Synthesis, Docking Studies, and Biological Evaluation of Betti Bases as Promising Anti-tubercular Agents

Abstract

Background: The occurrence of Tuberculosis (TB) has significantly increased worldwide. The extensively drug-resistant tuberculosis (XDR-TB) and multi-drug resistant tuberculosis (MDR-TB) have made it more challenging to treat this mycobacterial infection caused by the Mycobacterium tuberculosis MTB-H37Rv strain. The present treatments for tuberculosis are of long duration and with side effects. Thus, it is necessary to discover new drugs with short-term chemotherapy, fewer health hazards, and cost effectiveness. Objective: The objective of the study was to divulge the antitubercular properties of Betti base scaffolds. Method: Betti bases were designed, synthesized 4a-4h, 6a-6h, and investigated for their in vitro antitubercular activity using Microplate Alamar Blue assay (MABA) against the MTB-H37Rv strain. Their binding affinity with amino acids was studied by performing molecular docking studies using InhA (PDB ID: 2NSD) present in the MTB-H37Rv strain. Cytotoxicity assay and neutrophil function test (NFT) were also performed. Results: The Betti bases (4a-4h, 6d) showed minimum inhibitory concentration (MIC) values ranging from 1.6 μg/mL to 6.25 μg/mL against the MTB-H37Rv strain. The compounds (4a-4h, 6a-6h) were investigated for their ADME properties and good pharmacokinetic profiles were observed. In molecular docking studies, a strong binding affinity between InhA and the compounds (4a-4h, 6a-6h) was observed, which provided theoretical insight into the inhibitory action of the synthesized compounds (4a-4h, 6a-6h) against InhA. NFT of the compounds (4a-4h, 6a-6h) showed no harmful effects on the functions of neutrophils. In vitro cytotoxicity assay against Vero cell lines revealed the non-cytotoxic behavior of the compounds. Conclusion: Betti bases can be considered to be a promising class of molecular entities that can lead to the development of new anti-tubercular leads.