28IT

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

これはPDB形式変換不可エントリーです。

28IT の概要

• エントリーDOI: 10.2210/pdb28it/pdb
• 関連するPDBエントリー: 28IO 28IP 28IQ 28IR 28IS 28IU 28IV 28IW 28IX 28LL 28LM
• 分子名称: Enoyl-[acyl-carrier-protein] reductase [NADH], NICOTINAMIDE-ADENINE-DINUCLEOTIDE, (E)-2-(4-(4-((4-cyclopropyl-1H-1,2,3-triazol-1-yl)methyl)-2-hydroxyphenoxy)benzylidene)hydrazine-1-carbothioamide, ... (5 entities in total)
• 機能のキーワード: enoyl-acp-reductase type ii fatty acid synthase mycolic acids tuberculosis therapeutic target oxidoreductase, oxidoreductase
• 由来する生物種: Mycobacterium tuberculosis
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 30211.33

構造登録者

Tamhaev, R.,Lherbet, C.,Azema-Despeyroux, A.,Maveyraud, L.,Mourey, L. (登録日: 2026-02-02, 公開日: 2026-07-15)

主引用文献

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

実験手法

X-RAY DIFFRACTION (1.514 Å)