SYNTHESIS, IN VITRO BIOLOGICAL EVALUATION AND IN SILICO MOLECULAR DOCKING STUDIES OF SOME NOVEL DIHYDROPYRIMIDONES AS POTENTIAL CYTOTOXIC AGENTS

The major challenge in modern drug discovery has been the design and development of new anticancer drugs with improved efficacy and minimal side effects, especially due to a rapid rise in multidrug resistant tumors. In the recent past, United States Food & Drug Administration (US FDA) newly approved anticancer drugs such as Gefitinib (Iressa), Erlotinib (Tarceva), Lapatinib (Tykerb) and Vandetanib (Caprelsa) possess a pyrimidine nucleus as core moiety exert multiple mechanisms of action. Therefore in the present investigation, we have synthesised a series of pyrimidines (dihydropyrimidones) TVD, TVD1-4 and evaluated thier potential as anticancer agents by using in vitro brine shrimp (Artemia salina) cytotoxicity bioassay. Among the compounds tested, compound TVD4 has showed signifcant cytotoxicity at ED₅₀ value 3.11 ± 0.15 mg/mL. Consequently, in silico molecular docking studies have also been performed to evaluate the possible underlying mechanism of action of TVD4 against DHFR (Dihydrofolate reductase) anticancer drug target. Molecular docking results revealed that the TDV4 is less selective towards inhibition of DHFR.

Keywords:  Cancer, US FDA, Pyrimidine, Dihydropyrimidone, Brine shrimp lethality, Molecular docking, Dihydrofolate reductase (DHFR)