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Updated: Jul 9, 2026
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System for Efficacy and Cytotoxicity Screening of Inhibitors Targeting Intracellular Mycobacterium tuberculosis
Published on: April 5, 2017
Rational Design of Diaryl Ether-Based Dual Inhibitors Targeting Successive Essential Enzymes HadAB and InhA in
Rasoul Tamhaev1,2, Deborah Recchia3, Monika Záhorszká4
1Univ Toulouse, CNRS, SPCMIB, 31062 Toulouse, France.
Journal of Medicinal Chemistry
|July 8, 2026
Summary
New dual inhibitors targeting the Mycobacterium tuberculosis FAS-II pathway show promise. These compounds inhibit key enzymes HadAB and InhA, offering a potential strategy against drug-resistant tuberculosis.
Area of Science:
- Medicinal Chemistry
- Microbiology
- Structural Biology
Background:
- Drug-resistant tuberculosis demands novel therapies targeting essential metabolic pathways.
- The fatty acid synthesis II (FAS-II) system in Mycobacterium tuberculosis is a validated target for antimycobacterial drugs.
Purpose of the Study:
- To design, synthesize, and evaluate novel dual inhibitors targeting the HadAB and InhA enzymes within the M. tuberculosis FAS-II pathway.
- To explore the potential of a diaryl ether scaffold for developing dual-target inhibitors.
Main Methods:
- Synthesis of six thiosemicarbazone derivatives and their aldehyde intermediates.
- Enzymatic assays to determine inhibition of HadAB and InhA.
- Antimycobacterial activity testing against susceptible and resistant M. tuberculosis strains.
- Crystallographic studies to elucidate binding interactions and inhibition mechanisms.
Main Results:
- Thiosemicarbazone derivatives and aldehyde intermediates effectively inhibited InhA.
- Thiosemicarbazones demonstrated potential inhibition of HadAB via covalent interaction with the HadA subunit.
- Several compounds exhibited low micromolar to submicromolar activity against various M. tuberculosis strains, including an ethA-deficient mutant.
- Crystallographic data provided insights into enzyme-ligand interactions and inhibition mechanisms.
Conclusions:
- The developed compounds show potential as dual-target inhibitors of the M. tuberculosis FAS-II pathway.
- The findings support the dual-target strategy for combating drug-resistant tuberculosis.
- Further optimization is warranted to address cytotoxicity concerns and enhance therapeutic efficacy.
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