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 (ER alpha) 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.

Automated summary

The study synthesized chalcone derivatives and their pyrimidine and thiopyrimidine derivatives, showing potential anticancer activity against human cancer cell lines. Compound 20b emerged as the most potent inhibitor against rhDHFR, indicating potential for further development as anticancer agents. Docking simulations also revealed interactions with hDHFR and ERα.