新型苯并噻唑衍生物作为抗结核药物的合成与结构解析：用于可能靶点识别的计算机模拟筛选
Synthesis and Structural Elucidation of Novel Benzothiazole Derivatives as Anti-tubercular Agents: In-silico Screening for Possible Target Identification.
作者信息
Venugopala Katharigatta N, Chandrashekharappa Sandeep, Pillay Melendhran, Bhandary Subhrajyoti, Kandeel Mahmoud, Mahomoodally Fawzi M, Morsy Mohamed A, Chopra Deepak, Aldhubiab Bandar E, Attimarad Mahesh, Alwassil Osama I, Harsha Sree, Mlisana Koleka, Odhav Bharti
机构信息
Department of Pharmaceutical Sciences, College of Clinical Pharmacy, King Faisal University, Al-Ahsa 31982, Saudi Arabia.
Department of Biotechnology and Food Technology, Durban University of Technology, Durban 4001, South Africa.
出版信息
Med Chem. 2019;15(3):311-326. doi: 10.2174/1573406414666180703121815.
BACKGROUND
Benzothiazole derivatives are known for anti-TB properties. Based on the known anti-TB benzothiazole pharmacophore, in the present study, we described the synthesis, structural elucidation, and anti-tubercular screening of a series of novel benzothiazole (BNTZ) derivatives (BNTZ 1-7 and BNTZ 8-13).
OBJECTIVE
The study aims to carry out the development of benzothiazole based anti-TB compounds.
METHODS
Title compounds are synthesized by microwave method and purified by column chromatography. Characterization of the compounds is achieved by FT-IR, NMR (1H and 13C), LCMS and elemental analysis. Screening of test compounds for anti-TB activity is achieved by Resazurin Microplate Assay (REMA) Plate method.
RESULTS
It was noted that the BNTZ compound with an isoquinoline nucleus (BNTZ 9) exhibited remarkable anti-tubercular activity at 8 µg/mL against both the susceptible strain H37Rv and the multi-drug resistant tuberculosis strains of Mycobacterium tuberculosis. On the other hand, the BNTZ compound with a naphthalene nucleus (BNTZ 2) revealed anti-tubercular activity at 6 µg/mL and 11 µg/mL against both the susceptible strain H37Rv and the multi-drug resistant tuberculosis strains of M. tuberculosis, respectively. One of the selected BNTZ derivatives BNTZ 13 was used for single crystal X-ray studies.
CONCLUSION
To identify the appropriate target for potent BNTZ compounds from the series, molecular modeling studies revealed the multiple strong binding of several BNTZs with mycobacterium lysine-ɛ-aminotransferase and decaprenyl-phosphoryl-β-D-ribose 2'-oxidase. The interaction is derived by forming favorable hydrogen bonds and stacking interactions. This new class of BNTZ compounds gave promising anti-tubercular actions in the low micromolar range, and can be further optimized on a structural basis to develop promising, novel, BNTZ pharmacophore-based anti-tubercular drugs.
背景
苯并噻唑衍生物以其抗结核特性而闻名。基于已知的抗结核苯并噻唑药效团，在本研究中，我们描述了一系列新型苯并噻唑（BNTZ）衍生物（BNTZ 1 - 7和BNTZ 8 - 13）的合成、结构解析及抗结核筛选。
目的
本研究旨在开发基于苯并噻唑的抗结核化合物。
方法
通过微波法合成标题化合物，并通过柱色谱法进行纯化。通过傅里叶变换红外光谱（FT - IR）、核磁共振（1H和13C）、液相色谱 - 质谱联用（LCMS）及元素分析对化合物进行表征。通过刃天青微板法（REMA）筛选测试化合物的抗结核活性。
结果
值得注意的是，具有异喹啉核的BNTZ化合物（BNTZ 9）在8 μg/mL浓度下对敏感菌株H37Rv和结核分枝杆菌的多药耐药菌株均表现出显著的抗结核活性。另一方面，具有萘核的BNTZ化合物（BNTZ 2）分别在6 μg/mL和11 μg/mL浓度下对敏感菌株H37Rv和结核分枝杆菌的多药耐药菌株显示出抗结核活性。所选的BNTZ衍生物之一BNTZ 13用于单晶X射线研究。
结论
为了从该系列中确定有效的BNTZ化合物的合适靶点，分子模拟研究表明几种BNTZ与分枝杆菌赖氨酸 - ε - 氨基转移酶和癸酰基磷酸化 - β - D - 核糖2'-氧化酶存在多个强结合。这种相互作用是通过形成有利的氢键和堆积相互作用产生的。这类新型BNTZ化合物在低微摩尔范围内具有良好的抗结核作用，并且可以在结构基础上进一步优化，以开发出有前景的、基于BNTZ药效团的新型抗结核药物。
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