Molecular docking, synthesis, and cytotoxic evaluation of novel quinazoline-quinazolinone hybrid compounds

Cancer represents a significant public health challenge and a leading cause of mortality globally. Quinazolinones represent a class of privileged structures that exhibit a broad spectrum of biological activities such as anticancer, antihypertensive, antifungal, antibacterial, and anti-inflammatory properties. In the present study, the synthesis of quinazoline-quinazolinone hybrids as anticancer agents and their cytotoxic evaluation are reported.

Initial studies were done by molecular docking of five analogs of quinazoline- quinazolinone hybrids, erlotinib, and doxorubicin against the epidermal growth factor receptor. Treatment of 3-amino quinazolinone with 4-chloro-2-phenylquinazoline afforded final compounds by the nucleophilic substitution of the chloride with the amine of 3-amino quinazolinone derivatives. The cytotoxic effects of the final compounds were determined in vitro against the MCF-7 cell line using the MTT assay.

Compound 5b (7-hydroxy-2-methyl-3-(2-phenylquinazolin-4-ylamino) quinazolin-4(3H)- one) showed the highest docking score of -10.1 kcal/mol. Additionally, compound 5d (2-methyl-7-nitro-3-(2- phenylquinazolin-4-ylamino) quinazolin-4(3H)-one) exhibited remarkable in-vitro cytotoxic activity at 100 μM against the MCF-7 cells.

In the present study, quinazoline-quinazolinone hybrids were synthesized, and their cytotoxic effects on the MCF-7 cell line were evaluated. Among them, compound 5d exhibited the most significant cytotoxic activity. The insertion of a nitro group at the 7 position of quinazolinone enhanced the cytotoxic efficacy against MCF-7 cells, likely attributable to electronic influences. Consequently, this compound could serve as a lead compound in the search for new classes of effective anticancer agents.