Investigation of Potent Anti-Mycobacterium tuberculosis Agents Derived from Pyridine Derivatives Targeting the Enoyl Acyl Carrier Protein Reductase (InhA): Design, Synthesis, and Computational Analysis

Ahmed Sabt,1 Małgorzata Korycka-Machala,2 Asmaa F Kassem,3 Ninh The Son,4 Nguyen Xuan Ha,4 Anna Brzostek,2 Mohamed G Thabit,5 Malwina Kawka,6 Bożena Dziadek,6 Abdelsamed I Elshamy,1 Ahmed M Atwa,7,8 Jarosław Dziadek2 1Chemistry of Natural Compounds Department, Pharmaceutical and Drug Industries Research Institute, National Research Centre, Cairo, 12622, Egypt; 2Laboratory of Genetics and Physiology of Mycobacterium, Institute of Medical Biology of the Polish Academy of Sciences, Lodz, Poland; 3Department of Chemistry, College of Science and Humanities in Al-Kharj, Prince Sattam Bin Abdulaziz University, Al-Kharj, Saudi Arabia; 4Institute of Chemistry, Vietnam Academy of Science and Technology, Hanoi, 10000, Vietnam; 5Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Pharos University (PUA), Alexandria, Egypt; 6Department of Molecular Microbiology, Faculty of Biology and Environmental Protection, University of Lodz, Lodz, Poland; 7College of Pharmacy, Al-Ayen Iraqi University, AUIQ, An Nasiriyah, Iraq; 8Department of Pharmacology and Toxicology, Faculty of Pharmacy, Egyptian Russian University, Cairo, 11829, EgyptCorrespondence: Ahmed Sabt, Email sabt.nrc@gmail.com Jarosław Dziadek, Email jdziadek@cbm.pan.plIntroduction: Tuberculosis is a very complicated disease because of how the TB bacteria behaves in the human body. This makes it hard to diagnose, treat, and control. Because of this, the World Health Organization’s latest reports show that there are still very few good treatment options for drug-resistant TB.Methods: A novel series of pyridine-derived compounds were rationally designed and synthesized to evaluate their potential as antitubercular agents. These derivatives were specifically developed to target the enoyl acyl carrier protein reductase (InhA), and molecular docking studies were performed to predict binding modes with InhA.Results: All compounds exhibited notable antitubercular activity, with minimum inhibitory concentrations (MIC) ranging from 0.5 to 2.0 μg mL− 1 against Mycobacterium tuberculosis H37Rv.Discussion: Derivative 6 was the most potent compound (MIC: 0.5 μg mL− 1), inhibiting intracellular bacteria, disrupting biofilms, and potently targeting InhA (IC50: 0.36 μM). Its pyridine-thiazole scaffold was key for stable binding, as shown by molecular modeling.Keywords: pyridine, thiazole derivatives, Mycobacterium tuberculosis, InhA enzyme, docking and molecular dynamics