Wang resin mediated unexpected greener access to 2-substituted quinazoline-4(3H)-ones and their evaluation against chorismate mutase

Abstract

In spite of reported study on MtbCM inhibitory potential of 2,3-dihydroquinazolin-4(1H)-ones the evaluation of quinazolin-4(1H)-ones for the same purpose remained unexplored. This prompted us to synthesize and evaluate quinazolin-4(1H)-ones against MtbCM, a pharmacological target for the identification of potential anti-tubercular agents. During our synthesis effort we observed that the use of excess of Wang-OSO₃H (20% w/w) could afford quinazolin-4(1H)-ones as the only product via the corresponding 2,3-dihydro derivatives. Thus an eco-friendly synthesis of 2-substituted quinazolin-4(1H)-ones was achieved via the reaction of 2-aminobenzamide with aldehydes in the presence of Wang-OSO₃H using water as the reaction media. While, recovery and reusability of Wang-OSO₃H was demonstrated, the milder conditions, shorter reaction time, metal and additional oxidant-free reaction are the other features of the current methodology. Having synthesized a range of desired products in good to excellent (> 80%) yield the in vitro testing of these compounds was performed when three of them showed > 50% inhibition at 30 µM. According to the SAR analysis, the nature and type of C-2 substituent played a key role in the inhibition of MtbCM. In general, an aryl or heteroaryl ring was favored over the alkyl moiety at the C-2 position. Among the aryl or heteroaryl group, the suitably substituted benzene ring or a 2-thienyl ring was preferred. The in silico docking of these compounds into MtbCM showed their interactions with some of the critical residues such as ARG49, ARG134, LYS60, GLU109 and GLN76 and their binding orientation similar to TSA. With the IC₅₀ value 15.16 ± 0.58, 14.47 ± 0.91 and 11.43 ± 0.25 µM against MtbCM, the compound 3a, 3b and 3c was also predicted to show favorable ADME or pharmacokinetic properties.