Synthesis of new quinazoline-isoxazole-piperazine conjugates; in vitro anticancer evaluation and in-silico molecular docking and ADMET studies

We described the synthesis of a new series of quinazoline-isoxazole-piperazine conjugates ( 7a-n ) in a one-pot synthetic method. The synthesised conjugates cytotoxicity was assessed on human breast tumour cell lines such as MCF-7 and MDA-MB231. All these compounds show moderate to better cytotoxicity. Among them, conjugates 7e (IC 50 = 3.54 ± 0.28, 4.23 ± 0.05), 7f (1.86 ± 0.03, 1.53 ± 0.02), and 7 g (2.34 ± 0.12, 1.95 ± 0.64) showed potent activity on tested cancer cell lines compared to the conventional drug Erlotinib. Moreover, in silico molecular docking studies show that these conjugates strongly interrelate and bind with the EGFR active site. Using Erlotinib as the reference drug, the potent conjugates examined for their in vitro tyrosine kinase EGFR inhibitory activities. Compared to the reference drug Erlotinib, the two conjugates 7f and 7 g have the strongest tyrosine kinase EGFR inhibitory potency. The potent conjugates 7e , 7f , and 7 g in silico pharmacokinetic profiles were calculated by using pkCSM and SWISS-ADME, and all three conjugates follow four conditions exactly (Veber rule, Egan rule, Lipinski rule, and Muegge rule), with the exception of the Ghose rule.