Pyridine-3-Carboxamide–1,3,4-Thiadiazole Hybrids as Antimicrobial Agents: Synthesis, Biological Evaluation, In Vivo Toxicity, and Computational Studies
7 affiliations
- 1Department of Medicinal Chemistry, Faculty of Pharmacy, Wroclaw Medical University, Borowska 211, 50-556 Wroclaw, Poland
- 2Faculty of Chemistry, University of Wroclaw, F. Joliot-Curie 14, 50-383 Wroclaw, Poland
- 3Platform for Unique Models Application, Department of Translational Technologies, Faculty of Pharmacy, Wroclaw Medical University, Borowska 211, 50-556 Wroclaw, Poland
- 4College of Life Sciences and Medicine, Zhejiang Sci-Tech University, Hangzhou 310018, China
- 5Department of Pharmaceutical, Organic and Bioorganic Chemistry, Danylo Halytsky Lviv National Medical University, Pekarska 69, 79010 Lviv, Ukraine
- 6Molecular Design Center, Danylo Halytsky Lviv National Medical University, Pekarska 69, 79010 Lviv, Ukraine
- 7Department of Biotechnology and Cell Biology, Medical College, University of Information Technology and Management in Rzeszow, Sucharskiego 2, 35-225 Rzeszow, Poland
Abstract
The rapid emergence of antimicrobial resistance necessitates the development of novel antimicrobial agents with improved efficacy and favorable safety profiles. In this study, a new series of pyridine-3-carboxamide–1,3,4-thiadiazole hybrids and their corresponding N-Mannich bases bearing structurally diverse piperazine substituents were designed, synthesized, and characterized by FT-IR, 1H/13C NMR, and HR-MS. Their antimicrobial activity was evaluated against reference and clinical bacterial and fungal strains using broth microdilution and agar diffusion assays. The compounds exhibited selective activity against Gram-positive bacteria, with minimum inhibitory concentrations of 0.034–0.069 mg/mL against Staphylococcus aureus ATCC 33591 and bactericidal effects reflected by MBC values comparable to MICs. No activity was observed against Pseudomonas aeruginosa or Candida albicans, and the compounds were ineffective in eradicating preformed staphylococcal biofilms. In vivo toxicity studies using the Galleria mellonella model indicated no-to-low apparent acute toxicity under the applied experimental conditions for most derivatives. DFT and QTAIM analyses revealed substituent-dependent electronic and conformational differences, while molecular docking identified DNA gyrase as the most likely molecular target, with compounds 6 and 7 showing the strongest predicted binding. These results identify pyridine-3-carboxamide–1,3,4-thiadiazole Mannich bases as promising leads for developing new antibacterial agents against Gram-positive pathogens.
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BibTeX
@article{swiatek2026pyridine3carboxamide134thiadiazole,
title = {{Pyridine-3-Carboxamide–1,3,4-Thiadiazole Hybrids as Antimicrobial Agents: Synthesis, Biological Evaluation, In Vivo Toxicity, and Computational Studies}},
author = {Piotr Świątek and Małgorzata Strzelecka and Łukasz Szczukowski and Aneta Jezierska and Jarosław J. Panek and Adam Junka and Aleksandra Woytoń and Roman Lesyk and Teresa Glomb},
journal = {Molecules},
year = {2026},
month = oct,
doi = {10.3390/molecules31203700},
url = {https://www.mdpi.com/1420-3049/31/20/3700},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Pyridine-3-Carboxamide–1,3,4-Thiadiazole Hybrids as Antimicrobial Agents: Synthesis, Biological Evaluation, In Vivo Toxicity, and Computational Studies
AU - Piotr Świątek
AU - Małgorzata Strzelecka
AU - Łukasz Szczukowski
AU - Aneta Jezierska
AU - Jarosław J. Panek
AU - Adam Junka
AU - Aleksandra Woytoń
AU - Roman Lesyk
AU - Teresa Glomb
PY - 2026
DA - 2026/10/01
JO - Molecules
DO - 10.3390/molecules31203700
UR - https://www.mdpi.com/1420-3049/31/20/3700
AB - The rapid emergence of antimicrobial resistance necessitates the development of novel antimicrobial agents with improved efficacy and favorable safety profiles. In this study, a new series of pyridine-3-carboxamide–1,3,4-thiadiazole hybrids and their corresponding N-Mannich bases bearing structurally diverse piperazine substituents were designed, synthesized, and characterized by FT-IR, 1H/13C NMR, and HR-MS. Their antimicrobial activity was evaluated against reference and clinical bacterial and fungal strains using broth microdilution and agar diffusion assays. The compounds exhibited selective activity against Gram-positive bacteria, with minimum inhibitory concentrations of 0.034–0.069 mg/mL against Staphylococcus aureus ATCC 33591 and bactericidal effects reflected by MBC values comparable to MICs. No activity was observed against Pseudomonas aeruginosa or Candida albicans, and the compounds were ineffective in eradicating preformed staphylococcal biofilms. In vivo toxicity studies using the Galleria mellonella model indicated no-to-low apparent acute toxicity under the applied experimental conditions for most derivatives. DFT and QTAIM analyses revealed substituent-dependent electronic and conformational differences, while molecular docking identified DNA gyrase as the most likely molecular target, with compounds 6 and 7 showing the strongest predicted binding. These results identify pyridine-3-carboxamide–1,3,4-thiadiazole Mannich bases as promising leads for developing new antibacterial agents against Gram-positive pathogens.
SN - 1420-3049
ER -