Synthesis, antitubercular profile and molecular docking studies of quinazolinone-based pyridine derivatives against drug-resistant tuberculosis

Abstract

The promising quinazolinone-based pyridine derivatives (4a-j) were synthesized and subsequently tested for their antimycobacterial activities against the various drug-sensitive and drug-resistant Mycobacterium tuberculosis (Mtb) strains to combat infectious diseases and address growing concerns about the devastating effects of tuberculosis (TB). Utilizing H-1 NMR, C-13 NMR, and mass spectra, the structural and molecular confirmation of the synthesized compounds were deciphered. With minimum inhibitory concentration (MIC) values ranging from 0.31 to 19.13 mu M, the results showed that compounds 4e and 4f showed promise anti-TB action against both drug-sensitive and drug-resistant TB strains. To study the cytotoxicity of synthesized molecules, normal Vero and mouse macrophage (RAW264.7) cell lines were utilized. Remarkably, it was revealed that at the highest concentration tested, none of the newly synthesized molecules were toxic to the Vero cell line. The binding patterns of the potent compounds 4b, 4e and 4f in the active site of the mycobacterial membrane protein Large 3 (MmpL3) protein are also revealed by molecular docking studies, which has contributed to the development of a structural rationale for Mtb inhibition. The physicochemical characteristics of the compounds were then predicted using theoretical calculations. Overall, the molecular docking results, physiochemical properties, and observed antimycobacterial activity all point to compound 4e with trifluoromethyl and compound 4f with nitro moiety as potential quinazolinone linked pyridine-based MmpL3 inhibitors.