, the designed compounds revealed good, in vivo, antinociceptive activity and satisfactory anti-inflammatory profile. Flexible molecular docking with COX-1/COX-2 has shown putative binding modes of the designed compounds while the theoretical evaluation of cell permeability based on Lipinski's rule of five has helped rationalize the biological results.▪
Keywords: Molecular docking; Sulindac analogues; NSAIDs; Antinociceptive; Anti-inflammatory drugs;

A variety of 5-amino-6,8-dicyano-1H-[1,2,4]triazolo[1,5-a]pyridin-4-ium-2-thiolate containing compounds 3ai, 5ac were prepared via reaction of arylidenemalononitriles 1ac, 4a and 4b with 2-[(substituted amino)thiocarbonyl]cyanoacetohydrazides 2ad in refluxing ethanol in the presence of triethylamine. Anti-inflammatory activity screening of the synthesized compounds (at a dose of 50 mg/kg body weight) utilizing in vivo acute carrageenan-induced paw oedema standard method in rats exhibited that the prepared heterocycles possess considerable pharmacological properties especially, 3f, 3h, 5b and 5c which reveal remarkable activities relative to indomethacin (which was used as a reference standard at a dose of 10 mg/kg body weight). PGE2 inhibitory properties of the highly promising synthesized anti-inflammatory active agents (3f, 3h, 5b and 5c) were determined by PGE2 assay kit technique, which reveal remarkable activity coinciding greatly with the observed anti-inflammatory properties. Anti-tumor activity screening of 3b and 3e, as representative examples of the synthesized compounds, at a dose of 10 μM utilizing 59 different human tumor cell lines, representing leukemia, melanoma and cancers of the lung, colon, brain, ovary, breast, prostate and kidney exhibited that the tested compounds reflect mild or no activity at all against most of the used human tumor cell lines. However, compound 3e reveals considerable anti-tumor properties against leukemia CCRF-CEM and HL-60(TB) cell line.Display Omitted
Keywords: 5-Amino-6,8-dicyano-1H-[1,2,4]triazolo[1,5-a]pyridines; Ylidenemalononitriles; 2-[(Substituted amino)thiocarbonyl]cyanoacetohydrazides; Anti-inflammatory; PGE2; Anti-tumor;

The structure–bioavailability approach in antifungal agents by Monika Grudzień; Anna Król; Grażyna Paterek; Karolina Stępień; Franciszek Pluciński; Alexander P. Mazurek (1978-1981).
The thermodynamic and electrostatic properties of antifungal triazole and imidazole derivatives: itraconazole, fluconazole, miconazole and ketoconazole molecules were calculated. The main aim of our investigations was to identify molecular determinants that have an effect on bioavailability of studied compounds. This is solvation energy estimated by the ΔG values as well as electrostatic properties of the molecules. The influence of another substituents was also considered.The presented values are discriminative and reflect very low solubility of ketoconazole in water in comparison with other molecules. The thermodynamic and electrostatic properties of molecules appeared to be good indicators of bioavailability of compounds studied here and they are likely to be used as screening parameters in Biopharmaceutical Classification System (BCS) development.The free enthalpy of solvation as a determinant of availability of some antifungal triazole and imidazole derivatives.Display Omitted
Keywords: Antifungal agent; BCS system; Bioavailability;

Discovering novel quercetin-3-O-amino acid-esters as a new class of Src tyrosine kinase inhibitors by He Huang; Qi Jia; Jingui Ma; Guangrong Qin; Yingyi Chen; Yonghua Xi; Liping Lin; Weiliang Zhu; Jian Ding; Hualiang Jiang; Hong Liu (1982-1988).
Quercetin-3-O-amino acid-esters, a new type of quercetin derivatives, were successfully prepared for the first time. Different from quercetin, the novel compounds show higher selectivity as inhibitors against Src tyrosine kinase (IC50 values ranging from 3.2 μM to 9.9 μM) than against EGFR tyrosine kinase. Molecular docking reveals that both hydrophobic and hydrogen bonding interactions are important to the selectivity. Therefore, this study provides a new promising scaffold for further development of new anticancer drugs targeting Src tyrosine kinase.Novel quercetin-3-O-amino acid-esters as a new class of Src tyrosine kinase inhibitors were successfully prepared for the first time. ▪
Keywords: Quercetin; Amino acid; Src; EGFR; Inhibitor;

Novel pyridazine derivatives: Synthesis and antimicrobial activity evaluation by N.G. Kandile; M.I. Mohamed; H. Zaky; H.M. Mohamed (1989-1996).
A general method for the preparation of new hydrazones is reported. The 1-[4-(2-methoxybenzyl)-6-aryl pyridazin-3(2H)-ylidene] hydrazines or their tautomeric structures (1 ad ) were condensed with different aldehydes, dialdehydes, ketones, α-dicarbonyl compounds and simple carbohydrates to afford the hydrazones and dihydrazones (2 ad ), (3 ad ), (4 ad ), (5 ad ), (6 d ), (7 c ), (8 ad ), (9 ad ), (10 ad ), (11 ad ), (12 a,c,d ), (13 ad ), (14 ad ), (15 ad ), (16 ad ) and (17 ad ). The structures of all synthesized compounds were confirmed from microanalytical and spectral data. Some of the products were screened for their antimicrobial activity against Staphylococcus aureus and Streptococcus faecalis, Escherichia coli and Pseudomonas aeruginosa. The hydrazone derivative 15 d (1-[4-(2-methoxybenzyl)-6-methylphenyl pyridazin-3(2H)-ylidene]-2-(2-carboxydiphenyl methyl) hydrazine) showed the highest biological activity.New pyridazine derivatives were synthesized and their antimicrobial activities were evaluated against Staphylococcus aureus and Streptococcus faecalis, Escherichia coli and Pseudomonas aeruginosa.Display Omitted
Keywords: Hydrazones; Pyridazine; Aldehydes; Carbohydrates; Dihydrazones; Antimicrobial activity;

N1-Alkylated 3,4-dihydropyrimidine-2(1H)-ones: Convenient one-pot selective synthesis and evaluation of their calcium channel blocking activity by Kamaljit Singh; Divya Arora; Elizabeth Poremsky; Jazmyne Lowery; Robert S. Moreland (1997-2001).
It has been found that selective N1-alkylation of 3,4-dihydropyrimidine-2(1H)-ones can be achieved under solvent-less, mild phase transfer catalytic (PTC) conditions with tetrabutylammonium hydrogen sulfate and 50% aqueous NaOH as the catalyst and base, respectively. The procedure is tolerant to substitutional variation at key diversity points on the pyrimidinone moiety. N1-Alkylation of 3,4-dihydropyrimidine-2(1H)-ones can be achieved under solvent-less, mild phase transfer catalytic (PTC) conditions with tetrabutylammonium hydrogen sulfate and 50% aqueous NaOH as the catalyst and base, respectively. N1-Substituted DHPM derivatives show moderate calcium channel blocking activity.Display Omitted
Keywords: Phase transfer catalysis; N-Alkylation; Biginelli dihydropyrimidinones; Regioselective; Tetrabutylammonium hydrogen sulfate; Vascular smooth muscle;

A series of 2′-arylsubstituted-1H,1′H-[2,5′]-bisbenzimidazolyl-5-carboxamidines were prepared in a six-step process starting from 4-amino-3-nitrobenzonitrile. The antiparasitic activity against Trypanosoma brucei rhodesiense (T.b.r.), Plasmodium falciparum (P.f.), Leishmania donovani (L.d.) and Trypanosoma cruzi (T.c.) and antifungal activity against Candida albicans and Candida krusei were evaluated in vitro. Several compounds showed promising in vitro activity against T.b.r., P.f. and C. albicans and had superior activity against P.f. as compared to chloroquine.The synthesis and potent antiparasitic activity of bisbenzimidazolyl-carboxamidines are described.Display Omitted
Keywords: Bisbenzimidazoles; Carboxamidine; Antiparasitic agents; Antifungal agents;

Sulphonamide-based bombesin prodrug analogues for glutathione transferase, useful in targeted cancer chemotherapy by I. Axarli; N.E. Labrou; C. Petrou; N. Rassias; P. Cordopatis; Y.D. Clonis (2009-2016).
Glutathione transferases (GSTs) are enzymes involved in cellular detoxification by catalysing the nucleophilic attack of glutathione (GSH) on the electrophilic centre of a number of toxic compounds and xenobiotics, including certain chemotherapeutic drugs. The encountered chemotherapeutic resistant of tumour cells, thus, has been associated with the increase of total GST expression. GSTs, in addition to GSH-conjugating activity, exhibit sulphonamidase activity, catalyzing the GSH-mediated hydrolysis of sulphonamide bonds. Such reactions are of interest as potential tumour-directed prodrug activation strategies. In the present work we report the design and synthesis of novel chimaeric sulphonamide derivatives of bombesin, able to be activated by the model human isoenzyme GSTA1-1 (hGSTA1-1). These derivatives bear a peptidyl-moiety (analogues of bombesin peptide: R–[Lue13]-bombesin, R–[Phe13]-bombesin and R–[Ser3,Arg10,Phe13]-bombesin, where R = C6H5SO2NH–) as molecular recognition element for targeting the drug selectively to tumour cells. The released S-alkyl-glutathione, after hGSTA1-1-mediated cleavage of the sulphonamide bond, provides an inhibitor of varied strength against GSTs from different sources. These prodrugs are envisaged as a plausible means to sensitize drug-resistant tumours that overexpress GSTs.The work presents the synthesis of novel chimaeric sulphonamide-bombesin prodrug analogues (the structure of the prodrug sulphonamide [Ser3,Arg10,Phe13]-bombesin is shown) susceptible to activation by the human enzyme glutathione S-transferase (isoenzyme hGSTA1-1; the interaction of the sulphanilamide lead-ligand with the isoernzyme is shown). Followed GST-mediated cleavage of the sulfonamide bond, the prodrug releases a potent GST inhibitor. The decrease of GST activity is associated with a decrease of tumour cells resistance to antineoplastic agents and a more effective cancer chemotherapy.Display Omitted
Keywords: Alkylating agents; Antineoplastic therapy; Drug resistance; Detoxification; Enzyme-activated prodrug; Glutathione transferase;

Synthesis, anti-tuberculosis activity and 3D-QSAR study of amino acid conjugates of 4-(adamantan-1-yl) group containing quinolines by Amit Nayyar; Sanjay R. Patel; Mushtaque Shaikh; Evans Coutinho; Rahul Jain (2017-2029).
The synthesis, antimycobacterial activity and 3D-QSAR study of two series of 4-(adamantan-1-yl) group containing quinolines conjugated to amino acids are described. The most potent analogs displayed in vitro antimycobacterial activity ranging between 1.00 and 3.125 μg/mL. To understand the relationship between structure and activity, a 3D-QSAR analysis has been carried out by Comparative Molecular Field Analysis (CoMFA). The activities of molecules in the test sets were nicely predicted by the CoMFA model generated with field alignment. The best model was obtained using atom-fit alignment. Based on the molecular fields the relationships between structure and activity were easily rationalized.Display Omitted
Keywords: Tuberculosis; Ring-substituted quinolines; CoMFA; Amino acid conjugates; Anti-tuberculosis;

Mucoadjuvant properties of lipo- and glycoconjugated derivatives of oligochitosans by E.V. Svirshchevskaya; L.G. Alekseeva; P.D. Reshetov; N.N. Phomicheva; S.A. Parphenyuk; A.V. Ilyina; V.S. Zueva; S.A. Lopatin; A.N. Levov; V.P. Varlamov (2030-2037).
Chitosan, (1-4)-2-amino-2-deoxy-beta-d-glucan, is a deacetylated form of chitin, an abundant biodegradable, positively charged natural polysaccharide. Chitosan is used for antigen delivery through mucosal barrier due to its ability to disrupt tight junctions. Here we produced new water-soluble low-molecular weight chitosan (LMW-Chi) lipid derivatives and compared their ability to stimulate humoral response with the effect of unmodified LMW-Chi or its oligosaccharide derivatives. LMW-Chi effectively penetrated into macrophage-like, lymphoid and epithelial cells. It also stimulated in mice IgG production to model proteins delivered either by subcutaneous or intranasal routes. Adjuvant effect of chitosan derivatives was comparable to or lower than that of unmodified LMW-Chi. Thus, it is possible that adjuvant effect is induced by unmodified glucosamine units of chitosan.The conjugates of low-molecular weight chitosans with fatty acids and carbohydrates were compared for their ability to stimulate IgG response in mice to model proteins delivered via subcutaneous or mucosal routes.▪
Keywords: Mucosal immunization; Mucoadjuvant; Lipid chitosan derivatives; Low-molecular weight chitosan;

Synthesis, antimicrobial and cytotoxic activities of some 5-arylidene-4-thioxo-thiazolidine-2-ones by Frederico L. Gouveia; Renata M.B. de Oliveira; Tatiane B. de Oliveira; Ivanildo M. da Silva; Silene C. do Nascimento; Kêsia X.F.R. de Sena; Julianna F.C. de Albuquerque (2038-2043).
Several 5-arylidene-4-thioxo-thiazolidine-2-ones (3an) were synthesized and evaluated as antimicrobial agents against representative strains, including multidrug-resistant strains of clinical isolates. Also, the antiproliferative activity was evaluated against two human carcinoma cell lines (NCI-H292 and HEp-2). The compounds containing the 5-arylidene subunit presented greater antimicrobial activities against Gram positive bacteria, including the multidrug-resistant clinical isolates, than the 4-thioxo-thiazolidine-2-one. Important SAR information was also gathered, such as the contribution of thiocarbonyl attached at 4-position on the thiazolidine heterocyclic for antimicrobial properties. None of the derivatives exhibited significant antiproliferative activity against the human carcinoma cell lines.New antimicrobial structures: 5-arylidene-4-thioxo-thiazolidine-2-ones represent a compound class that are antimicrobial agents, and viewed with the capacity to inhibit the proliferation of representative strains, including multidrug-resistant isolates. Important SAR information was also gathered, and is different from previously reported SARs of this scaffold.Display Omitted
Keywords: 4-Thioxothiazolidinones; Benzylidene derivatives; Antimicrobial activity; Cytotoxic activity;

Synthesis and DNA-binding studies of two ruthenium(II) complexes of an intercalating ligand by D. Lawrence Arockiasamy; S. Radhika; R. Parthasarathi; Balachandran Unni Nair (2044-2051).
Two new ruthenium(II) complexes [Ru(bpy)2(HBT)]2+ (1) and [Ru(phen)2(HBT)]2+ (2) (bpy = 2,2′-bipyridine; phen = 1,10-phenanthroline; HBT = 11H, 13H-4, 5,9,10,12,14-hexaaza-benzo [b] triphenylene) have been synthesized and characterized by elemental analysis, mass spectra, 1H NMR and cyclic voltammetry. The DNA binding property of the two complexes has been investigated employing absorption spectroscopy, fluorescence spectroscopy and viscosity measurements. Both complexes 1 and 2 have been found to prefer intercalative binding to DNA. The DNA binding constants for the two complexes have been measured to be 5.71 ± 0.20 × 107 and 4.65 ± 0.20 × 107  M−1 through ethidium bromide displacement method. Molecular modeling studies too indicate that both complexes 1 and 2 prefer intercalative binding to DNA and both these complexes exhibit similar DNA binding energies. Both complexes 1 and 2 bring about photocleavage of plasmid DNA when irradiated at 440 nm.▪
Keywords: Ruthenium(II) complexes; DNA; Polypyridyl; Photocleavage; Ethidium bromide;

Condensed 1,4-dihydropyridines with various esters and their calcium channel antagonist activities by Bahadir Bülbül; Gökçe Sevim Öztürk; Mert Vural; Rahime Şimşek; Yusuf Sarioğlu; Anthony Linden; Mert Ülgen; Cihat Şafak (2052-2058).
New alkyl 2,6,6-(2,7,7)-trimethyl-4-(2-fluoro-3-chloro-5-trifluoromethylphenyl)-5-oxo-1,4,5,6,7,8-hexahydroquinoline-3-carboxylates and 9-(3-chloro-2-fluoro-5-trifluoromethylphenyl)-6,6(7,7)-dimethyl-6,7-dihydrofuro[3,4-b]quinoline-1,8-diones have been synthesised and their calcium antagonistic activities on isolated rabbit sigmoid colon have been investigated and compared with Nifedipine. The investigation examined the influence of ester groups in the 3-position of the HHQ ring and the 2-methoxyethyl analogs were found to be the most active derivatives.New alkyl 2,6,6-(2,7,7)-trimethyl-4-(2-fluoro-3-chloro-5-trifluoromethylphenyl)-5-oxo-1,4,5,6,7,8-hexahydroquinoline-3-carboxylates and 9-(3-chloro-2-fluoro-5-trifluoromethylphenyl)-6,6(7,7)-dimethyl-6,7-dihydrofuro[3,4-b]quinoline-1,8-diones were synthesised and their calcium antagonistic activities of all compounds were determined.Display Omitted
Keywords: Hexahydroquinoline; Furoquinoline; Calcium antagonistic activity; Biotransformation;

Thiocarbamates as non-nucleoside HIV-1 reverse transcriptase inhibitors: Docking-based CoMFA and CoMSIA analyses by Elena Cichero; Sara Cesarini; Paola Fossa; Andrea Spallarossa; Luisa Mosti (2059-2070).
Thiocarbamates (TCs) have been recently identified as a new class of potent non-nucleoside HIV-1 Reverse Transcriptase (RT) inhibitors. A computational strategy based on molecular docking studies, followed by CoMFA and CoMSIA analyses, has been used to elucidate the atomic details of the RT/TC interactions and to identify the most important features impacting the TC antiretroviral activity. The CoMFA model resulted to be the more predictive, and gave r 2  = 0.93, r cv 2  = 0.53, SEE = 0.292, F  = 180, and r test 2  = 0.70. The 3D-QSAR field contributions and the structural features of the RT binding site showed a good correlation. These studies will be useful to design new TCs with improved potency also against clinically relevant resistant mutants.▪
Keywords: HIV-1; Reverse transcriptase; 3D-QSAR; CoMFA; CoMSIA; Thiocarbamates;

Large ring 1,3-bridged 2-azetidinones: Experimental and theoretical studies by Allan Urbach; Georges Dive; Bernard Tinant; Valérie Duval; Jacqueline Marchand-Brynaert (2071-2080).
The relationship between angular strain and (re)activity of bicyclic 2-azetidinones is still an open question of major concern in the field of penicillin antibiotics. Our study deals with original 13-membered-ring 1,3-bridged 2-azetidinones related to the carbapenem family, and featuring a “planar amide” instead of the “twisted amide” typical of penam derivatives. The bicycles 11 and 12 were obtained from acetoxy-azetidinone 7, via the key-intermediate 10, by using the RCM (ring closing metathesis) strategy. Theoretical predictions and experimental results of hydrolysis showed that the large bicycle 12, endowed with high conformational flexibility, is more reactive than the bicycle 11, including a C=C bond of E configuration, and the monocyclic 2-azetidinone precursor 10. The processing of 2-azetidinones 1012 in the active site of serine enzymes has been computed by ab initio methods, considering three models. Due to geometrical parameters of the enzymic cavity (nucleophilic attack from the α-face), precursor 10 was predicted more active than 11 and 12 in the acylation step by Ser–OH. Indeed, bicycles 11 and 12 are modest inhibitors of PBP2a, while 10 is a good to excellent inhibitor of PBP2a and R39 bacterial enzymes.A non traditional approach for designing reactive b-lactams and possibly new anti-bacterial agents has been explored, based on large, flexible 1,3-bridged 2-azetidinones featuring a “planar amide” instead of the traditional “twisted amide” found in the penicillin family.Display Omitted
Keywords: Bicyclic β-lactam; RCM reaction; Conformational study; Ab initio reactivity; Serine–enzyme inhibition;

Substituted quinolinyl chalcones and quinolinyl pyrimidines as a new class of anti-infective agents by Moni Sharma; Vinita Chaturvedi; Y.K. Manju; Shalini Bhatnagar; Kumkum Srivastava; S.K. Puri; Prem M.S. Chauhan (2081-2091).
Frequency of tuberculosis and malaria is progressively increasing worldwide. New emerging strain of bacterium and resistance to currently available drugs make this field more conscientious and alarming. In this connection a series of substituted quinolinyl chalcones and substituted quinolinyl pyrimidines were synthesized and evaluated for their in vitro antitubercular activity against Mycobacterium tuberculosis H37RV and antimalarial activity against NF-54 strain of Plasmodium falciparum. A comparison of structure–activity relationship reveals that different physicochemical and structural requirements exist for these two activities. Out of synthesized compounds, compound nos. 22 and 23 have shown antitubercular activity of MIC 3.12 μg/mL and were nontoxic against VERO, MBMDM cell lines and compounds 54, 55, and 56 have shown antimalarial activity of MIC 1 μg/mL.A series of substituted quinolinyl chalcones and pyrimidines have been synthesized and evaluated for antitubercular and antimalarial activity. Among all, two compounds have shown antitubercular activity of MIC 3.12 μg/mL and three compounds have shown antimalarial activity of MIC 1.0 μg/mL.▪
Keywords: Tuberculosis; Malaria; Chalcones; Pyrimidines;

New insights into the antioxidant activity of hydroxycinnamic acids: Synthesis and physicochemical characterization of novel halogenated derivatives by Alexandra Gaspar; E. Manuela Garrido; Mário Esteves; Elias Quezada; Nuno Milhazes; Jorge Garrido; Fernanda Borges (2092-2099).
An interdisciplinary research project was developed combining the synthesis of a series of hydroxycinnamic acid derivatives and the evaluation of their physicochemical parameters (namely redox potentials and partition coefficients), along with the corresponding antioxidant activity. A structure–property–activity relationship (SPAR) approach was then applied aiming at establishing a putative relation between the physicochemical parameters of the compounds under study and their antioxidant activity.The results gathered allow concluding that the redox potentials could contribute to the understanding of the antioxidant activity and that the presence of an electron withdrawing group (EWG) of halogen type, namely a bromo atom, in an ortho position to a phenolic group of the cinnamic scaffold does not influence the antioxidant activity. On the other hand after the introduction of this type of substituent a significant increase on the lipophilicity of cinnamic derivatives was observed, which is a feature of extreme importance in the development of novel lipophilic antioxidants.The SPAR results revealed a relation between the redox potentials and the antioxidant activity of hydroxycinnamic acids and derivatives. The data obtained operate as a positive reinforce of the tendency to use redox properties as a guideline of the rational design of this type of compounds.Display Omitted
Keywords: Bromohydroxycinnamic acids; Ethyl bromohydroxycinnamates; Synthesis; Antioxidant activity; Voltammetry;

Studies on the interaction of caffeine with bovine hemoglobin by Yan-Qing Wang; Hong-Mei Zhang; Qiu-Hua Zhou (2100-2105).
Caffeine (CF) is a member of the methylxanthine family with numerous biological activities, which may contribute to the prevention of human disease but also may be potentially harmful. In the present study, the interaction of CF with bovine hemoglobin (BHb) under physiological condition was studied by fluorescence and UV/vis spectroscopy. Fluorescence data revealed that the fluorescence quenching of BHb by CF was the result of the formed complex of CF–BHb. The binding constants and thermodynamic parameters at three different temperatures, the binding position, and the binding force were determined. The hydrophobic and hydrogen bonds interactions were the predominant intermolecular forces to stabilize the complex. The conformation of BHb was discussed by synchronous fluorescence techniques. The synchronous spectra indicated that the structures of the Tyr and Try residues environments were altered and the physiological functions of BHb were affected by 0. This study provides important insight into the mechanism of erythrocyte sickling, which may be a useful guideline for further toxicology investigation.When different concentration of caffeine solution was titrated into a fixed concentration of bovine hemoglobin (BHb), a remarkable fluorescence decrease of BHb was observed. The caffeine is easily integrated into the hydrophobic pocket of BHb and has a profound effect on the conformation of BHb.Display Omitted
Keywords: Caffeine; Bovine hemoglobin; Fluorescence spectroscopy; UV/vis absorption; Thermodynamic parameters;

Synthesis, antimicrobial and cytotoxic activities of 1,3,4-oxadiazoles, 1,3,4-thiadiazoles and 1,2,4-triazoles by V. Padmavathi; G. Sudhakar Reddy; A. Padmaja; P. Kondaiah; Ali-Shazia (2106-2112).
A new class of 1,3,4-oxadiazoles were prepared from acid hydrazides on treatment with different carboxylic acids in the presence of phosphorus oxychloride. Interconversion of oxadiazoles to thiadiazoles and triazoles was carried out with appropriate reagents. The antimicrobial and cytotoxic activities of compounds 7ad to 12ad were tested. Compounds 10d and 12d showed pronounced antimicrobial activity. Further, compound 10d exhibited maximum cytotoxicity.A new class of 1,3,4-oxadiazoles were prepared from acid hydrazides on treatment with different carboxylic acids in the presence of phosphorus oxychloride. Interconversion of oxadiazoles to thiadiazoles and triazoles was carried out with appropriate reagents. The antimicrobial and cytotoxic activities of compounds 7ad to 12ad were tested. Compounds 10d and 12d showed pronounced antimicrobial activity. Further compound 10d exhibited maximum cytotoxicity.Display Omitted
Keywords: 1,3,4-Oxadiazoles; 1,3,4-Thiadiazoles; 1,2,4-Triazoles; Antimicrobial activity; Cytotoxicity;

A new series of nitrogen-containing heterocycles 4H-1,3,4-oxadiazin-5(6H)-ones derivatives with hydrophobic and long chains were designed and synthesized by direct cyclization reaction of N′-alkylation substituted aroylhydrazines with chloroacetyl chloride. The preliminary assays showed that some of the compounds displayed moderate to good inhibitory activities toward monoamine oxidase (MAO) at the concentration of 10−5–10−3  M, and antitumor activities against human lung cancer A-549 and human prostate cancer PC-3 cell lines at μM level, which might provide new scaffold for anticancer agents. Furthermore, compounds 5i and 5m exhibited significant inhibitory activity on chitin biosynthesis, which might represent a novel class of highly potential inhibitors of chitin synthesis.▪
Keywords: 1,3,4-Oxadiazin-5(6H)-ones; Heterocycle; Bioactive diversity;

A new series of 8-(substituted-phenyl)xanthines have been synthesized and compounds were evaluated for their affinity for A1 and A2 adenosine receptors (AR) using radioligand binding assays. The effects of varying the positions of 8-phenyl substituents on affinity and selectivity at A1 and A2A adenosine receptors have been studied. Isovanilloid 1,3-dimethyl-8-[4-methoxy-3-(2-morpholin-4-ylethoxy)phenylxanthine (9d) displayed the highest affinity and selectivity towards A2A AR subtypes with K i  = 100 nM over A1 receptors (Ki > 100 mM). It has been observed that substitution pattern on 8-phenyl group greatly affects the affinity and selectivity at adenosine receptors, with A2A tolerating bulkier substituents than did A1 receptors.A new series of 8-(substituted-phenyl)xanthines have been synthesized. On evaluation of the binding affinity of compounds for adenosine receptors, it was observed that substitution pattern on 8-phenyl group greatly affects the affinity and selectivity at various AR subtypes.Display Omitted
Keywords: 8-Arylxanthines; Adenosine receptor antagonists; Radioligand binding assays; A1 and A2A adenosine receptors;

Computational modeling and surface plasmon resonance analyses in the assessment of peptide ligands interacting with fibrin γ(312–324) epitope by Ilaria Massarelli; Anna M. Bianucci; Federica Chiellini; Chaim Eidelman; Emo Chiellini (2128-2134).
Fibrin represents a suitable target for addressing delivery systems loaded by fibrinolytic drugs. Selective ligands capable to recognize fibrin could be used as targeting moieties for such systems. In this study the interactions between the γ(312–324) epitope of human fibrin and peptidic ligands were analyzed by using experimental and computational methods. Binding free energies were calculated through the molecular mechanics/generalized born surface area approach. Good qualitative agreements between the experimental and calculated data were obtained. The binding affinity seems to be well correlated (R 2  = 0.69) with the changes of the nonpolar solvation energy term computed from solvent-accessible surface area calculation. These results indicate that current methods of estimating binding free energies are efficient for achieving information on protein–ligand interactions.Display Omitted
Keywords: Fibrin; GBSA; SPR (surface plasmon resonance);

Design, cytotoxic and fluorescent properties of novel N-phosphorylalkyl substituted E,E-3,5-bis(arylidene)piperid-4-ones by Michael V. Makarov; Ekaterina Yu. Rybalkina; Gerd-Volker Röschenthaler; Kurt W. Short; Tatiana V. Timofeeva; Irina L. Odinets (2135-2144).
A series of E,E-N-phosphorylalkylene-3,5-bis(arylidene)piperid-4-ones 7ak was prepared via the condensation of aromatic aldehydes with ω-aminophosphonates 5ac and 6a,b bearing piperidone or a protected piperidone moiety, respectively. The synthetic routes to the starting aminophosphonates 5ac and 6a,b varied depending on the number of methylene groups in the alkylene chain and comprised the Kabachnik–Fields reaction (n  = 1), the aza-Michael reaction (n  = 2) or alkylation of 4-piperidone hydrochloride with diethyl ω-bromoalkylphosphonates under phase transfer catalysis conditions (n  = 3,4). Phosphoryl substituted 3,5-bis(arylidene)piperid-4-ones 7b,c,e,f,h,i,k bearing both nitro groups and fluorine atoms in the para-position of the arene rings possess cytotoxicity toward human carcinoma cell lines CaOv3, Scov3, PC3 and A549 in the low micromolar range while their analogues having para-dimethylamino groups had IC50 values greater than 50 μM. In contrast, only Me2N-substituted phosphonates 7g,j (n  = 3 and 4) and the salts of Me2N-substituted phosphonic acids 10c,f (n  = 2 and 3) display fluorescence.Condensation of ω-aminophosphonates bearing piperidone or a protected piperidone moiety with aromatic aldehydes provides a convenient approach to E,E-N-phosphorylalkylene-3,5-bis(arylidene)piperid-4-ones possessing dark cytotoxicity towards human carcinoma cell lines CaOv3, Scov3, PC3 and A549 in the low micromolar range in the case of electron withdrawing substituents in the benzene rings and fluorescence properties for those having electron-donating groups.▪
Keywords: Aminophosphonates; N-phosphorylalkylene-piperid-4-ones; N-phosphorylalkylene-3,5-bis(arylidene)piperid-4-ones; Synthesis; Structure–cytotoxicity–fluorescence relationship;

Synthesis, antimicrobial evaluation and QSAR study of some 3-hydroxypyridine-4-one and 3-hydroxypyran-4-one derivatives by Afshin Fassihi; Daryoush Abedi; Lotfollah Saghaie; Razieh Sabet; Hossein Fazeli; Ghasem Bostaki; Omid Deilami; Hekmatollah Sadinpour (2145-2157).
A series of Mannich bases of 2-alkyl-3-hydroxy-pyridine-4-ones, namely 2-alkyl-3-hydroxy-5-N-piperidylmethyl or N,N-dialkylaminomethyl pyridine-4-ones 9, 10 and 1518, two derivatives of N-aryl-2-methyl-3-hydroxy-pyridine-4-ones 19, 20 and two N-alkyl derivatives of maltol, 21 and 22 were prepared. They were screened for their antibacterial and antifungal activities against a variety of microorganisms using micro plate Alamar Blue® assay (MABA) method. Multiple linear regressions (MLR) analysis was performed for the synthesized compounds as well as a series of pyridinone and pyranone derivatives 2343 which have been synthesized and evaluated for antimicrobial activity by other researchers previously. Studied compounds showed a better quantitative structure–activity relationship (QSAR) model for the antimicrobial activity against Candida albicans and Staphylococcus aureus in comparison with other tested microorganisms.Display Omitted
Keywords: 3-Hydroxypyridin-4-ones; 3-Hydroxypyran-4-ones; Antimicrobial activity; QSAR;

A quantitative structure–activity relationship study of a series of HIV-1 reverse transcriptase inhibitors (2-amino-6-arylsulfonylbenzonitriles and their thio and sulfinyl congeners) was performed. Topological and geometrical, as well as quantum mechanical energy-related and charge distribution-related descriptors generated from CODESSA, were selected to describe the molecules. Principal component analysis (PCA) was used to select the training set. Six techniques: multiple linear regression (MLR), multivariate adaptive regression splines (MARS), radial basis function neural networks (RBFNN), general regression neural networks (GRNN), projection pursuit regression (PPR) and support vector machine (SVM) were used to establish QSAR models for two data sets: anti-HIV-1 activity and HIV-1 reverse transcriptase binding affinity. Results showed that PPR and SVM models provided powerful capacity of prediction.A QSAR study of a series of HIV-1 NNRTIs was performed based on six different methods: MLR, MARS, RBFNN, GRNN, PPR and SVM. PPR and SVM yielded the best models.Display Omitted
Keywords: QSAR; HIV-1 non-nucleoside reverse transcriptase inhibitors; NNRTI; SVM; PPR;

A variety of bis(3-aryl-4,5-dihydro-1H-pyrazole-1-thiocarboxamides) 2ah were prepared via reaction of bis(2-propen-1-ones) 1ah with thiosemicarbazide in ethanolic KOH solution. Meanwhile, bis(3-aryl-4,5-dihydro-1H-pyrazole-1-carboxamides) 3ad were obtained through reaction of 1ad with semicarbazide hydrochloride in refluxing with acetic acid. Anti-inflammatory activity screening of the synthesized compounds 2af,h; 3ad (at a dose of 50 mg/kg of body weight) utilizing in vivo acute carrageenan-induced paw oedema standard method in rats exhibited that many of the tested compounds reveal considerable anti-inflammatory properties, especially 2e and f which reveal remarkable activities relative to indomethacin (which was used as a reference standard at a dose of 10 mg/kg of body weight). Ulcerogenic liability for the most promising prepared anti-inflammatory active agents (2b,c,e and f) (at a dose of 50 mg/kg of body weight) using indomethacin as a reference standard (at a dose of 10 mg/kg of body weight) indicated that compounds 2b and c exhibit lower ulcer index values than the used reference standard itself. PGE2 inhibitory properties of the highly promising synthesized anti-inflammatory active agents (2b,c,e and f) were determined by PGE2 assay kit technique, which reveal remarkable activities coincide greatly with the observed anti-inflammatory properties.▪
Keywords: Bis(2-propen-1-ones); Bis(3-aryl-4,5-dihydro-1H-pyrazole-1-carboxamides); Bis(3-aryl-4,5-dihydro-1H-pyrazole-1-thiocarboxamides); Anti-inflammatory; PGE2;

Fullerene derivatized s-triazine analogues as antimicrobial agents by Anish Kumar; Shobhana Karuveettil Menon (2178-2183).
A series of novel fullerene derivatives bearing s-triazine moiety have been synthesized by adopting 1,3 dipolar cycloaddition reaction of C60 and azomethine ylides generated from the corresponding Schiff bases of 2,4,6 trisubstituted s-triazine. All the compounds synthesized were characterized by elemental analysis, FT-IR, 1H NMR, 13C NMR and FAB-MS. The compounds were then screened for their antibacterial activity against both gram-positive (Staphylococcus aureus, Bacillus subtilis, Bacillus pumilis) and gram-negative (Escherichia coli, Pseudomonas aeruginosa and Klebsiella pneumoniae) bacteria by disc diffusion method. All the compounds were found to be active against these strains at very low concentration and were comparable to standard drug ciprofloxacin.Fullerene–triazine conjugate disrupting the cell wall of bacteriaDisplay Omitted
Keywords: Fulleropyrrolidine; s-Triazine; Schiff base; Prato reaction; Antibacterial;

A series of 2-(2,4-disubstituted-thiazole-5-yl)-3-aryl-3H-quinazoline-4-one derivatives were designed and synthesized. Synthesized molecules were further evaluated for their inhibitory activity towards transcription factors NF-κB and AP-1 mediated transcriptional activation in a cell line based in vitro assay as well as for their anti-inflammatory activity in in vivo model of acute inflammation. This series provides us with selective and dual inhibitors of NF-κB and AP-1 mediated transcriptional activation which also exhibit significant efficacy in in vivo model of inflammation. Two of the compounds 9m and 9o turned out to be the most promising dual inhibitors of NF-κB and AP-1 mediated transcriptional activation with an IC50 of 3.3 μM for both. 9n (IC50  = 5.5 μM) and 9p (IC50  = 5.5 μM) emerged as selective inhibitors of NF-κB mediated transcriptional activation and 9c (IC50  = 5.5 μM) and 9d (IC50  = 5.5 μM) were found to be more selective inhibitor of AP-1 mediated transcriptional activity. Though the relationship between the activities shown by these compounds in in vivo and in vitro model is still to be established, these results suggest the suitability of the designed molecular framework as a potential anti-inflammatory molecular framework which also exhibits the inhibitory activity towards NF-κB and AP-1 mediated transcriptional activation. This will be worth studying further to explore its complete potential particularly in chronic inflammatory conditions. The structure activity relationship (SAR) of this series has been discussed herein.A series of 2-(2,4-disubstituted-thiazole-5-yl)–3-aryl-3H-quinazoline-4-one derivatives were designed, synthesized and evaluated for its inhibitory activity towards transcription factors NF-κB and AP-1 mediated transcriptional activation and as anti-inflammatory agents.Display Omitted
Keywords: Thiazole; Inhibitors of NF-κB and AP-1 mediated transcriptional activation; Anti-inflammatory agents and transcription inhibitors;

Parallel synthesis, molecular modelling and further structure–activity relationship studies of new acylthiocarbamates as potent non-nucleoside HIV-1 reverse transcriptase inhibitors by Andrea Spallarossa; Sara Cesarini; Angelo Ranise; Silvia Schenone; Olga Bruno; Alberto Borassi; Paolo La Colla; Margherita Pezzullo; Giuseppina Sanna; Gabriella Collu; Barbara Secci; Roberta Loddo (2190-2201).
The structure–activity relationships (SARs) of acylthiocarbamates (ATCs), a new class of non-nucleoside HIV-1 reverse transcriptase inhibitors, have been expanded. Sixty-six new analogues were prepared by parallel solution-phase synthesis. In general, the potency of new ATCs was better than that of the first series and O-[2-phthalimidoethyl] 4-chlorophenyl(3-nitrobenzoyl) thiocarbamate turned out to be the most potent ATC so far synthesized (EC50  = 1.5 nM). Several ATCs were active at micromolar concentrations against HIV-1 strains carrying the RT Y181C mutation and one of them was also moderately active against the K103R variant. Docking simulations were carried out to rationalize the most relevant SARs.Display Omitted
Keywords: Acylthiocarbamates; HIV-1; Non-nucleoside reverse transcriptase inhibitors; Parallel synthesis;

Design, synthesis and antibacterial activity of novel actinonin derivatives containing benzimidazole heterocycles by Datong Zhang; Zongheng Wang; Weiren Xu; Fanggang Sun; Lida Tang; Jianwu Wang (2202-2210).
A series of novel actinonin derivatives containing a benzimidazole heterocycle linked as amide isostere have been designed and synthesized. The structures of all the synthesized compounds were confirmed by analytical and spectroscopic methods. All the compounds were evaluated in vitro against Staphylococcus aureus, Klebsiella pneumoniae, and Sarcina lutea. Among them, compound 1a with unsubstituted benzimidazole ring exhibited potent antibacterial activities.Display Omitted
Keywords: Actinonin derivatives; Benzimidazole; Synthesis; Antibacterial activity;

Examination of growth inhibitory properties of synthetic chalcones for which antibacterial activity was predicted by Daniela Batovska; Stoyan Parushev; Bistra Stamboliyska; Iva Tsvetkova; Mariana Ninova; Hristo Najdenski (2211-2218).
A large series of chalcones were synthesized and studied against Staphylococcus aureus and Escherichia coli. Chalcones were either unsubstituted in ring A or possessed 4′-chloro or 3′,4′,5′-trimethoxy groups. Their other ring B was variously substituted. It was found that the anti-staphylococcal activity of chalcones was related to the energy difference between the two highest occupied molecular orbitals (HOMO and HOMO-1). Presence of hydroxyl group in ring B was not a determinant factor for the anti-staphylococcal activity, but the lipophilicity of ring A of the hydroxyl chalcones was of importance.▪Amongst a large series of synthetic chalcones, 2-hydroxychalcone and 3′,4′,5′-trimethoxy chalcones with electron withdrawing substituents at p-position in ring B were the most active towards S. aureus.
Keywords: Chalcones; Antibacterial activity; Staphylococcus aureus; Escherichia coli; SAR;

The interactions of phenobarbital with different generations of amine-terminated poly(amidoamine) (PAMAM) dendrimers were investigated by using two dimensional-nuclear Overhauser effect spectroscopic (2D-NOESY) investigations. The NOESY spectra clearly showed that there were cross-peaks from NOE interactions between the protons of phenobarbital and the protons in interior cavities of generation 5 or generation 6 PAMAM dendrimers but none of such cross-peaks was found in the case of generation 3 or generation 4 dendrimers. The NOESY analysis, together with aqueous solubility data, suggested that higher generation dendrimers are more capable of encapsulating phenobarbital molecules into the interior cavities than lower generation dendrimers, and that lower generation dendrimers are much easier for the electrostatic attachment of phenobarbital molecules than higher ones at a fixed mass concentration. Proposed localizations of phenobarbital molecules in the cavities of PAMAM dendrimers. The arrows indicate the most possible sites for the PAMAM dendrimers to entrap phenobarbital molecules.Display Omitted
Keywords: Polyamidoamine; PAMAM; Dendrimer; Encapsulation; Electrostatic attachment; NOESY; Drug delivery;

Synthesis and anticonvulsant activity of new N-[(4-arylpiperazin-1-yl)-alkyl] derivatives of 3-phenyl-pyrrolidine-2,5-dione by Jolanta Obniska; Krzysztof Kaminski; Dorota Skrzynska; Joanna Pichor (2224-2233).
In the present study, on the development of new anticonvulsants, the series of N-[(4-arylpiperazin-1-yl)-alkyl]-3-(2-methylphenyl)- (8ae, 10ah) and 3-(2-trifluoromethyl-phenyl)-pyrrolidine-2,5-diones (9ae, 11ai) were synthesized and tested for anticonvulsant activity using the maximal electroshock (MES), subcutaneous pentylenetetrazole (scPTZ) screens. Their neurotoxicity were determined applying the rotorod test. In this series, the most active were N-[(4-phenylpiperazin-1-yl)-methyl]-3-(2-trifluoromethylphenyl)-pyrrolidine-2,5-dione (9a) with the ED50  = 20.78 mg/kg, when given orally to rats and N-[3-{4-(3-trifluoromethylphenyl)-piperazin-1-yl}-propyl]-3-(2-trifluoromethylphenyl)-pyrrolidine-2,5-dione (11i) with the ED50  = 132.13 mg/kg after intraperitoneally injection to mice.A new series of N-[(4-arylpiperazin-1-yl)-alkyl]-3-phenyl-pyrrolidine-2,5-diones were synthesized. Majority of these compounds were effective in the MES test.▪
Keywords: 3-(2-Methylphenyl)-pyrrolidine-2,5-dione; 3-(2-Trifluoromethylphenyl)-pyrrolidine-2,5-dione; 4-Arylpiperazine derivatives; Anticonvulsant activity;

A three-step synthesis from rebeccamycin of an efficient checkpoint kinase 1 inhibitor by Fabrice Anizon; Roy M. Golsteyn; Stéphane Léonce; Bruno Pfeiffer; Michelle Prudhomme (2234-2238).
Rebeccamycin derivative 1 bearing a sugar moiety linked to both indole nitrogens and an amino substituent on the carbohydrate unit was synthesized in three steps from the bacterial metabolite. This compound was found to be a highly potent checkpoint kinase 1 inhibitor with an IC50 value of 2.8 nM.Display Omitted
Keywords: Rebeccamycin; Staurosporine; Antitumor agents; Indolocarbazoles; Chk1 inhibitors;

Synthesis of (±)Abyssinone I and related compounds: Their anti-oxidant and cytotoxic activities by Gudapati Venkateswara Rao; Badrappa Narayana Swamy; Venkateshappa Chandregowda; G. Chandrasekara Reddy (2239-2245).
An efficient and facile synthesis of naturally occurring prenylated flavonoids and their analogs have been described. Abyssinone I (9a) was prepared by condensing 2,2-dimethyl chrom-3-en-6-carboxaldehyde (5a) with protected resacetophenone under phase transfer conditions followed by deprotection and cyclization. The influence of prenyl group on anti-oxidant and cytotoxic activities was studied. The presence of 3′-prenyl group as in 8c enhanced radical scavenging activity but decreased reducing power activity when compared to non-prenylated analog 8f. In vitro testing in MCF-7 cell line revealed that prenylated chalcones and flavanones showed better inhibitory activity than their non-prenylated counterparts. Abyssinone I and its chalcone though exhibited negligible anti-oxidant activity their cytotoxic activities were comparable with other prenylated analogs.Display Omitted
Keywords: Abyssinone; Chalcone; Lipophilicity; Prenyl; Reducing power; Radical scavenging; MCF-7 cell line;

Amines and oximes derived from deoxybenzoins as Helicobacter pylori urease inhibitors by Huan-Qiu Li; Zhu-Ping Xiao; Yin-Luo; Tao Yan; Peng-Cheng Lv; Hai-Liang Zhu (2246-2251).
Twenty amines and oximes from deoxybenzoins were prepared and evaluated for their inhibitory activity against Helicobacter pylori urease. Among these compounds, high inhibitory activities were observed in amines and oximes, especially amines 1b (IC50  = 0.011 mM) and 6b (IC50  = 0.047 mM) exhibited good in vitro activities, and were comparable to acetohydroxamic acid (AHA). The hydroxyl groups on deoxybenzoin skeleton may be responsible for the inhibitory activity and coordinate with the nickel (active site) on enzyme. A direct interaction may exist between the OH group of hydroxylamines or NH group of amines and His α323 of H. pylori urease, which is on the flap of the enzyme active site.Display Omitted
Keywords: Amines; Oximes; Deoxybenzoin derivatives; H. polyri urease; Structure–activity relationships;

In continuation of our search for potential antiamoebic agents from folklore Indian medicinal plants, we found that the benzene and ethyl acetate extracts from the root bark of Adina cordifolia exhibited strong antiamoebic activity with IC50 values of 2.92 and 2.50 μg/ml, respectively. Bioassay-guided fractionation of benzene and ethyl acetate extracts led to the isolation of 7-hydroxycoumarin (umbelliferone 1) and 7-β-D-glucosylcoumarin (skimmin 2), respectively. Umbelliferone 1 was converted into 7-acetoxycoumarin 1a, which on treatment with aluminium chloride afforded 7-hydroxy-8-acetylcoumarin 2a. A new series of thiosemicarbazones 3ae of 7-hydroxy-8-acetylcoumarin with different thiosemicarbazides were synthesized. Umbelliferone was also converted into its methoxy derivative (7-methoxycoumarin 4). Subsequently, all the compounds were assessed for antiamoebic activity against HM1:IMMS strain of Entamoeba histolytica. Umbelliferone and skimmin were found to possess a very good activity with IC50 values of 6.38 and 4.35 μM/ml, respectively. The activity drastically increased on converting compound 2a into its thiosemicarbazone derivatives 3ae with IC50 values ranging between 1.06 and 4.46 μM/ml. Compounds 3b,c and e with IC50 values of 1.49, 1.56 and 1.06 μM/ml, respectively, exhibited even higher antiamoebic activity than the standard drug metronidazole (IC50  = 2.62 μg/ml). The activity of 7-methoxycoumarin (IC50  = 8.92 μM/ml) was less than umbelliferone. Compounds 3b, c and e were tested for toxicity using H9c2 cardiac myoblasts cell line. The compounds exhibit >80% viability at 3.125–200 μg/ml. It is apparent from these results that umbelliferone and skimmin may be a useful lead for the development of new antiamoebic drugs.The root bark of Adina cordifolia led to the isolation of 7-hydroxycoumarin 1 and 7-β-D-glucosylcoumarin 2. A new series of thiosemicarbazones 3ae of 7-hydroxy-8-acetylcoumarin with different thiosemicarbazides were synthesized. Compounds 3b, c, and e with IC50 values 1.49, 1.56, 1,06 μM/ml exhibited higher antiamoebic activity than the standard drug metronidazole (IC50  = 2.63 μM/ml). All the active compounds were tested for toxicity using H9c2 cardiac myoblasts cell line and all were found to exhibit >80% viability at 3.125–200 μg/ml.Display Omitted
Keywords: Adina cordifolia; Umbelliferone; Skimmin; Thiosemicarbazones; Entamoeba histolytica; MTT assay;

Organoiodine (III)-mediated synthesis of 3-aryl/heteroaryl-5,7-dimethyl-1,2,4-triazolo[4,3-c]pyrimidines as antibacterial agents by Ravi Kumar; Reshmi R. Nair; Saurabh Sudha Dhiman; Jitender Sharma; Om Prakash (2260-2264).
Synthesis of 12 new 3-aryl/heteroaryl-5,7-dimethyl-1,2,4-triazolo[4,3-c]pyrimidines (3al) has been accomplished by the oxidation of pyrimidinylhydrazones (2al) of various aryl/heteroaryl aldehydes using 1.1 equiv. of iodobenzene diacetate (IBD) in dichloromethane. All the compounds 3al tested in vitro for their antibacterial activity against two Gram-positive bacteria namely, Bacillus subtilis, Bacillus stearothermophilus and two Gram-negative bacteria Pseudomonas putida, Escherichia coli. Two compounds, namely 3-(2,4-dichlorophenyl)-5,7-dimethyl-1,2,4-triazolo [4,3-c]pyrimidine (3j) and 3-(4-hydroxy-2-methoxyphenyl)-5,7-dimethyl-1,2,4-triazolo[4,3-c]pyrimidine (3l) were found to be equipotent or more potent than the commercially available antibiotics (chloramphenicol and streptomycin).Display Omitted
Keywords: Iodobenzene diacetate; Triazolopyrimidines; Antibacterial activity;

The paper describes the synthesis of new 1-alkyl/cyclohexyl-3,3-diaryl-1′-methylspiro[azetidine-2,3′-indoline]-2′,4-diones from the reactions of the 2-diazo-1,2-diarylethanones with 1-methyl-3-(alkyl/cyclohexylimino)indolin-2-ones under thermal condition. The compounds, characterized by satisfactory analytical and spectral (IR, 1H NMR and 13C NMR) data, have been screened for their antibacterial and antifungal activities.A series of 10 new spiro[azetidine-2,3′-indoline]-2′,4-diones have been synthesized by ketene–imine cycloadditon and evaluated for their antibacterial and antifungal activities.Display Omitted
Keywords: Spiroazetidinones; Diarylketenes; 3-Iminoindolin-2-ones; Cycloaddition; Antimicrobial activity;

We investigated the antibacterial activity of some new steroidal thiosemicarbazone and their Pd(II) metal complexes. Metal complexes were prepared from the reaction of steroidal thiosemicarbazone with [Pd(DMSO)2Cl2]. Coordination via the thionic sulphur and the azomethine nitrogen atom of the thiosemicarbazone to the metal ion, the thiosemicarbazone derivatives were obtained by the thiosemicarbazide with steroidal ketones. All the compounds have been confirmed by spectral data. The antibacterial activity of these compounds was first tested in vitro by the disk diffusion assay against two gram-positive and two gram-negative bacteria, and then the minimum inhibitory concentration (MIC) was determined. The results showed that steroidal complexes are better inhibit growth as compared to steroidal thiosemicarbazones of both types of the bacteria (gram-positive and gram-negative); compound Ia is better antibacterial agent as compared to amoxicillin.I investigated the antibacterial activity of some new steroidal thiosemicarbazone and their Pd(II) metal complexes. Metal complexes were prepared from the reaction of steroidal thiosemicarbazone with [PD(DMSO)2Cl2]. Coordination via the thionic sulphur and the azomethine nitrogen atom of the thiosemicarbazone to the metal ion, the thiosemicarbazone derivatives were obtained by the thiosemicarbazide with steroidal ketones. All the compounds have been confirmed by spectral data. The antibacterial activity was first tested in vitro by the disk diffusion assay against two gram-positive and two gram-negative bacteria, and then the minimum inhibitory concentration (MIC) of compounds was determined. The results showed that steroidal complexes are better inhibit growth as compared to steroidal thiosemicarbazones of both types of the bacteria (gram-positive and gram-negative); compound Ia is better antibacterial agent as compared ton amoxicillin.▪
Keywords: Thiosemicarbazone; Palladium(II); Antibacterial activity;

Diazinium salts with dihydroxyacetophenone skeleton: Syntheses and antimicrobial activity by Ana Maria Balan; Ondina Florea; Costel Moldoveanu; Gheorghita Zbancioc; Dorina Iurea; Ionel I. Mangalagiu (2275-2279).
Herein we report a feasible study concerning syntheses, structure and antimicrobial activity of some new diazinium salts with dihydroxyacetophenone skeleton. A fast, general, environmentally friendly, and facile method for preparation of diazinium salts under microwave and ultrasounds irradiation is presented. Antimicrobial tests prove that some diazine compounds have a remarkable activity against different microorganisms (germs and fungi), the pyrimidine derivatives being more active. Correlations between structure and antimicrobial activity are reported.Synthesis, structure and antimicrobial activity of six new diazinium salts with dihydroxyacetophenone skeleton are described.Display Omitted
Keywords: Diazine salts; Microwave; Ultrasounds; Antimicrobial activity;

Synthesis and biological activity evaluation of 1H-benzimidazoles via mammalian DNA topoisomerase I and cytostaticity assays by Gunes Coban; Sevil Zencir; István Zupkó; Borbála Réthy; H. Semih Gunes; Zeki Topcu (2280-2285).
Benzimidazoles are important compounds because of their antibacterial, antifungal, antimicrobial, antiprotozoal and antihelmintic activities. Some benzimidazole derivatives also interfere with the reactions of DNA topoisomerases, enzymes functioning at almost all stages of the cell cycle. In this study, nine 1H-benzimidazole derivatives with substituents at positions 2 and 5 were synthesized and the structure of the compounds was elucidated by instrumental methods. The characterized compounds were screened to identify if they interfered with mammalian type I DNA topoisomerase activity via in vitro supercoil relaxation assays. Selected compounds were subjected to cytostatic assays using HeLa (cervix adenocarcinoma), MCF7 (breast adenocarcinoma) and A431 (skin epidermoid carcinoma) cells. Our results showed that 5-chloro-2-(2-hydroxyphenyl)-1H-benzimidazole exerted the most profound topoisomerase I inhibition and cytotoxicity.Display Omitted
Keywords: 1H-Benzimidazole derivatives; Synthesis; Type I DNA topoisomerase; MTT assay; Plasmid Supercoil relaxation assays;

Preparation and in vitro evaluation of benzylsulfanyl benzoxazole derivatives as potential antituberculosis agents by Věra Klimešová; Jan Kočí; Karel Waisser; Jarmila Kaustová; Ute Möllmann (2286-2293).
A set of 2-benzylsulfanyl derivatives of benzoxazole was synthesized and evaluated for their in vitro antimycobacterial activity against Mycobacterium tuberculosis, non-tuberculous mycobacteria and multidrug-resistant M. tuberculosis. The activities were expressed as the minimum inhibitory concentration (MIC) in mmol/L. The substances showed similar activity against all tested strains. The lead compounds in the set, dinitro derivatives exhibited significant activity against both sensitive and resistant strains of M. tuberculosis and also against non-tuberculous mycobacteria. To facilitate drug design of benzoxazole as potential antituberculosis agent, we have explored the quantitative structure–activity relationship (QSAR). We demonstrated that lower lipophilicity has significant contribution to activity. Dinitrobenzylsulfanyl derivative of benzoxazole represents the promising small-molecule synthetic antimycobacterials.Synthesis of a series of 2-benzylsulfanyl derivatives of benzoxazole and their antimycobacterial activities in vitro against sensitive and drug-resistant strains is presented. Dinitro and thioamide derivatives are showed to be the most active compounds.Display Omitted
Keywords: Benzoxazole; 2-Benzylsulfanyl derivatives; Antimycobacterial activity; Mycobacterium tuberculosis; Multidrug-resistant M. tuberculosis; Non-tuberculous mycobacteria; Quantitative structure–activity relationship;

The efficient synthesis of novel azetidin-2-ones 6 has been established. Thus, condensation of 5-[(2-methyl-1H-benzimidazol-1-yl)methyl]-1,3,4-thiadiazol-2-amine 4 with various aromatic aldehydes afforded 5-[(2-methyl-1H-benzimidazol-1-yl)methyl]-N-[(substituted) phenylmethylidene]-1,3,4-thiadiazol-2-amine 5 which on cycloaddition with chloroacetyl chloride in the presence of triethylamine catalyst yielded 3-chloro-1-{5-[(2-methyl-1H-benzimidazol-1-yl)methyl]-1,3,4-thiadiazol-2-yl}-4-(substituted) phenylazetidin-2-one 6. Structures of the synthesized compounds have been elucidated on the basis of their elemental analyses and spectral data. All the synthesized compounds were screened for their antimicrobial activity.Display Omitted
Keywords: 2-Benzimidazoles; Azetidin-2-ones; Thiadiazole; Antibacterial activity; Antifungal activity;

Simple synthesis of carbon-11 labeled styryl dyes as new potential PET RNA-specific, living cell imaging probes by Min Wang; Mingzhang Gao; Kathy D. Miller; George W. Sledge; Gary D. Hutchins; Qi-Huang Zheng (2300-2306).
A new type of styryl dyes have been developed as RNA-specific, live cell imaging probes for fluorescent microscopy technology to study nuclear structure and function. This study was designed to develop carbon-11 labeled styryl dyes as new probes for biomedical imaging technique positron emission tomography (PET) imaging of RNA in living cells. Precursors (E)-2-(2-(1-(triisopropylsilyl)-1H-indol-3-yl)vinyl)quinoline (2), (E)-2-(2,4,6-trimethoxystyryl)quinoline (3) and (E)-4-(2-(6-methoxyquinolin-2-yl)vinyl)-N,N-diemthylaniline (4), and standards styryl dyes E36 (6), E144 (7) and F22 (9) were synthesized in multiple steps with moderate to high chemical yields. Precursor 2 was labeled by [11C]CH3OTf, trapped on a cation-exchange CM Sep-Pak cartridge following a quick deprotecting reaction by addition of (n-Bu)4NF in THF, and isolated by solid-phase extraction (SPE) purification to provide target tracer [11C]E36 ([11C]6) in 40–50% radiochemical yields, decay corrected to end of bombardment (EOB), based on [11C]CO2. The target tracers [11C]E144 ([11C]7) and [11C]F22 ([11C]9) were prepared by N-[11C]methylation of the precursors 3 and 4, respectively, using [11C]CH3OTf and isolated by SPE method in 50–70% radiochemical yields at EOB. The specific activity of the target tracers [11C]6, [11C]7 and [11C]9 was in a range of 74–111 GBq/μmol at the end of synthesis (EOS).This paper reports the simple synthesis of new carbon-11 labeled styryl dyes as potential PET RNA-specific, living cell imaging probes.▪
Keywords: Positron emission tomography; Carbon-11; Styryl dyes; RNA; Live cell; Imaging;

Synthesis, pharmacological screening, quantum chemical and in vitro permeability studies of N-Mannich bases of benzimidazoles through bovine cornea by E. Philip Jesudason; S.K. Sridhar; E.J. Padma Malar; P. Shanmugapandiyan; Mohammed Inayathullah; V. Arul; D. Selvaraj; R. Jayakumar (2307-2312).
A novel series of N-Mannich bases of benzimidazole derivatives were synthesized and characterized by 1H NMR, IR spectral studies and elemental analysis. The compounds were screened for analgesic and anti-inflammatory activity. 1-((Diethylamino)-methyl)-2-styryl benzimidazole 4 at 40 mg/kg was found to be equipotent to paracetamol. 1-((Piperidin-1-yl) methyl)-2-styryl-benzimidazole 6 at 40 mg/kg was found to be more potent than Diclofenac. Corneal permeability and quantum chemical calculations were performed to correlate the hydrogen bonding ability with permeability and activity. The energies of the highest occupied molecular orbital (HOMO) and the lowest unoccupied molecular orbital (LUMO) were correlated with pharmacological activity. The semi-empirical PM3 calculations (quantum chemical calculations) revealed that E LUMO and energy gap ΔE were capable of accounting for the high in vitro bovine corneal permeability and activity of the compounds.A novel series of N-Mannich bases of benzimidazole derivatives were synthesized and characterized by 1H NMR, MS, IR spectral studies and elemental analysis. The compounds were screened for analgesic and anti-inflammatory activity.Display Omitted
Keywords: Mannich base; Benzimidazole; Analgesic; Anti-inflammatory; Corneal permeability; Quantum chemical calculations;

Synthesis and bioassay of a new class of heterocycles pyrrolyl oxadiazoles/thiadiazoles/triazoles by V. Padmavathi; A.V. Nagendra Mohan; P. Thriveni; A. Shazia (2313-2321).
A new class of heterocycles pyrrolyl thiadiazoles, pyrrolyl oxadiazoles and pyrrolyl triazoles were prepared from arylsulfonylethenesulfonylacetic acid methyl ester and tested for their antimicrobial and cytotoxic activities.A new class of heterocycles pyrrolyl thiadiazoles, pyrrolyl oxadiazoles and pyrrolyl triazoles were prepared from arylsulfonylethenesulfonylacetic acid methyl ester and tested for their antimicrobial and cytotoxic activities.Display Omitted
Keywords: Pyrroles; 1,3,4-Thiadiazoles; 1,3,4-Oxadiazoles; Antimicrobial activity; Cytotoxic activity;

Synthesis, characterization and antitumor activity of new type binuclear platinum(II) complexes by Jinchao Zhang; Lei Liu; Yuqiu Gong; Xiaoming Zheng; Mengsu Yang; Jingrong Cui; Shigang Shen (2322-2327).
Five new type binuclear platinum(II) complexes (ae) have been synthesized and characterized by elemental analysis, conductivity, thermal analysis, IR, UV, 1H NMR and mass spectral techniques. The cytotoxicity of the complexes was tested by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) and sulforhodamine B (SRB) assays. The acute toxicity and antitumor activity of complex e in vivo were also studied. The results indicate that complexes ad have no activity against HL-60, MCF-7, BGC-823, EJ and HCT-8 cell lines, with a higher IC50 value (>50 μM). Complex e confers substantially greater cytotoxicity against HL-60, MCF-7, BGC-823, EJ and HCT-8 cell lines with an IC50 value of 0.02 ± 0.009, 1.70 ± 0.21, 4.00 ± 0.35, 0.98 ± 0.02 and 1.02 ± 0.21 μM, respectively. LD50 of complex e is 815.3 mg/kg, it was significantly higher than that of cisplatin and carboplatin. Complex e at dose of 4, 12 and 20 mg/kg has no activity against mouse hepatocarcinoma H22 and Lewis lung carcinoma in mice, but displays significant activity against human ovarian carcinoma A2780 and human colon carcinoma HCT-116 in nude mice at dose of 12 mg/kg, and activity is similar to that of cisplatin at dose of 4 mg/kg. Complex e at dose of 20 mg/kg has no activity against human lung adenocarcinoma A549 in nude mice (P  > 0.05). The results suggest that the species of amine for the new type binuclear platinum complexes have important effect on their cytotoxicity, and they may be a new class platinum anticancer drugs. Five new type binuclear platinum(II) complexes (ae) have been synthesized and characterized by elemental analysis, conductivity, thermal analysis, IR, UV, 1H NMR and mass spectral techniques. The cytotoxicity of the complexes was tested by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) and sulforhodamine B (SRB) assays. The acute toxicity and antitumor activity of complex e in vivo were also studied.Display Omitted
Keywords: Binuclear platinum(II) complexes; Synthesis; Cytotoxicity; Acute toxicity;

Synthesis and anti-microbial screening of some Schiff bases of 3-amino-6,8-dibromo-2-phenylquinazolin-4(3H)-ones by Perumal Panneerselvam; Bilal Ahmad Rather; Dontireddy Ravi Sankar Reddy; Natesh Ramesh Kumar (2328-2333).
In the present study, a series of novel Schiff bases were synthesized by condensation of 3-amino-6,8-dibromo-2-phenylquinazolin-4(3H)-ones with different aromatic aldehydes via cyclized intermediate 6,8-dibromo-2-phenyl benzoxazin-4-one. The chemical structures were confirmed by means of IR, 1H NMR, 13C NMR, Mass spectral and Elemental analysis. These compounds were screened for anti-bacterial (Staphylococcus aureus ATCC-9144, Staphylococcus epidermidis ATCC-155, Micrococcus luteus ATCC-4698, Bacillus cereus ATCC-11778, Escherichia coli ATCC-25922, Pseudomonas aeruginosa ATCC-2853, and Klebsiella pneumoniae ATCC-11298) and anti-fungal (Aspergillus niger ATCC-9029 and Aspergillus fumigatus ATCC-46645) activities by paper disc diffusion technique. The minimum inhibitory concentrations (MICs) of the compounds were also determined by agar streak dilution method. Among the synthesized compounds 3-(3,4,5-trimethoxybenzylideneamino)-6,8-dibromo-2-phenylquinazolin-4(3H)-one 10 was found to be the most potent anti-microbial activity with MICs of 18.9, 19.1, 18.8, 21.7, 18.2, 19.3, 16.7, 8.6 and 10.1 μg/ml against above mentioned respective strains. Compounds were found to exhibit more anti-fungal than anti-bacterial activity.Synthesis, characterization and anti-microbial studies of novel Schiff bases of 3-amino-6,8-dibromo-2-phenylquinazolin-4(3H)-ones were described against the standard Gram-positive, Gram-negative and fungi strains and compound 10 was found to be the most effective.Display Omitted
Keywords: Quinazolin-4(3H)-one; Schiff base; Anti-bacterial; Anti-fungal;

A macrolactone from benzo[a]phenazine with potent activity against Mycobacterium tuberculosis by Raphael S.F. Silva; Maria do Carmo F.R. Pinto; Marília O.F. Goulart; José D. de Souza Filho; Ivan Neves; Maria Cristina S. Lourenço; Antonio V. Pinto (2334-2337).
We report here an alternative to the MCPBA or ozonolysis-based oxidation methods of quinoxaline-featuring compounds prepared from beta-lapachones. The use of peracetic acid allowed a simple preparation of the corresponding macrolactones by cleavage of the ring system. These lactones were evaluated for their antimycobacterial potential and compound 4 turned out to have an MIC of 0.62 μg per mL on Mycocabteriumtuberculosis H37Rv. These results justify further research into its value as a potential lead for an original treatment of tuberculosis.A macrolactone derived from β-lapachone phenazine has shown high activity against Mycobacterium tuberculosis and it is presented as an alternative method for preparation of lactones from benzo[a]phenazines. Display Omitted
Keywords: Lapachol; Phenazines; Peracetic acid oxidation; Macrolactones; Tuberculosis;