Design and Synthesis of Quinazolinone-Triazole Hybrids as Potent Anti-Tubercular Agents

Abstract

A straightforward and convenient methodology has been developed for the reaction of 2-aminobenzamide and carbonyls affording 2,3-dihydroquinazolin-4(1<i>H</i>)-ones using aqueous solution of [C₁₂Py][FeCl₃Br]. The developed methodology was applied for the synthesis of 25 quinazolinone-triazole hybrids followed by evaluation of their <i>in vitro</i> anti-tubercular (TB) activity. The results revealed that 8 quinazolinone-triazole hybrids displayed promising activity having MIC values of 0.78-12.5 <i>μ</i>g/mL. The compound <b>3if</b> with MIC 0.78 <i>μ</i>g/mL was found to be the lead nominee among the series, better than Ethambutol, a first line anti-TB drug and comparable with Rifampicin. The active compounds with MIC values ≤ 6.25 <i>μ</i>g/mL were subjected to <i>in vitro</i> cytotoxicity and found nontoxic. In drug-drug interaction, compounds <b>3ia</b> and <b>3ii</b> interacted synergistically with all the three anti-TB drugs, INH, RFM, and EMB. Other 3 compounds interacted either in synergistic or additive manners. Important information on the binding interaction of the target compounds with the active sites of 1DQY Antigen 85C from <i>Mycobacterium tuberculosis</i> and Enoyl acyl carrier protein reductase (InhA) enzymes was obtained from molecular docking studies. Screening of the drug-likeness properties and bioactivity score indicates that synthesized molecules could be projected as potential drug candidates. Based on the current study, quinazolinone-triazole hybrids framework can be useful in drug development for TB.