Synthesis of isoniazid analogs with promising antituberculosis activity and bioavailability: Biological evaluation and computational studies

Abstract

A series of aliphatic isoniazid carbo(x/thio)amides has been synthesized by a facile one-pot green method in aqueous media by harnessing microwave irradiations. In vitro antitubercular screening of the synthesized compounds against Mycobacterium tuberculosis H37Rv (MTB strain) reveals promising antimycobacterial potential with MIC in the range of 1 to 4 µg/ml. A computational approach comprising DFT modeling, molecular docking and ADMET analysis was executed to elucidate the chemical nature, binding affinity and ADMET efficacy of the lead compounds. The docking of synthesized analogs with InhA displays weak binding interactions with the receptor and the absence of important interactions specific to direct inhibitors. However, the docking results illustrate notable binding affinity of the synthesized molecules with the KatG receptor 1SJ2 and compounds 3h and 3e showed the best docking scores (-7.2 and -6.8 kcal/mol, respectively) indicating the KatG mediated mechanism of InhA inhibition similar to isoniazid. In silico ADMET analysis of the title compounds indicate their outstanding pharmacokinetic proficiency and lower toxicity than isoniazid. The bioavailability radar further illustrates their exemplary oral availability and drug-likeliness.