28IX

structure of InhA from Mycobacterium tuberculosis in complex with (E)-2-(4-(4-((4-butyl-1H-1,2,3-triazol-1-yl)methyl)-2-hydroxyphenoxy)-3-fluorobenzylidene)hydrazine-1-carbothioamide (compound 6f)

This is a non-PDB format compatible entry.

Summary for 28IX

• Entry DOI: 10.2210/pdb28ix/pdb
• Related: 28IO 28IP 28IQ 28IR 28IS 28IT 28IU 28IV 28IW 28LL 28LM
• Descriptor: Enoyl-[acyl-carrier-protein] reductase [NADH], NICOTINAMIDE-ADENINE-DINUCLEOTIDE, (E)-2-(4-(4-((4-butyl-1H-1,2,3-triazol-1-yl)methyl)-2-hydroxyphenoxy)-3-fluorobenzylidene)hydrazine-1-carbothioamide, ... (6 entities in total)
• Functional Keywords: oxidoreductase
• Biological source: Mycobacterium tuberculosis
• Total number of polymer chains: 4
• Total formula weight: 120007.20

Authors

Tamhaev, R.,Valentin, L.,Lherbet, C.,Azema-Despeyroux, J.,Mourey, L.,Maveyraud, L. (deposition date: 2026-02-02, release date: 2026-07-15)

Primary citation

Tamhaev, R.,Recchia, D.,Zahorszka, M.,Stelitano, G.,Chiarelli, L.R.,Rizet, J.,Rima, J.,Chebaiki, M.,Valentin, L.,Azema-Despeyroux, J.,Hoffmann, P.,Preuilh, N.,Dumais, B.,Britton, S.,Degiacomi, G.,Maveyraud, L.,Kordulakova, J.,Pasca, M.R.,Mourey, L.,Lherbet, C.
Rational Design of Diaryl Ether-Based Dual Inhibitors Targeting Successive Essential Enzymes HadAB and InhA in Mycobacterium tuberculosis.
J.Med.Chem., 2026

PubMed Abstract: The emergence of drug-resistant underscores the need for innovative therapeutic strategies targeting essential metabolic pathways. We designed, synthesized, and evaluated a series of dual inhibitors targeting two key enzymes of the mycobacterial FAS-II system, HadAB and InhA. Using a diaryl ether scaffold, six thiosemicarbazone derivatives and their aldehyde intermediates were prepared and tested for enzymatic and antimycobacterial activity. Thiosemicarbazone derivatives and aldehyde intermediates both strongly inhibited InhA, and the thiosemicarbazones additionally potentially inhibited HadAB through covalent interaction with the HadA subunit, supporting the dual-target approach. Several compounds showed low micromolar to submicromolar activity against drug-susceptible and clinical strains, including an -deficient mutant. Crystallographic structures of InhA-ligand complexes revealed key binding interactions and clarified inhibition mechanisms. Despite some cytotoxicity concerns, these findings provide a promising basis for developing optimized dual-target inhibitors of the FAS-II pathway.

PubMed: 42415474
DOI: 10.1021/acs.jmedchem.6c01302

Experimental method

X-RAY DIFFRACTION (1.871 Å)