Design, synthesis and evaluation of novel enzalutamide analogues as potential anticancer agents.

The androgen receptor inhibitor, Enzalutamide, proved effective against castration resistance prostate cancer, has demonstrated clinical benefits and increased survival rate in men. However, AR mutation (F876L) converts Enzalutamide from antagonist to agonist indicating a rapid evolution of resistance. Hence, our goal is to overcome this resistance mechanism by designing and developing novel Enzalutamide analogues. We designed a dataset of Enzalutamide derivatives using Enzalutamide's shape and electrostatic features to match with pharmacophoric features essential for tight binding with the androgen receptor. Based on this design strategy ten novel derivatives were selected including 5,5-dimethyl-3-(6-substituted benzo[d]thia/oxazol-2-yl)-2-thioxo-1-(4-(trifluoromethyl)pyridin-2-yl)imidazolidin-4-one (6a-j) for synthesis. All the compounds were evaluated in-vitro on prostate cancer cell lines DU-145, LNCaP and PC3. Interestingly, two compounds 3-(6-hydroxybenzo[d]thiazol-2-yl)-5,5-dimethyl-2-thioxo-1-(4-(trifluoromethyl)pyridin-2-yl) imidazolidin-4-one (6c, IC50 - 18.26 to 20.31µM) and 3-(6-hydroxybenzo[d]oxazol-2-yl)-5,5-dimethyl -2-thioxo- 1- (4-(trifluoromethyl) pyridin-2-yl)imidazolidin-4-one (6h, IC50 - 18.26 to 20.31µM) were successful with promising in-vitro antiproliferative activity against prostate cancer cell lines. The binding mechanism of potential androgen receptor inhibitors was further studied by molecular docking, molecular dynamics simulations and MM-GBSA binding free energy calculations and found in agreement with the in vitro studies. It provided strong theoretical support to our hypothesis.

Water-powered self-propelled magnetic nanobot for rapid and highly efficient capture of circulating tumor cells.

Nanosized robots with self-propelling and navigating capabilities have become an exciting field of research, attributable to their autonomous motion and specific biomolecular interaction ability for bio-analysis and diagnosis. Here, we report magnesium (Mg)-Fe3O4-based Magneto-Fluorescent Nanorobot ("MFN") that can self-propel in blood without any other additives and can selectively and rapidly isolate cancer cells. The nanobots viz; Mg-Fe3O4-GSH-G4-Cy5-Tf and Mg-Fe3O4-GSH-G4-Cy5-Ab have been designed and synthesized by simple surface modifications and conjugation chemistry to assemble multiple components viz; (i) EpCAM antibody/transferrin, (ii) cyanine 5 NHS (Cy5) dye, (iii) fourth generation (G4) dendrimers for multiple conjugation and (iv) glutathione (GSH) by chemical conjugation onto one side of Mg nanoparticle. The nanobots propelled efficiently not only in simulated biological media, but also in blood samples. With continuous motion upon exposure to water and the presence of Fe3O4 shell on Mg nanoparticle for magnetic guidance, the nanobot offers major improvements in sensitivity, efficiency and speed by greatly enhancing capture of cancer cells. The nanobots showed excellent cancer cell capture efficiency of almost 100% both in serum and whole blood, especially with MCF7 breast cancer cells.

Self-Propelling Targeted Magneto-Nanobots for Deep Tumor Penetration and pH-Responsive Intracellular Drug Delivery.

Self-propelling magnetic nanorobots capable of intrinsic-navigation in biological fluids with enhanced pharmacokinetics and deeper tissue penetration implicates promising strategy in targeted cancer therapy. Here, multi-component magnetic nanobot designed by chemically conjugating magnetic Fe3O4 nanoparticles (NPs), anti-epithelial cell adhesion molecule antibody (anti-EpCAM mAb) to multi-walled carbon nanotubes (CNT) loaded with an anticancer drug, doxorubicin hydrochloride (DOX) is reported. Autonomous propulsion of the nanobots and their external magnetic guidance is enabled by enriching Fe3O4 NPs with dual catalytic-magnetic functionality. The nanobots propel at high velocities even in complex biological fluids. In addition, the nanobots preferably release DOX in the intracellular lysosomal compartment of human colorectal carcinoma (HCT116) cells by the opening of Fe3O4 NP gate. Further, nanobot reduce ex vivo HCT116 tumor spheroids more efficiently than free DOX. The multicomponent nanobot's design represents a more pronounced method in targeting tumors with self-assisted anticancer drug delivery for 'far-reaching' sites in treating cancers.

Discovery of new leads against Mycobacterium tuberculosis using scaffold hopping and shape based similarity.

BM212 [1,5-diaryl-2-methyl-3-(4-methylpiperazin-1-yl)-methyl-pyrrole] is a pyrrole derivative with strong inhibitory activity against drug resistant Mycobacterium tuberculosis and mycobacteria residing in macrophages. However, it was not pursued because of its poor pharmacokinetics and toxicity profile. Our goal was to design and synthesize new antimycobacterial BM212 analogs with lower toxicity and better pharmacokinetic profile. Using the scaffold hopping approach, three structurally diverse heterocycles - 2,3-disubstituted imidazopyridines, 2,3-disubstituted benzimidazoles and 1,2,4-trisubstituted imidazoles emerged as promising antitubercular agents. All compounds were synthesized through easy and convenient methods and their structures confirmed by IR, 1H NMR, 13C NMR and MS. In-vitro cytotoxicity studies on normal kidney monkey cell lines and HepG2 cell lines, as well as metabolic stability studies on rat liver microsomes for some of the most active compounds, established that these compounds have negligible cytotoxicity and are metabolically stable. Interestingly the benzimidazole compound (4a) is as potent as the parent molecule BM212 (MIC 2.3µg/ml vs 0.7-1.5µg/ml), but is devoid of the toxicity against HepG2 cell lines (IC50 203.10µM vs 7.8µM).

New horizons in antimalarial drug discovery in the last decade by chemoinformatic approaches.

Antimalarial drug discovery process is progressively carried out by a combination of innovation and knowledge based methods that include computational and experimental approaches to achieve potent leads. Among the various computational approaches, chemoinformatics plays a critical role in the discovery of new leads or drug candidates. Chemoinformatics provides researchers tools to derive information on substructures, chemical space, similarity and diversity. It also helps to manage and store chemical data, study important molecular properties and filter libraries with regard to specified criteria in the database. To accomplish these ends it uses various tools amongst which are docking, 3D-QSAR, similarity search, virtual screening, database mining and pharmacophore mapping. This review is a perspective of the utility of chemoinformatic approaches in antimalarial drug design. It covers various facets such as targets that have been exploited for antimalarial drug discovery by chemoinformatic methods; potential antimalarial targets that have not yet been explored; the challenges faced in antimalarial drug discovery, and future directions for discovery of novel antimalarial agents.