Targeting Mycobacterium tuberculosis: Synthesis, in vitro and in silico evaluation of novel N1‐(benzo[d]oxazol‐2‐yl)‐N4‐arylidine compounds

The development of novel antimycobacterial agents is an urgent challenge to eradicate the increasing emergence and rapid spread of multidrug‐resistant strains. Filamentous temperature‐sensitive protein Z (FtsZ) is a crucial cell division protein. Alteration of FtsZ assembly leads to cell division inhibition and cell death. To find novel antimycobacterial agents, a series of N1‐(benzo[d]oxazol‐2‐yl)‐N4‐arylidine compounds 5a–o were synthesized. The activity of the compounds was evaluated against drug‐sensitive, multidrug‐resistant, and extensive‐drug‐resistant Mycobacterium tuberculosis. Compounds 5b, 5c, 5l, 5m, and 5o showed promising antimycobacterial activity with minimum inhibitory concentrations (MIC) in the range of 0.48–1.85 µg/mL and with low cytotoxicity against human nontumorigenic lung fibroblast WI‐38 cells. The activity of the compounds 5b, 5c, 5l, 5m, and 5o was evaluated against bronchitis causing‐bacteria. They exhibited good activity against Streptococcus pneumoniae, Klebsiella pneumoniae, Mycoplasma pneumonia, and Bordetella pertussis. Molecular dynamics simulations of Mtb FtsZ protein‐ligand complexes identified the interdomain site as the binding site and key interactions. ADME prediction indicated that the synthesized compounds have drug‐likeness. The density function theory studies of 5c, 5l, and 5n were performed to investigate E/Z isomerization. Compounds 5c and 5l are present as E‐isomers and 5n as an E/Z mixture. Our experimental outcomes provide an auspicious lead for the design of more selective and potent antimycobacterial drugs. A series of N1‐(benzo[d]oxazol‐2‐yl)‐N4‐arylidine compounds were designed, synthesized, and evaluated against Mycobacterium tuberculosis strains, as well as against different bacteria‐causing bronchitis. Cytotoxicity was evaluated against human nontumorigenic lung fibroblast cells. Molecular dynamics simulations of Mtb filamentous temperature‐sensitive protein Z protein‐ligand complexes identified the interdomain site as the binding site.