Pyridine Regioisomerism and Aryl Substitution Govern the Divergent Cyclization of Isoniazid-Derived Thiosemicarbazides: Mechanistic DFT Analysis and Antimycobacterial Evaluation
- 1Department of Organic Chemistry, Medical University of Lublin, Chodzki 4A, 20-093 Lublin, Poland
- 2Department of Microbiology, National Tuberculosis and Lung Diseases Research Institute, Plocka 26, 01-138 Warsaw, Poland
- 3Institute of Applied Radiation Chemistry, Faculty of Chemistry, Lodz University of Technology, Zeromskiego 116, 90-924 Lodz, Poland
Abstract
Isoniazid is an established antitubercular pharmacophore widely used as a structural platform for developing compounds with potential activity against Mycobacterium tuberculosis. This study investigated isoniazid-derived thiosemicarbazides as precursors for the synthesis of thiazolidin-4-one derivatives, focusing on the influence of pyridine regioisomerism and aryl substitution on cyclization outcomes. Thiosemicarbazides containing 2-, 3-, or 4-pyridyl moieties and fluoro- or chloro-substituted phenyl groups were synthesized and subjected to cyclization with ethyl bromoacetate. Density functional theory (DFT) calculations were performed to compare the competing pathways leading to thiazolidin-4-one and 1,3,4-oxadiazole formation, and the resulting heterocyclic compounds were evaluated against four M. tuberculosis strains. An initial control experiment using a 2-pyridyl/2-fluorophenyl thiosemicarbazide yielded the target thiazolidin-4-one as the sole product. However, investigation of the broader substrate series revealed pronounced substrate-dependent differences in cyclization selectivity. Most substrates afforded 1,3,4-oxadiazoles, whereas 2-pyridyl thiosemicarbazides bearing ortho-fluoro or ortho-chloro substituents selectively formed thiazolidin-4-ones. DFT calculations provided an energetic rationale for the observed divergence in cyclization pathways. Despite systematic structural diversification, none of the investigated 1,3,4-oxadiazole or thiazolidin-4-one derivatives, including ester-functionalized analogues, exhibited appreciable antimycobacterial activity (MIC ≥ 512 µg/mL). These findings demonstrate that pyridine regioisomerism combined with aryl substitution strongly influences the cyclization pathways of isoniazid-derived thiosemicarbazides. However, the pronounced structure–reactivity relationship governing cyclization was not accompanied by a meaningful structure–activity relationship against Mycobacterium tuberculosis. The combined experimental and computational results provide insight into the factors governing cyclization selectivity and inform the design of future INH-derived analogues.
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BibTeX
@article{paneth2026pyridine,
title = {{Pyridine Regioisomerism and Aryl Substitution Govern the Divergent Cyclization of Isoniazid-Derived Thiosemicarbazides: Mechanistic DFT Analysis and Antimycobacterial Evaluation}},
author = {Agata Paneth and Nazar Trotsko and Agnieszka Głogowska and Ewa Augustynowicz-Kopeć and Piotr Paneth},
journal = {International Journal of Molecular Sciences},
year = {2026},
month = oct,
doi = {10.3390/ijms27219477},
url = {https://www.mdpi.com/1422-0067/27/21/9477},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Pyridine Regioisomerism and Aryl Substitution Govern the Divergent Cyclization of Isoniazid-Derived Thiosemicarbazides: Mechanistic DFT Analysis and Antimycobacterial Evaluation
AU - Agata Paneth
AU - Nazar Trotsko
AU - Agnieszka Głogowska
AU - Ewa Augustynowicz-Kopeć
AU - Piotr Paneth
PY - 2026
DA - 2026/10/23
JO - International Journal of Molecular Sciences
DO - 10.3390/ijms27219477
UR - https://www.mdpi.com/1422-0067/27/21/9477
AB - Isoniazid is an established antitubercular pharmacophore widely used as a structural platform for developing compounds with potential activity against Mycobacterium tuberculosis. This study investigated isoniazid-derived thiosemicarbazides as precursors for the synthesis of thiazolidin-4-one derivatives, focusing on the influence of pyridine regioisomerism and aryl substitution on cyclization outcomes. Thiosemicarbazides containing 2-, 3-, or 4-pyridyl moieties and fluoro- or chloro-substituted phenyl groups were synthesized and subjected to cyclization with ethyl bromoacetate. Density functional theory (DFT) calculations were performed to compare the competing pathways leading to thiazolidin-4-one and 1,3,4-oxadiazole formation, and the resulting heterocyclic compounds were evaluated against four M. tuberculosis strains. An initial control experiment using a 2-pyridyl/2-fluorophenyl thiosemicarbazide yielded the target thiazolidin-4-one as the sole product. However, investigation of the broader substrate series revealed pronounced substrate-dependent differences in cyclization selectivity. Most substrates afforded 1,3,4-oxadiazoles, whereas 2-pyridyl thiosemicarbazides bearing ortho-fluoro or ortho-chloro substituents selectively formed thiazolidin-4-ones. DFT calculations provided an energetic rationale for the observed divergence in cyclization pathways. Despite systematic structural diversification, none of the investigated 1,3,4-oxadiazole or thiazolidin-4-one derivatives, including ester-functionalized analogues, exhibited appreciable antimycobacterial activity (MIC ≥ 512 µg/mL). These findings demonstrate that pyridine regioisomerism combined with aryl substitution strongly influences the cyclization pathways of isoniazid-derived thiosemicarbazides. However, the pronounced structure–reactivity relationship governing cyclization was not accompanied by a meaningful structure–activity relationship against Mycobacterium tuberculosis. The combined experimental and computational results provide insight into the factors governing cyclization selectivity and inform the design of future INH-derived analogues.
SN - 1422-0067
ER -