Development of a Scalable Process for the Synthesis of DNDI-VL-2098: A Potential Preclinical Drug Candidate for the Treatment of Visceral Leishmaniasis.

A process suitable for kilogram-scale synthesis of (2R)-2-methyl-6-nitro-2-{[4-(trifluoromethoxy)phenoxy]methyl}-2,3-dihydroimidazo[2,1-b][1,3]oxazole (DNDI-VL-2098, 2), a preclinical drug candidate for the treatment of visceral leishmaniasis, is described. The four-step synthesis of the target compound involves the Sharpless asymmetric epoxidation of 2-methyl-2-propen-1-ol, 8. Identification of a suitable synthetic route using retrosynthetic analysis and development of a scalable process to access several kilograms of 2 are illustrated. The process was simplified by employing in situ synthesis of some intermediates, reducing safety hazards, and eliminating the need for column chromatography. The improved reactions were carried out on the kilogram scale to produce 2 in good yield, high optical purity, and high quality.

Design and synthesis of novel HDAC8 inhibitory 2,5-disubstituted-1,3,4-oxadiazoles containing glycine and alanine hybrids with anti cancer activity.

Oxadiazole is a heterocyclic compound containing an oxygen atom and two nitrogen atoms in a five-membered ring. Of the four oxadiazoles known, 1,3,4-oxadiazole has become an important structural motif for the development of new drugs and the compounds containing 1,3,4-oxadiazole cores have a broad spectrum of biological activity. Herein, we describe the design, synthesis and biological evaluation of a series of novel 2,5-disubstituted 1,3,4-oxadiazoles (10a-10j) as class I histone deacetylase (HDAC) inhibitors. The compounds were designed and evaluated for HDAC8 selectivity using in silico docking software (Glide) and the top 10 compounds with high dock score and obeying Lipinski's rule were synthesized organically. Further the biological HDAC inhibitory and selectivity assays and anti-proliferative assays were carried out. In in silico and in vitro studies, all compounds (10a-10j) showed significant HDAC inhibition and exhibited HDAC8 selectivity. Among all tested compounds, 10b showed substantial HDAC8 inhibitory activity and better anticancer activity which is comparable to the positive control, a FDA approved drug, vorinostat (SAHA). Structural activity relation is discussed with various substitutions in the benzene ring connected on 1,3,4-oxadizole and glycine/alanine. The study warranted further investigations to develop HDAC8-selective inhibitory molecule as a drug for neoplastic diseases. Novel 1,3,4-oxadizole substituted with glycine/alanine showed HDAC8 inhibition.

Synthesis of new secretory phospholipase A2-inhibitory indole containing isoxazole derivatives as anti-inflammatory and anticancer agents.

Secretory phospholipase A2 (sPLA2) is an important enzyme that plays a key role in various inflammatory diseases including cancer and its inhibitors have been developed as preventive or therapeutic agents. In the present study, a series of new indole containing isoxazole derivatives (10a-10o) is synthesized and evaluated for their sPLA2 inhibitory activities. All compounds (10a-10o) showed significant sPLA2 inhibition activities both in vitro and in vivo studies which is substantiated in in silico studies. Among all the tested compounds, 10o showed potent sPLA2 inhibition activity, that is comparable or more to ursolic acid (positive control). Further studies demonstrated that 10o showed in vitro antiproliferative activity when tested against MCF-7 breast and DU145 prostate cancer cells. Furthermore, compounds 10a-10o obeyed lipinsky's rule of 5 and suggesting druggable properties. The in vitro, in vivo and in silico results are encouraging and warrant pre-clinical studies to develop sPLA2-inhibitory compound 10o as novel therapeutic agent for various inflammatory disorders and several malignancies.