Letters in Drug Design & Discovery (v.9, #4)

Graphical Abstracts by Kadria A. Elkhodairy (i-v).
Full text available

It has been recognised that there is no need for phosphorous acid during the conversion of 1-heteroarylacetic acids to the corresponding dronic acids, as phosphorus trichloride (PCl3) is the real reagent. We could prove that the first intermediate toward the formation Risedronic acid is 3-pyridylacetyl chloride that was prepared in different ways using inorganic halides in toluene or in methanesulfonic acid (MSA). The intermediate was then reacted with two equivalents of PCl3 to afford risedronic acid after hydrolysis and pH adjustment. The pyridylacetyl chloride intermediate was identified on the basis of its esterification and amidation reaction. In MSA as the solvent, mixed anhydrides may also be formed as the intermediates from which the dronic acids may be formed in reaction with PCl3. A similar situation was anticipated for the reaction sequence of Zoledronic acid.

Literature reports show numerous studies concerning the occurrence, evolution, detection and removal of, generically, pharmaceutical pollutants in/from environment. The current report is focused on the Phenothiazines class, in particular on Thioridazine (Thr). We discuss the time evolution of the absorption spectra of Thioridazine HCl solutions in ultra-pure water considering the racemic mixture and the two enantiomers: Thioridazine (-) and Thioridazine (+); the utilized concentration range was 10-5M-10-3M, and the temperature/light conditions were: 4

In this paper we describe the preparation, characterization and antimalarial activity in vivo of novel quinoline/mercatopurine conjugates. The compounds were tested in vivo in a murine model using chloroquine as a reference compound. The values of inhibition of parasite multiplication relative to chloroquine were determined and the compound 4-(6'-mercatopurine)-7-chloroquinoline was considered statistically identical to chloroquine at the same dosage. The compounds were not cytotoxic at the maximum concentration used (100 μg/mL). Possible mechanisms of action are discussed. In light of these data, the title compounds may serve as prototypes for the development of novel antimalarial agents.

Quantitative structure-activity relationships (QSAR) of 65 different molecular series histone deacetylase inhibitors (HDACIs) with only one common pyrrole ring were studied by using comparative molecular field analysis (CoMFA), comparative molecular similarity indices analysis (CoMSIA) and hologram quantitative structure-activity relationship (HQSAR). The leave-one-out cross-validation q2 values of CoMFA, CoMSIA and HQSAR models were 0.623, 0.662 and 0.716, and non-cross-validated r2 values were 0.952, 0.909 and 0.891, respectively. The contour maps and atom contribution map provided helpful visualization information for structural modification of the HDACIs for better activity. A further docking study was carried out by using Surflex-dock method. Sixty-five compounds were docked into histone deacetylase (PDB ID 1T64). A reasonable docking model between inhibitors and the protein was obtained. The interaction between ligands and the receptor can reveal the binding mode of the HDAC inhibitors and HDAC enzyme. According to QSAR and docking results, eight new molecules were proposed, and their activities were predicted by using the established QSAR model and docking method. The results indicated that the proposed potential molecules have a potent activity.

A series of novel cis-furoquinoline derivatives was synthesized and tested for their antitumor activities in vitro against HepG2 cells, Lu-04 cells and Leu02 cells to evaluate structure-activity relationships. Assay-based antiproliferative activity study revealed that several compounds had significant effects on cytotoxicity, among which compounds 2f, 2l, 2q were found to be the most active compounds. Above all, compounds 2f, 2l, 2q would be potential anticancer agents which deserved further research.

A quantitative structure- activity relationship (QSAR) study has been made on a series of thiophene derivatives acting as anti-HCV agents. Significant correlations are found between anti-HCV potencies and some physicochemical parameters. The study reveals that the activity can be controlled by molecular connectivity, Hammett constant, and some indicator variables. Using the correlations obtained, some new prospective compounds having high potency have been predicted.

Studies have shown that natural product scopoletin has significant pharmacological activities, such as antiarthritic, spasmolytic, antitumoral, antidepressant-like, antifungal, antihyperglycemic and antioxidative. In search of new antitumor agents, twelve scopoletin derivatives were designed and synthesized by a systematic combinatorial chemical approach and their chemical structures were confirmed by MS, IR, 1H NMR spectra and elemental analysis. Preliminary screening against mammary cells HUVEC and MCF-7 indicated that three compounds (5a, 5b, 5e) displayed reasonable antitumor activity with IC50 values below 18 μM whereas scopoletin showed its IC50 values above 100 μM. These results clearly indicated that structural modification of scopoletin can greatly increase its antitumor activity in vitro.

A novel series of ten N-(aryl)-2-(2-methyl-1H-imidazol-1-yl)acetamides (5a-j) were synthesized by reacting 2- methylimidazole (4) with the corresponding &#x3C9;- chloroacetanilides (3a-j) in Dimethly Formamide and potassium carbonate. The compounds have been characterized on the basis of elemental analysis and spectral data. All the synthesized compounds were screened for their anticonvulsant activity. Among the compounds subjected to anticonvulsant activity, compounds 5a, 5b, 5d, 5f, 5g, 5h, 5i and 5j, at a dose of 100mg/kg body weight i.p. showed significant anticonvulsant activity (p < 0.01) as they delayed the onset of convulsions. The compounds 5a, 5d, 5h, 5i and 5j also decreased the duration of seizures significantly (p < 0.01 and P < 0.05) and the results were comparable to the diazepam treated group. Compound 5g is the most active molecule as; it increased the onset of convulsion time to nearly two fold and comparable duration of action to that of diazepam.

A series of 1-alkoxy-4-(1H-1,2,4-triazol-1-yl)phthalazine derivatives were synthesized using 2,3- dihydrophthalazine-1,4-dione as starting material. The structures of the compounds were characterized by elemental analysis, IR, 1H-NMR and MS data. Anticonvulsant activities of these compounds were evaluated by maximal electroshock (MES) test following intraperitoneal injection in mice. Among the synthesized compounds 3a-3t, compound 3e was the most active compound with an ED50 of 28.9 mg/kg, TD50 of 173.6 mg/kg and protective index (PI) of 6.0.

Twenty-one 2-(N-arylsulfonylindol-3-yl)-3-aryl-1,3-thiazolidin-4-ones (4a-u) were synthesized and evaluated as HIV-1 inhibitors in vitro. Among all compounds, compounds 4n and 4p displayed the potent anti-HIV-1 activities with EC50 values of 3.48 and 8.61 &#956;g/mL, and TI values of 34.08 and > 23.22, respectively. It demonstrated that, to a series of 2-(N-arylsulfonyl-6-methylindol-3-yl)-3-aryl-1,3-thiazolidin-4-one derivatives, introduction of R2 as 4-Cl and R3 as H or 3-Cl could afford the more promising and potent compounds.

The present work was aimed that in vitro antioxidant activity of some novel synthetic mononuclear Ruthenium (II) compounds namely, Ru (1, 10-phenanthroline)2(2-nitro Phenyl thiosemicarbazone)Cl2 (compound R1) and Ru (1, 10- phenanthroline)2(2-hydroxy-phenyl thiosemicarbazone)Cl2 (compound R2) using [2, 29-azinobis-(3-ethylbenzothiazoline- 6-sulfonic acid)] (ABTS), Ferric reducing antioxidant power (FRAP), N, N-dimethyl-p-phenylenediamine (DMPD), 1, 1- diphenyl-2-picryl hydrazine (DPPH) and Nitro blue tetrazolium (NBT) assays. The results concluded that both the compounds (R1) exhibited a significant antioxidant activity. But compared to reference standards, R1 was found to be better free radical scavenging activity than R2.

Drug target proteins (DTPs) are mainly distributed in several druggable families. Although proteins in one druggable family are similar in sequence and structure, not all of them are DTPs. However, the difference between DTPs and potential target proteins (PTPs) is not yet clear. We explored the topological difference between DTPs and PTPs in the human protein-protein interaction (PPI) network. Hence we found DTPs exhibited patterns of topological similarity in the human PPI network. Moreover, we hypothesize that DTPs perturb the network in a controlled manner because their influences on the PPI network were greater than PTPs' but less than hubs'. At last, we applied the similarity of topological features to prioritize PTPs in two largest families. These results demonstrated the potential application of topological features, which could be helpful to find new DTP candidates.

A new series of 1,2,4-triazoles containing cyclopropane moiety were synthesized and characterized by 1H NMR and elemental analyses. The biological activities results showed that most of them exhibited significant fungicidal activity towards six test fungi. Among them, several showed superiority over the commercial fungicide during the present study.

The objective of the present study is to investigate the potential of nanoemulsion formulations for transdermal delivery of indomethacin (IND). Nanoemulsions formulations with different Surfactant: co surfactant ratios (S mix); F1 - F6 (1:1, 2;2, 3:1, 4;1, 1:2 and 3:2) were prepared by the spontaneous emulsification method, and characterized for morphology, droplet size, and rheological characteristics. The ex vivo skin permeation studies were performed using Franz diffusion cell with rabbit skin as permeation membrane. A significant increase in the steady-state flux (Jss), permeability coefficient (Kp), and enhancement ratio (Er) was observed in nanoemulsion formulations compared with the conventional IND gel. The anti-inflammatory effects of nanoemulsion formulations showed a significant increase in percent edema inhibition value after 4 hours. The optimized formulation showed significant increase in the steady-state flux (Jss) and permeability coefficient (Kp). Enhancement ratio (Er) was found to be 8.939 in optimized formulation F1 compared with IND gel.