Esma Özcan, Siva Krishna Vagolu, Rasoul Tamhaev, Christian Lherbet, Lionel Mourey, Tone Tønjum, Miyase Gözde Gündüz, Şengül Dilem Doğan
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Upon confirmation of their proposed structures by various spectral techniques, <b>IP1</b>-<b>IP13</b> were evaluated for their antimycobacterial capacity against <i>Mtb</i> H37Rv strain and INH-resistant clinical isolates with <i>katG</i> and <i>inhA</i> 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 (<b>IP7</b>-<b>IP13</b>) were promising antitubercular drug candidates, exhibiting drug-like properties and negligible cytotoxicity. Out of these, <b>IP11</b> (<i>N</i>'-(4-(4-cyclohexylpiperazin-1-yl)benzylidene)isonicotinohydrazide) emerged as the most promising derivative, demonstrating the lowest MIC values against all <i>Mtb</i> 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 <b>IP11</b> 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 <b>IP11</b> to InhA was analyzed through molecular docking and molecular dynamics simulations. 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引用次数: 0
摘要
异烟肼(异烟酸肼,INH)是用于治疗结核病(TB)的关键药物,结核病仍然是世界上最致命的传染病。然而,由于出现了对INH具有耐药性的结核分枝杆菌(Mtb)菌株,INH的疗效已经减弱。我们在这项研究中的目标是对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与内部获得的带有哌啶或哌嗪环的苯甲醛在回流乙醇中反应合成了INH基腙(IP1-IP13)。在各种光谱技术确认其结构后,利用微孔板Alamar Blue Assay (MABA)评估IP1-IP13对Mtb H37Rv菌株和具有katG和inhA突变的inh耐药临床分离株的抗菌能力。另外还测试了这些化合物的细胞毒性。所获得的数据表明,与INH (IP7-IP13)相比,具有适度增加的亲脂性的化合物是有希望的抗结核候选药物,具有药物样特性和可忽略的细胞毒性。其中,IP11 (N'-(4-(4-环己基哌嗪-1-基)苄基)异烟碱肼)是最有希望的衍生物,对所有测试的结核分枝杆菌菌株显示最低的MIC值。随后,我们评估了目标分子对InhA的主要靶酶——烯酰酰基载体蛋白还原酶(InhA)的抑制能力。除了IP11在50 μM浓度下表现出81%的InhA抑制外,研究表明直接抑制InhA不是化合物抗结核活性的主要机制。通过分子对接和分子动力学模拟分析了IP11与InhA的结合机理。总之,我们的研究确定了一种修改INH的新方法,以应对耐药结核菌株日益流行所带来的挑战。
Isoniazid-Derived Hydrazones Featuring Piperazine/Piperidine Rings: Design, Synthesis, and Investigation of Antitubercular Activity.
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 Mycobacterium tuberculosis (Mtb) 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 (IP1-IP13) 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, IP1-IP13 were evaluated for their antimycobacterial capacity against Mtb H37Rv strain and INH-resistant clinical isolates with katG and inhA 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 (IP7-IP13) were promising antitubercular drug candidates, exhibiting drug-like properties and negligible cytotoxicity. Out of these, IP11 (N'-(4-(4-cyclohexylpiperazin-1-yl)benzylidene)isonicotinohydrazide) emerged as the most promising derivative, demonstrating the lowest MIC values against all Mtb 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 IP11 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 IP11 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 Mtb strains.
BiomoleculesBiochemistry, Genetics and Molecular Biology-Molecular Biology
CiteScore
9.40
自引率
3.60%
发文量
1640
审稿时长
18.28 days
期刊介绍:
Biomolecules (ISSN 2218-273X) is an international, peer-reviewed open access journal focusing on biogenic substances and their biological functions, structures, interactions with other molecules, and their microenvironment as well as biological systems. Biomolecules publishes reviews, regular research papers and short communications. Our aim is to encourage scientists to publish their experimental and theoretical results in as much detail as possible. There is no restriction on the length of the papers. The full experimental details must be provided so that the results can be reproduced.