Synthesis of anticancer agents: molecular docking and ADME studies of new hydropyrimidine linked amide-pyridine...

To develop novel hydropyrimidine linked amide-pyridine hybrids as anticancer agents.

An array of molecular hybrids 6a-6n has been synthesized and evaluated for their in vitro cytotoxicity against breast (MCF-7, MDA-MB-231), pancreatic (AsPC-1, BxPC-3, SW1990), and normal cell lines (HEK-293, MRC-5, and MCF-10A). Further, in silico absorption, distribution, metabolism, and excretion (ADME), docking, molecular dynamics (MD) simulation and density functional theory (DFT) studies of potent hybrids were executed.

Hybrids 6i and 6l showed enhanced activity against breast cancer cells with IC₅₀ between 6.15 ± 0.39 and 41.82 ± 4.94 µM, while 6m exhibited enhanced activity against both breast and pancreatic cancer cells with IC₅₀ between 8.72 ± 0.64 and 36.24 ± 3.34 µM (p < 0.05, three independent biological replicates). Against breast cancer cells, 6m displayed ~3-fold superior activity than 5-fluorouracil while against pancreatic cancer cells, it exhibited comparable to superior activity. Further, 6m selectively targets cancer cells over normal cells considerably, binds well with thymidylate synthase (-8.8 kcal·mol^-1) and forms stable complex as revealed from docking and MD simulations. ADME analysis proposes favorable features for good oral bioavailability.

This study ascertains 6m as a promising lead for further biological evaluation and structural optimization toward the development of potential anticancer agents against pancreatic and breast cancers.