Letters in Drug Design & Discovery - Volume 13, Issue 6, 2016

An efficient method was developed for the synthesis of pamidronic acid involving the reaction of β-alanine with three equivalents of phosphorus trichloride and two equivalents of phosphorous acid at 75 °C in the presence of 0.3 or 0.6 equivalents of [BMIM][PF6] as an additive.

A new series of indolizine derivatives were synthesized and screened for the antiproliferative potential against NCI 60 tumor cell line panel. The results of the study revealed a selective and good antitumor growth inhibitory activity against SNB-75 CNS cancer cell line for 1-cyanoindolizine derivative 10b. Moreover, a supplementary in vitro biological evaluation showed that compound 9d exhibited a significant farnesyltransferase inhibition activity (IC50 = 1.07 ± 0.34 μM) and could represent a lead for the development of new antitumoral chemical entities.

A series of macamides (1-4) and their synthetic analogs (5-14) were synthesized and evaluated for in vitro inhibitory activities against breast cancer cell MCF-7. The results of bioactive assay showed that two of the macamides (compound 1 and 4) and one synthetic analog (compound 5) displayed comparable inhibitory activities against MCF-7 cell line, with IC50 values of 29.6, 36.2 and 27.2 μM, respectively.

Resveratrol (3,4,5'-trihydroxy-trans-stilibene) is a famous natural product which exhibits potential antitumor activity both in vitro and in vivo. In this article, A series of formamide derivatives of resveratrol (C1-27) were synthesized and their cytotoxic activities were evaluated, with results indicating that most of the compounds exhibited antitumor activity against both Smmc7721 and SGC7901 cancer cell lines. Among them, compound C21 displayed the most potent antitumor activities, with IC50 values of 7.68 and 6.16 μM against Smmc7721 and SGC7901 cancer cell lines respectively. All compounds reported herein were characterized by 1H NMR, 13C NMR, MS and IR spectrum. Additionally, the structure of compound C10 was confirmed by X-ray crystallographic analysis.

A base catalyzed sequential one-pot protocol for an effective preparation of 3-(substitutedphenyl) -6,6-dimethyl-2-(substitutedphenylcarbonyl)-3,5,6,7-tetrahydro-1-benzofuran- 4(2H)-one derivatives have been described. One-pot reaction of aromatic aldehydes, various phenacyl bromide and dimedone gives corresponding substituted benzofurans in economically affordable yields with stereo specificity at 2nd and 3rd position via formation of substituted pyridinium ylides. Newly synthesized compounds were characterized by different spectral techniques such as IR, 1H NMR, 13C NMR and Mass spectrometry. Furthermore, the structure of compound 4f was unambiguously assigned by X-ray crystallography. All the synthesized compounds were subjected to in-vitro antimicrobial screening against a panel of pathogenic strains of bacteria to evaluate their potency as a MIC. Some of the compounds were found to be equipotent or extra potent than commercial antibiotics against some active strains.

Background: The prediction of physicochemical properties is important task of the natural sciences. Quantitative structure – property relationships (QSPR) are a tool to solve the task. Objective: QSPR for dispersibility of graphene in various organic solvents has been built up by means of the CORAL software (http://www.insilico.eu/coral). Method: The Monte Carlo technique is the basis of the models for dispersibility of graphene in various organic solvents. Simplified molecular input-line entry systems (SMILES) are used to represent the molecular structure for the QSPR analysis. In other words, the graphene dispersibility is modeled as a mathematical function of the molecular structure. Results: The statistical characteristics of the models are quite good. They have the mechanistic interpretation: the structural features of molecules of solvents which are promoters of increase or decrease of graphene dispersibility have been discovered. Conclusion: The suggested approach can be used to predict dispersibility of graphene in various organic solvents.

A novel series of novel 1,2,4-triazolo[4,3-a]pyridines were designed and synthesized under microwave irradiation condition. The structures were identified by 1H NMR, MS and elemental analysis, and the antifungal activities of them were evaluated at 100 ppm. It was found that some of the 1,2,4-triazolo[4,3-a]pyridines displayed good antifungal activity. Among them, compound 2e exhibited good antifungal activity against Stemphylium lycopersici (Enjoji) Yamamoto and Fusarium oxysporum. Sp. Cucumebrium.

Tropomysin receptor kinase A (TrkA) is an excellent drug target for its important roles in pain sensation as well as tumour cell growth. Up to now, the discovered TrkA inhibitors belong mostly to type-I class targeting the ATP binding site, while we aim to find type-II inhibitors because they are deemed to have improved kinase selectivity and slower off-rates than their counterparts. The type-II inhibitors can induce TrkA in an inactive DFG-out form and insert in an additional hydrophobic cavity adjacent to the ATP binding pocket. The current article describes efforts to discover novel type-II scaffolds against TrkA via integrating pharmacophore-based 3D-QSAR modeling, database screening and molecular docking. The robustness of the best model, AAHRR.8, was seriously ascertained by the high R2 (0.9027), Q2 (0.7048), low RMSE (0.4016) and SD (0.3635). It was further used as a 3D query to screen against our in-house collection of almost 1.3 million compounds followed by molecular docking simulations using three docking protocols involving Glide SP, Surflex and Glide XP. 12 hits, which mapped well on the best pharmacophore model, displayed good docking score and rational binding mode, were selected as promising selective leads of TrkA. Finally, ADME study was carried out and the results indicated that these 12 compounds own drug-like properties. The 12 hits together with the best 3D-QSAR model will be helpful for future potent TrkA agent development.

With ever-increasing drug resistant clinical isolates, novel antibiotics with new targets are urgently needed. Tuberculosis, caused by Mycobacterium tuberculosis, showed formidable antibiotics resistance. InhA, the enoyl-acyl carrier protein (ACP) reductase involved in the type II fatty acid synthesis pathway (FASII) in Mycobacterium tuberculosis, represents an appealing target for the development of new anti-tuberculosis (TB) agents. Inhibitors against InhA might be ideal lead or antibiotics. The latest development of InhA inhibitors is summarized in this paper.

The new series of 2-(substituted-phenyl)acetohydrazides analogs, S-alkylated 5-substituted-1,3,4-oxadiazoles- 2-thione derivatives and 5-arylidene-3-substituted-1,2,4-triazines have been synthesized in good yields and characterized by IR, NMR, mass spectral and elemental analyses. All the synthesized compounds 4(a-d), 5(a-d), 7(a-b), and 8(a-f) are evaluated for their in vitro DPPH scavenging, antimicrobial activity, in vivo analgesic, anti-inflammatory activities. The results of the anti-inflammatory activity are supported by molecular docking study with mouse COX-1 (PDB ID: 2CZT) and COX-2 (PDB ID: 3LN1) enzymes to predict their putative interactions. Among all the assays conducted, the compounds 5-(4-bromophenyl)-3-(naphthalen-2-ylmethyl)-1,2,4-triazine (4d) and2-{[5-(diphenylmethyl)-1,3,4-oxadiazol-2- yl]sulfanyl}-N-(pyrazin-2-yl)acetamide (8a) have emerged as the most potent molecules.

The synthesis of 2-arylidene 6-(2-aryl-2-oxoethoxy)benzofuran-3-one derivatives was reported and selected compounds were determined for their anticancer activity evaluation in National Cancer Institute NCI, USA according to the drug screening protocol of the institute against approximately 60 tumor cell lines derived from nine cancer diseases. Compound 3r, namely 2-(4- chlorobenzylidene)-6-[2-(4-methoxyphenyl)-2-oxoethoxy]benzofuran-3-one exhibited the highest antitumor activity against non-small lung cancer cell lines.

6-mercaptopurine (6-MP) is the first active metabolite inhibitor shown to suppress cancer cells. The aim of this study is to investigate the bioactivity of 6-MP derivatives and discover new anti-cancer agents. Four 6-mercaptopurine (6-MP) derivatives were synthesized and their anti-cancer activities were analyzed. All of the compounds showed anti-proliferative effects against HepG2 and A2780 cancer cells. Among the synthesized derivatives, 6-((naphthalen-2-ylmethyl)thio)-9H-purine (NMSP) which possessing a β-naphthalene, showed better anti-cancer activity than other compounds, with an IC50 value 6.09μg/mL. NMSP could induce S phase cell cycle arrest and apoptosis in HepG2 cells. Western blot analysis indicated that NMSP induced apoptosis is mitochondria-dependent. The novel 6-MP derivative discovered in this study is a promising drug candidate to be used as an anti-cancer agent.