Design, synthesis, in-vitro, in-vivo and ex-vivo pharmacology of thiazolidine-2,4-dione derivatives as selective and reversible monoamine oxidase-B inhibitors.

Neurodegenerative ailments are a diverse set of syndromes distinguished by gradual deterioration of the structure as well as functions of the central nervous system or peripheral nervous system. Alzheimer's disease (AD) and Parkinson's disease (PD) have no cure, common, and are high prevalent neurodegenerative pathologies. In current research, rationally designed thiazolidine-2,4-dione based analogs were synthesized and tested for their inhibition potential against two isoforms of monoamine oxidase (MAO-A / MAO-B). Structure activity relationships were explored. Pyridinyl and thiazolyl hydrazone derivative 43 and 44 with IC50 value of 0.013 µM and 0.008 µM (selectivity 228 / 226 times) exhibited higher potency than reference drug safinamide. Most active compounds showed BBB penetration in PAMPA in-vitro assay. Except nitro derivative 41, all compounds were non-neurotoxic in the studied concentration. Molecular docking studies supported the in-vitro experimental results and the selectivity by comparing the binding energy values against both MAO-A and MAO-B isoforms. All the results of current research suggest compounds 43 and 44 may serve as promising candidates for further research for treatment of neurodegenerative diseases.

Synthesis, pharmacological evaluation and Molecular modelling studies of pregnenolone derivatives as inhibitors of human dihydrofolate reductase.

In current study, we synthesized chalcone derivatives (13a-c) via base-catalyzed Claisen-Schmidt condensation reaction. We further treated diamino compounds with synthesized chalcones to produce 3,4-dihydropyrimidin-2(1H)-one (18a-c), 3,4-dihydropyrimidin-2(1H)-thione (19a-c) and 2-aminopyrimidine (20a-c) derivatives of pregnenolone by cyclization reaction. Cell viability test of synthesized steroidal chalcones and their pyrimidine and thiopyrimidine derivatives against human breast (MCF-7), human lung (A549) and human prostate (PC-3) cancer cell lines was performed using (4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT), assay. Compounds were further evaluated for their inhibition potential against recombinant human DHFR (rhDHFR). All compounds showed activity from low micromolar to submicromolar range. Compound 20b with IC50 value of 180 nM emerged as most potent compound against rhDHFR. Interaction of the newly synthesized pregnenolone derivatives with hDHFR and estrogen receptor alpha (ERα) were also explored via docking simulations. The overall results of hDHFR inhibition have shown that these analogues can be further optimized and developed as potent anticancer agents.