A rapid construction of 4(3H)-quinazolinone and related ring under ultrasound irradiation: In silico/in vitro studies of compounds synthesized

Abstract

Because of importance of the quinazolinone framework particularly in medicinal and pharmaceutical chemistry efforts have been devoted to establish convenient methods for the synthesis of quinazolinone derivatives. Due to our interest in this class of compounds as potential inhibitor chorismate mutase (MtbCM), a known target for the identification of anti-tubercular agents we report the rapid construction of 4(3H)-quinazolinone ring under ultrasound irradiation. The current sonochemical approach involved an iodine mediated reaction of 2-aminobenzamide or its derivatives with readily available alcohols in aqueous DMSO under ultrasound. A series of 4(3H)-quinazolinone derivatives were prepared where substituents like aryl or heteroaryl ring or an alkyl or styryl moiety can be present at the C-2 position of the product. The analogues of quinazolinone such as pteridin-4(3H)-one and pyrido[2,3-d]pyrimidin-4(3H)-one derivatives were also prepared using this sonochemical approach. Generally, a good yield of product was obtained when the C-2 substituent of the product was an arene moiety whereas the yield was acceptable to moderate in rest of the cases. The use of milder condition, inexpensive iodine as well as aqueous media and shorter duration seemed to be key features of this methodology. The in silico docking studies indicated 3d, 3n and 3u as possible inhibitors that showed H-bonding with the residues ASP69 and GLU106 and a common pi-alkyl interaction with the critical dimer interface residue ARG103 of MtbCM. When tested in vitro against MtbCM these compounds exhibited good activities (> 50% inhibition). The brief Structure-Activity-Relationship (SAR) study indicated beneficial effects of the C-2 substituent in the order benzene > pyridine > indole ring.