Combinatorial Chemistry & High Throughput Screening - Volume 18, Issue 9, 2015

Antiandrogens bicalutamide, flutamide and enzalutamide etc. have been used in clinical trials to treat prostate cancer by binding to and antagonizing androgen receptor (AR). Although initially effective, the drug resistance problem will emerge eventually, which results in a high medical need for novel AR antagonist exploitation. Here in this work, to facilitate the rational design of novel AR antagonists, we studied the structure-activity relationships of a series of 2-quinolinone derivatives and investigated the structural requirements for their antiandrogenic activities. Different modeling methods, including 2D MLR, 3D CoMFA and CoMSIA, were implemented to evolve QSAR models. All these models, thoroughly validated, demonstrated satisfactory results especially for the good predictive abilities. The contour maps from 3D CoMFA and CoMSIA models provide visualized explanation of key structural characteristics relevant to the antiandrogenic activities, which is summarized to a position-specific conclusion at the end. The obtained results from this research are practically useful for rational design and screening of promising chemicals with high antiandrogenic activities.

Network pharmacology is an emerging technique, which integrates systems biology and computational biology to study multi-component and multi-targeted formulations. Ayurveda, the traditional system of Indian medicine, uses intelligent formulations; however, their scientific rationale and mechanisms remain largely unexplored. This paper presents the potential of network pharmacology to understand the rationale of a commonly used Ayurveda formulation known as Triphala. We have developed pharmacology networks of Triphala based on the information gathered from different databases and using the software Cytoscape. The networks depict the interaction of bioactives with molecular targets and their relation with diseases, especially cancer. The network pharmacology analysis of Triphala has offered new relationships among bioactives, targets and putative applications of cancer etiology. This pioneering effort might open new possibilities to know pharmacodynamics of Ayurvedic drugs like Triphala and also help in the discovery of new leads and targets for various diseases.

The RNA helicase DHX9 is an ATP-dependent DExH box helicase that can unwind DNA and RNA. Much evidence has implicated DHX9 at multiple levels of gene expression regulation ranging from genome stability and replication, to transcriptional control and translation regulation. Its association with the EWS-FLI1 fusion product, as well as the finding that its suppression can be synthetic lethal with the BCL-2 family inhibitor ABT-737 indicates a potential role in tumor maintenance. Hence, to identify small molecules that could interfere with its activity, we developed a homogenous RNA-dependent ATPase assay. We show that aurintricarboxylic acid, a promiscuous protein-nucleic acid inhibitor prevents DHX9-mediated hydrolysis demonstrating that the assay is also capable of detecting compounds that impinge on DHX9:RNA association.

Molecular docking studies of the designed two series (4a-l, 6a-l, 9 and 10) of novel substituted phosphorylated 1, 4-dihydropyridine and 1,2,3,4-tetrahydropyrimidine derivatives against the drug targets of DHFR from Bacillus cereus, LpxC from Pseudomonas aeruginosa, IDH from E. coli and MurB from Staphylococcus aureus were encouraged for their synthesis. These compounds were synthesized from substituted aromatic aldehydes, thiourea/urea and ethyl acetoacetate in the presence of polyphosphoric acid (PPA). These were further phosphorylated with diethyl (2-chloroethoxy) methyl phosphonate to get the desired products. In vitro anti-bacterial activity against the specified bacterial strains related to docked protein exhibited good inhibitory activity at different dose concentrations. Quantitative Structure Activity Relationship (QSAR) descriptors of the designed structures have demonstrated their satisfactory drug like properties. The results from Molecular Docking, QSAR descriptors and in vitro anti-bacterial activities led to the identification of safer and potential antibacterial agents of the title compounds screened. Compounds 4a, 4d, 4i, 6a, 6d, 9 and 10 were found to be potent antibacterial agents.

Three- component reactions of 1-(6-hydroxy-2-isopropenyl-1-benzofuran-yl)-1-ethanone, aldehydes and malononitrile or ethyl cyanoacetate in the presence of nanoparticles of ZnO as catalyst are explained as effective and green synthetic method for generating 9H- furo[2,3-f]chromenes in good yield.

Survival of cells and maintenance of genome depend on detection and repair of damaged DNA through intricate mechanisms. Cancer treatment relies on chemotherapy or radiation therapy that kills neoplastic cells by causing immense damage to the DNA. In many cases, escalated DNA repair mechanism leads to resistance against these therapies and therefore, there is a need to expand the interest in developing drugs that can sensitize the cells to such therapies by interfering with the DNA repair mechanism. Several studies have suggested a link between over expression of the primary mammalian enzyme, Apurinic/Apyrimidinic Endonuclease (APE1), responsible for abasic (or AP) site removal in the DNA and resistance of these cells to cancer therapy, whereas APE1 down-regulation sensitizes the cells to DNA damaging agents. Thus, the current treatment efficacy can be improved by aiding to selective sensitization of cancer cells and protection of normal cells. In the present study, we have used machine learning based approach by selecting assorted compounds with known activity for APE1 and constructed a range of in silico predictive classification models to discriminate between the inhibitors and non-inhibitors. These models can be applied to numerous other unscreened compounds to select the ones which are more likely to be the inhibitors for APE1. We have further found the common molecular substructures which were associated with the molecular activity of the compounds using a substructure search approach.

Eighteen hexahydropyrrolo[2,3-b]indole derivatives were synthesized and evaluated their in vitro antifungal activities against five phytopathogenic fungal strains through the mycelium growth rate method. Analysis of the structure-activity relationship on these synthesized compounds revealed that the introduction of benzyl or substituted benzyl group at the C-3a or N-8 position of the pyrroloindoline scaffold conferred higher antifungal activity against all tested phytopathogenic fungi than compound 4a (both C-3a and N-8 positions are prenyl groups). Especially, compound 4r, among all the tested compounds, showed the most effective antifungal activity against Fusarium coeruleum, and Fusarium graminearum with IC50 values of 4.61 and 5.02 μg/mL, respectively. Moreover, all synthesized compounds 4a-4r displayed higher activities against Curvularia lunata than the positive control thiabendazole, a commercial agricultural fungicide.

A simple, efficient, and environmentally benign procedure for the synthesis of 2-amino-4Hchromene ring has been achieved by the three-component reaction of an aromatic aldehyde, malononitrile and diverse enolizable C-H activated compound under ultrasound irradiation using sodium carbonate as a catalyst in aqueous media. Sodium carbonate as a natural salt, being available as an inexpensive catalyst combined with ultrasound method promoted this protocol in comparison to other methods and catalysts.

A simple and efficient synthesis of pyrimido[b]quinolinetriones is introduced using copper (I) iodide nanoparticles (CuI NPs) as an efficient heterogeneous catalyst in green media-water. The catalyst was prepared through the simple precipitation route and well characterized by various techniques such as XRD and SEM. The mild reaction conditions, using aqueous medium, reusability of the catalyst, simple reaction work-up and excellent yields of products make the present protocol sustainable and advantageous compared to the conventional methods.