Rational Design of Diaryl Ether-Based Dual Inhibitors Targeting Successive Essential Enzymes HadAB and InhA in Mycobacterium tuberculosis
Abstract
The emergence of drug-resistant Mycobacterium tuberculosis 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 M. tuberculosis strains, including an ethA-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 M. tuberculosis FAS-II pathway.
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BibTeX
@article{tamhaev2026rational,
title = {{Rational Design of Diaryl Ether-Based Dual Inhibitors Targeting Successive Essential Enzymes HadAB and InhA in Mycobacterium tuberculosis}},
author = {Rasoul Tamhaev and Deborah Recchia and Monika Záhorszká and Giovanni Stelitano and Laurent Robert Chiarelli and Julien Rizet and Julie Rima and Mélina Chebaiki and Lorena Valentin and Joëlle Azéma-Despeyroux and Pascal Hoffmann and Nadège Preuilh and Bastien Dumais and Sébastien Britton and Giulia Degiacomi and Laurent Maveyraud and Jana Korduláková and Maria Rosalia Pasca and Lionel Mourey and Christian Lherbet},
journal = {Journal of Medicinal Chemistry},
year = {2026},
month = sep,
doi = {10.1021/acs.jmedchem.6c01302},
url = {https://hal.science/hal-05763198v1},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Rational Design of Diaryl Ether-Based Dual Inhibitors Targeting Successive Essential Enzymes HadAB and InhA in Mycobacterium tuberculosis
AU - Rasoul Tamhaev
AU - Deborah Recchia
AU - Monika Záhorszká
AU - Giovanni Stelitano
AU - Laurent Robert Chiarelli
AU - Julien Rizet
AU - Julie Rima
AU - Mélina Chebaiki
AU - Lorena Valentin
AU - Joëlle Azéma-Despeyroux
AU - Pascal Hoffmann
AU - Nadège Preuilh
AU - Bastien Dumais
AU - Sébastien Britton
AU - Giulia Degiacomi
AU - Laurent Maveyraud
AU - Jana Korduláková
AU - Maria Rosalia Pasca
AU - Lionel Mourey
AU - Christian Lherbet
PY - 2026
DA - 2026/09/28
JO - Journal of Medicinal Chemistry
DO - 10.1021/acs.jmedchem.6c01302
UR - https://hal.science/hal-05763198v1
AB - The emergence of drug-resistant Mycobacterium tuberculosis 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 M. tuberculosis strains, including an ethA-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 M. tuberculosis FAS-II pathway.
SN - 0022-2623
SN - 1520-4804
ER -