CADD-guided design of novel triclosan–hydrazone hybrids with antibacterial and antimycobacterial activity as InhA inhibitors
Abstract
The development of new antitubercular agents targeting essential enzymes of Mycobacterium tuberculosis remains a critical priority due to the global rise of drug-resistant tuberculosis. In this study, a series of triclosan-inspired hydrazone hybrids was designed to explore whether incorporation of a hydrazone linker into the diphenyl ether scaffold could generate compounds with antibacterial and antimycobacterial activity while maintaining potential interaction with the enoyl-ACP reductase InhA. Sixteen derivatives were synthesized through a three-step synthetic route starting from triclosan and were structurally characterized by ¹H NMR, ¹³C NMR, HRMS, FT-IR, and HPLC analysis. Molecular docking and molecular dynamics simulations were performed to investigate the potential interaction of the compounds with both holo and apo forms of InhA. Among the series, compounds 3g and 3j displayed docking poses most comparable to triclosan and showed stable interaction patterns during molecular dynamics simulations. Microbiological evaluation revealed selective antibacterial activity against Gram-positive bacteria, while Gram-negative strains remained largely insensitive. The most active compound against Staphylococcus epidermidis ATCC 12228 was 3i (MIC = 1 μg/mL). In antimycobacterial assays against M. tuberculosis H37Rv, compounds 3f and 3m demonstrated the most potent activity (MIC = 6.25 μg/mL). Enzymatic assays showed moderate inhibition of InhA for compounds 3g and 3j (≤56% inhibition at 50 μM), suggesting that these derivatives can interact with the enzyme, although InhA inhibition alone may not fully account for the observed whole-cell activity. Overall, the results indicate that triclosan–hydrazone hybrids represent a synthetically accessible scaffold capable of producing compounds with measurable antibacterial and antimycobacterial activity. While the removal of the phenolic hydroxyl group reduced direct InhA inhibition compared with triclosan, the present study highlights the potential of this scaffold for further optimization toward improved enzyme binding, physicochemical properties, and antimycobacterial potency.
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BibTeX
@article{birgul2026caddguided,
title = {{CADD-guided design of novel triclosan–hydrazone hybrids with antibacterial and antimycobacterial activity as InhA inhibitors}},
author = {Kaan Birgül and Bahadır Bülbül and Serap İpek Dingiş Birgül and Göknil Pelin Coşkun Şahin and Antonio Curcio and Cansu Vatansever and Rasoul Tamhaev and Dhanji Rajani and Christian Lherbet and Lionel Mourey and Stefano Alcaro and Andrea Brancale},
journal = {Journal of Molecular Structure},
year = {2026},
month = sep,
doi = {10.1016/j.molstruc.2026.146063},
url = {https://hal.science/hal-05763183v1},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - CADD-guided design of novel triclosan–hydrazone hybrids with antibacterial and antimycobacterial activity as InhA inhibitors
AU - Kaan Birgül
AU - Bahadır Bülbül
AU - Serap İpek Dingiş Birgül
AU - Göknil Pelin Coşkun Şahin
AU - Antonio Curcio
AU - Cansu Vatansever
AU - Rasoul Tamhaev
AU - Dhanji Rajani
AU - Christian Lherbet
AU - Lionel Mourey
AU - Stefano Alcaro
AU - Andrea Brancale
PY - 2026
DA - 2026/09/28
JO - Journal of Molecular Structure
DO - 10.1016/j.molstruc.2026.146063
UR - https://hal.science/hal-05763183v1
AB - The development of new antitubercular agents targeting essential enzymes of Mycobacterium tuberculosis remains a critical priority due to the global rise of drug-resistant tuberculosis. In this study, a series of triclosan-inspired hydrazone hybrids was designed to explore whether incorporation of a hydrazone linker into the diphenyl ether scaffold could generate compounds with antibacterial and antimycobacterial activity while maintaining potential interaction with the enoyl-ACP reductase InhA. Sixteen derivatives were synthesized through a three-step synthetic route starting from triclosan and were structurally characterized by ¹H NMR, ¹³C NMR, HRMS, FT-IR, and HPLC analysis. Molecular docking and molecular dynamics simulations were performed to investigate the potential interaction of the compounds with both holo and apo forms of InhA. Among the series, compounds 3g and 3j displayed docking poses most comparable to triclosan and showed stable interaction patterns during molecular dynamics simulations. Microbiological evaluation revealed selective antibacterial activity against Gram-positive bacteria, while Gram-negative strains remained largely insensitive. The most active compound against Staphylococcus epidermidis ATCC 12228 was 3i (MIC = 1 μg/mL). In antimycobacterial assays against M. tuberculosis H37Rv, compounds 3f and 3m demonstrated the most potent activity (MIC = 6.25 μg/mL). Enzymatic assays showed moderate inhibition of InhA for compounds 3g and 3j (≤56% inhibition at 50 μM), suggesting that these derivatives can interact with the enzyme, although InhA inhibition alone may not fully account for the observed whole-cell activity. Overall, the results indicate that triclosan–hydrazone hybrids represent a synthetically accessible scaffold capable of producing compounds with measurable antibacterial and antimycobacterial activity. While the removal of the phenolic hydroxyl group reduced direct InhA inhibition compared with triclosan, the present study highlights the potential of this scaffold for further optimization toward improved enzyme binding, physicochemical properties, and antimycobacterial potency.
SN - 0022-2860
SN - 0022-2860
ER -