Özcan Esma, Vagolu Siva Krishna, Tamhaev Rasoul, Lherbet Christian, Mourey Lionel, Tønjum Tone, Gündüz Miyase Gözde, Doğan Şengül Dilem
Department of Basic Sciences, Faculty of Pharmacy, Erciyes University, 38039 Kayseri, Turkey.
Unit for Genome Dynamics, Department of Microbiology, University of Oslo, 0316 Oslo, Norway.
Biomolecules. 2025 Sep 11;15(9):1305. doi: 10.3390/biom15091305.
Isoniazid (isonicotinic acid hydrazide, INH) is a key drug used to treat tuberculosis (TB), which continues to be the world's most lethal infectious disease. Nevertheless, the efficacy of INH has diminished because of the emergence of () strains that are resistant to INH. Our goal in this study was to modify INH to reduce this significant resistance chemically. We synthesized INH-based hydrazones (-) through the reaction of INH with in-house obtained benzaldehydes carrying a piperidine or piperazine ring in refluxing ethanol. Upon confirmation of their proposed structures by various spectral techniques, - were evaluated for their antimycobacterial capacity against H37Rv strain and INH-resistant clinical isolates with and mutations using the Microplate Alamar Blue Assay (MABA). The compounds were additionally tested for their cytotoxicity. The obtained data indicated that the compounds with moderately increased lipophilicity compared to INH (-) were promising antitubercular drug candidates, exhibiting drug-like properties and negligible cytotoxicity. Out of these, ('-(4-(4-cyclohexylpiperazin-1-yl)benzylidene)isonicotinohydrazide) emerged as the most promising derivative, demonstrating the lowest MIC values against all strains tested. Subsequently, the target molecules were evaluated for their capacity to inhibit enoyl acyl carrier protein reductase (InhA), the main target enzyme of INH. Except for demonstrating 81% InhA inhibition at a concentration of 50 μM, direct InhA inhibition was shown not to be the primary mechanism responsible for the antitubercular activity of the compounds. The binding mechanism of to InhA was analyzed through molecular docking and molecular dynamics simulations. Altogether, our research identified a novel approach to modify INH to address the challenges posed by the rising prevalence of drug-resistant strains.
异烟肼（异烟酸酰肼，INH）是治疗结核病（TB）的关键药物，结核病仍是全球最致命的传染病。然而，由于对INH耐药的（）菌株的出现，INH的疗效已经降低。我们在本研究中的目标是对INH进行修饰，以化学方式降低这种显著的耐药性。我们通过INH与在回流乙醇中自行制备的带有哌啶或哌嗪环的苯甲醛反应，合成了基于INH的腙（-）。在用各种光谱技术确认其推测结构后，使用微孔板Alamar蓝测定法（MABA）评估了-对H37Rv菌株以及具有和突变的INH耐药临床分离株的抗分枝杆菌能力。此外，还测试了这些化合物的细胞毒性。获得的数据表明，与INH相比亲脂性适度增加的化合物（-）是有前景的抗结核药物候选物，具有类药物性质且细胞毒性可忽略不计。其中，（'-(4-(4-环己基哌嗪-1-基)亚苄基)异烟酰肼）成为最有前景的衍生物，对所有测试的菌株显示出最低的MIC值。随后，评估了目标分子抑制烯酰酰基载体蛋白还原酶（InhA）的能力，InhA是INH的主要靶酶。除了在50μM浓度下显示出81%的InhA抑制作用外，直接的InhA抑制并非这些化合物抗结核活性的主要作用机制。通过分子对接和分子动力学模拟分析了与InhA的结合机制。总之，我们的研究确定了一种修饰INH的新方法，以应对耐药菌株患病率上升带来的挑战。
