Shah Moksh, Patel Iva, Khona Pratik, Patel Harnisha, Yadav Mange Ram, Nagani Afzal
Parul Institute of Pharmacy, Parul University, Vadodara, Gujarat, India.
Research and Development Cell, Parul University, Vadodara, Gujarat, India.
Sci Rep. 2025 Aug 12;15(1):29586. doi: 10.1038/s41598-025-14734-1.
Tuberculosis (TB) remains a major global health challenge. This study presents the design, synthesis, and evaluation of some novel pyrazolo[3,4-b]pyridine-pyrimidone derivatives targeting Mycobacterium tuberculosis (Mtb). The compounds were assessed for anti-tubercular activity using the Microplate Alamar Blue Assay (MABA) against the Mtb H37Rv strain. Key derivatives (8 and 14) showed significant activity with minimum inhibitory concentration (MIC) values of 3.12 µg/mL, 12.5 µg/mL, respectively, comparable to the standard drugs and are nontoxic at their effective concentration as anti-TB agents. Molecular docking studies demonstrated strong binding interactions with DprE1 and Mtb-DHFR enzymes, suggesting inhibition of these critical proteins. Further computational analyses, including density functional theory (DFT) and molecular dynamics simulations, confirmed the binding stability of the compounds to the target proteins. Overall, these pyrazolo[3,4-b]pyridine-pyrimidone derivatives are potential leads for further development as future therapeutics for treating drug-resistant TB.
结核病（TB）仍然是一项重大的全球卫生挑战。本研究介绍了一些针对结核分枝杆菌（Mtb）的新型吡唑并[3,4 - b]吡啶 - 嘧啶酮衍生物的设计、合成及评估。使用微孔板阿拉玛蓝法（MABA）针对Mtb H37Rv菌株评估了这些化合物的抗结核活性。关键衍生物（8和14）显示出显著活性，最低抑菌浓度（MIC）值分别为3.12μg/mL、12.5μg/mL，与标准药物相当，并且在其作为抗结核药物的有效浓度下无毒。分子对接研究表明与DprE1和Mtb - DHFR酶有强烈的结合相互作用，表明这些关键蛋白受到抑制。包括密度泛函理论（DFT）和分子动力学模拟在内的进一步计算分析证实了化合物与靶蛋白的结合稳定性。总体而言，这些吡唑并[3,4 - b]吡啶 - 嘧啶酮衍生物是作为未来治疗耐多药结核病的潜在进一步开发先导物。
