Crystal structure and molecular docking studies of benzo[8]annulenes as potential inhibitors against Mycobacterium tuberculosis

Abstract

Tuberculosis is a disease caused by Mycobacterium tuberculosis. The bacterial cell wall has a characteristic low permeability, which essentially makes antibiotics ineffective. The cell wall material must be regulated so that its deposition does not compromise its structure. In this study, two new inhibitors, 2-amino-4-(4-cholorophenyl)-5,6,7,8,9,10-hexahydrobenzo[8] annulene-1,3,3(4H)-tricarbonitrile(Ia) and 2-amino-4-(4-bromophenyl)-5,6,7,8,9,10-hexahydrobenzo[8]annulene-1,3,3(4H)-tricarbonitrile(Ib) were synthesized. The crystal structures of the above compounds were determined by single crystal X-ray diffraction. The compounds C₂₁ H₁₉ Cl N₃ (Ia) and C₂₁ H₁₉ Br N₃ (Ib) were crystallized in the monoclinic and triclinic system. In both compounds, the cyclohexane ring was found to adopt a boat conformation. The cyclooctane ring of both compounds adopted a twisted chair-chair conformation.  In silico analyses revealed that both compounds showed good anti-mycobacterial activities against the enoyl-acyl carrier enzyme and the N-acetyl-gamma protein, both of which are critical for bacterial survival. Synthesis, structure determination, conformation, intra, inter-molecular interactions and docking studies of both compounds are presented herein.