Novel diaryl ether derivatives as InhA inhibitors: Design, synthesis and antimycobacterial activity

Discovery of new diaryl ether inhibitors against Mycobacterium tuberculosis targeting the minor portal of InhA

“…The second TCL molecule (TCL2) binds to the remaining part of the substrate-binding site in a rather hydrophobic region close to the minor portal. This spatial configuration of TCL1 and TCL2, which underlines the size of the InhA binding site, has been exploited to further develop TCL-based inhibitors of the enzyme [5,7,20,21,[23][24][25][26][27][30][31][32][33]. In the resolved structures of InhA complexes with TCL derivatives, the diaryl ether moiety systematically binds in the same position as TCL1 whereas the various chemical substituents, at position 5 of the A ring, reach the space occupied by the TCL2 A ring (Fig.…”

Protein targets in Mycobacterium tuberculosis and their inhibitors for therapeutic implications: A narrative review

“…Diphenyl ethers, a novel direct inhibitor of InhA work similarly to the mechanism of action of TCN [29]. Abdelaziz et al 2022, have explored TCN as an inhibitor for enoyl acyl carrier protein reductase InhA enzyme in susceptible and resistant Mtb strains [32].…”