Hybrid pharmacophore-based drug design, synthesis, and antiproliferative activity of 1,4-dihydropyridines-linked alkylating anticancer agents

摘要

Two series of novel substituted 1,4-dihydropyridine derivatives incorporating nitrogen mustard pharmacophore hybrids without spacer DHP-M (4a-4d) and with ethyl spacer DHP-L-M (8a-8g) were designed and synthesized. They were subjected to in silico ADME prediction study to check their drug-like properties and evaluated for their cytotoxicity against: A 549 (lung), COLO 205 (colon), U 87 (glioblastoma), and IMR-32 (neuroblastoma) human cancer cell lines in vitro using 3-(4,5-dimethylthiazole-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assay against chlorambucil and docetaxel. Majority of the test compounds exhibited moderate to significant cytotoxic activity. The highest activity in all the investigated cancer cells was displayed by DHP-M (4a). This may be due to the less steric hindrance offered by 4a.