Synthesis and Cytotoxic Activity of New Pyrimido[1,2-c]quinazolines, [1,2,4]triazolo[4,3-c]quinazolines and (quinazolin-4-yl)-1H-pyrazoles Hybrids

Abstract

New hybrid compounds with functionalized quinazoline derivatives and derived tricyclic compounds with varied condensed six and five-membered ring systems were synthesized from simple compounds. The 4-quinazolinimine, 2H-pyrimido[1,2-c] quinazolin-2-one, the pyrido[1,2-c]quinazoline and the [1,2,4]triazolo[4,3-c]quinazoline systems were synthesized starting form the key 4-azido compound and its isosteric analogue; 4-hydrazinyl derivative. Furthermore, a hybrid compound incorporating varied active motifs, the substituted tricyclic structural analog; 3-oxo-2-(quinazolin-4-yl)-2,3-dihydro-1H-pyrazole derivative, in which the pyrazole ring was attached to the quinazoline system via substitution at quinazoline-C4, was also prepared. The synthesized compounds were studied for their cytotoxic activity against the human breast cancer (MCF-7) cell line. The tested compounds possess a high effect against the breast cancer cell line (MCF-7), and compounds 6b, 6e, 8, and 11 showed comparable results to those obtained for the reference drug doxorubicin. The results also showed the effect of substituents in the pyrimidoquinazoline and triazoloquinazoline ring systems on the cytotoxic activity. Additionally, the docking studies revealed that the compounds 6b, 6e, 8, and 11 bound well within the active sites of EGFRWT and EGFRT790M kinases and could be the lead molecules in the discovery of anticancer agents targeting inhibition of EGFRWT and EGFRT790M.