Suresh Ayyadurai J, Nandini Sivashankar, Sangeetha Krishnanmurthy, Dhivya Loganathan S, Surya Parakkot R
Department of Pharmaceutical Chemistry, College of Pharmacy, Madras Medical College, Affiliated to "The Tamil Nadu Dr. M.G.R Medical University" Chennai - 600 003, Tamil, Nadu,India.
Curr Comput Aided Drug Des. 2021;17(6):773-784. doi: 10.2174/1573409916666200724152827.
Tuberculosis is a chronic infectious disease that affects one-third of the global population. The emergence of Multi-resistant (MDR) strains and high susceptibility of human immunodeficiency virus (HIV) infected persons to the disease forced to develop novel antituberculosis agents and preferably have a novel mechanism of action as to avoid cross-resistant with other agents. A literature survey indicated that Pyridine, Thiadiazole, Benzimidazole and Acetyl thiophene derivatives exhibit various pharmacological activities, including anti-mycobacterial activity.
Thus, a series of Pyridine, Thiadiazole, Benzimidazole and Acetyl thiophene based molecules were designed and docked against crucial mtb enzyme target InhA (Enoyl Acyl Carrier Protein Reductase) Enzyme. The docked molecules were screened against good docking-score and multiple interactions and opted for synthesis. Synthesized molecules were recrystallized to obtain purity. All the purified compounds were characterized by various spectral analyses and evaluated for antimycobacterial activity against tuberculosis H37RV strain by Microplate Alamar Blue Assay (MABA) method.
The experimental results showed that Schiff bases of Pyridine (Compounds 'd') and Benzimidazole derivatives (Compounds 'i' ) possess good anti-tubercular activity with an MIC below 1.6 μg /mL. Furthermore, compound 'e' of benzimdazole derivative showed good antitubercular activity with an MIC below 6.25 μg /mL, whereas 2 - acetyl thiopene compounds exhibited moderate antitubercular activity below 50μg/mL.
The comparative in vitro and molecular docking study analysis reveals that compared to chalcones of Acetyl thiophene derivatives, Pyridine, Thiadazole and Benzimidazole based Schiff bases exhibited best antitubercular activity.
结核病是一种影响全球三分之一人口的慢性传染病。多重耐药（MDR）菌株的出现以及人类免疫缺陷病毒（HIV）感染者对该疾病的高度易感性，促使人们开发新型抗结核药物，并且最好具有新的作用机制，以避免与其他药物产生交叉耐药性。文献调查表明，吡啶、噻二唑、苯并咪唑和乙酰噻吩衍生物具有多种药理活性，包括抗分枝杆菌活性。
因此，设计了一系列基于吡啶、噻二唑、苯并咪唑和乙酰噻吩的分子，并将其与关键的结核分枝杆菌酶靶点InhA（烯酰基载体蛋白还原酶）进行对接。对接的分子根据良好的对接分数和多种相互作用进行筛选，并选择进行合成。合成的分子进行重结晶以获得纯度。所有纯化的化合物通过各种光谱分析进行表征，并通过微孔板阿拉玛蓝测定法（MABA）评估其对结核H37RV菌株的抗分枝杆菌活性。
实验结果表明，吡啶席夫碱（化合物“d”）和苯并咪唑衍生物（化合物“i”）具有良好的抗结核活性，最低抑菌浓度（MIC）低于1.6μg/mL。此外，苯并咪唑衍生物的化合物“e”显示出良好的抗结核活性，MIC低于6.25μg/mL，而2-乙酰噻吩化合物表现出中等抗结核活性，低于50μg/mL。
比较体外和分子对接研究分析表明，与乙酰噻吩衍生物的查耳酮相比，基于吡啶、噻二唑和苯并咪唑的席夫碱表现出最佳的抗结核活性。
