Balaji Neduri V, Hari Babu Bollikolla, Subbaraju Gottumukkala V, Purna Nagasree Kurre, Murali Krishna Kumar Muthyala
Department of Chemistry, Acharya Nagarjuna University, Guntur, AP, India.
Department of Chemistry, Acharya Nagarjuna University, Guntur, AP, India.
Bioorg Med Chem Lett. 2017 Jan 1;27(1):11-15. doi: 10.1016/j.bmcl.2016.11.047. Epub 2016 Nov 18.
A series of 20 hispolons/dihydrohispolons were synthesized and characterized by spectral data. These compounds were subjected to in vitro antitubercular activity screening against Mycobacterium tuberculosis (H37Rv) strain. The synthesized compounds showed varied antitubercular activity ranging from 100 to 1.6μg/mL. Among the screened compounds, four compounds (H1, H2, H3 and H15) have shown moderate activity with MIC 25μg/mL. Potent activities were observed for the dihydrohispolon derivative H14 (MIC 1.6μg/mL) followed by H13 (6.25μg/mL) and H17 (12.5μg/mL), H19 (3.125μg/ML). Docking simulations gave good insights on the possible interactions between the tested compounds and β-keto acyl synthase enzyme (mtbFabH). Drug-inhibitor combination studies showed no synergism with the drugs targeting mycolic acid biosynthesis (isoniazid, ethambutol and thiolactomycin, a specific inhibitor of KAS-B enzyme) but showed significant synergism with other drugs including rifampicin and ciprofloxacin ascertaining the drug target for hispolons as inhibition of mycolic acid biosynthesis, probably via mtbFabH.
合成了一系列20种hispolons/二氢hispolons，并通过光谱数据对其进行了表征。对这些化合物针对结核分枝杆菌（H37Rv）菌株进行了体外抗结核活性筛选。合成的化合物显示出从100至1.6μg/mL不等的抗结核活性。在筛选出的化合物中，四种化合物（H1、H2、H3和H15）表现出中等活性，MIC为25μg/mL。观察到二氢hispolon衍生物H14（MIC 1.6μg/mL）具有强效活性，其次是H13（6.25μg/mL）、H17（12.5μg/mL）、H19（3.125μg/ML）。对接模拟对测试化合物与β-酮酰基合成酶（mtbFabH）之间可能的相互作用提供了很好的见解。药物抑制剂联合研究表明，与靶向分枝菌酸生物合成的药物（异烟肼、乙胺丁醇和硫霉素，一种KAS-B酶的特异性抑制剂）没有协同作用，但与包括利福平和环丙沙星在内的其他药物显示出显著的协同作用，确定了hispolons的药物靶点为抑制分枝菌酸生物合成，可能是通过mtbFabH实现的。
