Synthesis and Pharmacological Evaluation of Novel Pyrido-Quinazolinone Analogues as Potent

Abstract

The quinazolinone and pyridine nuclei are privileged scaffolds in medicinal chemistry, renowned for their diverse pharmacological profiles. Molecular hybridization of these two pharmacophores offers a promising strategy for developing novel therapeutic agents. This study describes the efficient synthesis and pharmacological evaluation of a novel series of pyrido-quinazolinone analogues. The target compounds were synthesized via a one-pot cyclocondensation reaction between 2-aminonicotinic acid, various substituted aldehydes, and ammonium acetate under optimized conditions. All synthesized compounds were characterized using spectroscopic techniques (IR, 11H NMR, 1313C NMR, and Mass Spectrometry). The chemical library was evaluated for in vitro biological activities, including anticancer activity against a panel of human cancer cell lines, antimicrobial activity against Gram-positive and Gram-negative bacteria, and anti-inflammatory activity using a COX-2 inhibition assay. Several compounds demonstrated significant and selective potency. Notably, analogue 7d bearing a p-chlorophenyl substituent emerged as the most active compound, exhibiting potent cytotoxic activity against the MCF-7 breast cancer cell line (IC₅₀ = 3.2 µM) and strong inhibition of COX-2 (IC₅₀ = 1.8 µM). Furthermore, a preliminary structure-activity relationship (SAR) was established, revealing that electron-withdrawing groups on the phenyl ring enhance biological activity. The results indicate that the pyrido-quinazolinone hybrid scaffold is a highly promising lead structure for the development of new multi-target therapeutic agents.