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. We described the synthesis of a new series of quinazoline-isoxazole-piperazine conjugates ( 7a-n ) in a one-pot synthetic method. We evaluated the cytotoxicity against breast cancer cell lines such as MCF-7 and MDA-MB231, and the results indicate that the conjugates 7e , 7f , and 7 g exhibit higher activity. Moreover, in silico molecular docking studies show that these conjugates strongly interact and bind with the EGFR active site. We further examined the potent conjugates for their in vitro tyrosine kinase EGFR inhibitory activities. The two conjugates, 7f and 7 g, have the strongest tyrosine kinase EGFR inhibitory potency. We calculated the in silico pharmacokinetic profiles of the potent conjugates 7e , 7f , and 7 g using SWISS-ADME and pkCSM, and found that all three conjugates exactly follow four conditions (Lipinski rule, Veber rule, Egan rule, and Muegge rule), except for the Ghose rule. • We report the synthesis of new quinazoline-isoxazole-piperazine conjugates in a one-pot method. • In vitro anti-proliferative activity: conjugates 7e, 7f, and 7 g were more effective than the standard drug Erlotinib against human breast cancer cell lines like MCF-7 and MDA-MB231 in stopping cell growth. • In silico molecular docking studies show that 7e , 7f , and 7 g conjugates strongly interrelate and bind with the EGFR active site. • In vitro tyrosine kinase EGFR inhibitory results: two conjugates, 7f and 7 g, show the strongest tyrosine kinase EGFR inhibitory potency.