a Department of Pharmaceutical Sciences , College of Clinical Pharmacy, King Faisal University , Al-Ahsa 31982 , Kingdom of Saudi Arabia.
b Department of Microbiology, National Health Laboratory Services , KZN Academic Complex, Inkosi Albert Luthuli Central Hospital, Durban 4001 , South Africa.
J Biomol Struct Dyn. 2018 Jun;36(8):2163-2178. doi: 10.1080/07391102.2017.1345325. Epub 2017 Aug 14.
A series of trisubstituted indolizine analogues has been designed as a result of a fragment-based approach to target the inhibition of mycobacterial enoyl-acyl carrier protein reductase. Anti-tuberculosis (TB) screening of the characterized compounds by a resazurin microplate assay method revealed that ethyl group at second position of indolizine nucleus exhibited activity against susceptible and multidrug-resistant strains of Mycobacterium tuberculosis at concentration of 5.5 and 11.3 μg/mL, respectively. A molecular docking study was also conducted to evaluate the stability of the active compounds, and compound with ethyl substitution at second position of indolizine nucleus showed the highest free binding energy of ΔG -24.11 (kcal/mol), a low clash score of 3.04, and high lipo score of -13.33. Indolizine analog with ethyl substitution at second position demonstrated Molecular Mechanics/Generalized Born Surface Area (-23.85 kcal/mol). Two molecular dynamics studies were computed (100 ps and 50 ns) to calculate the relationship between the potential and kinetic energies of the active anti-TB compound with time and temperature. The discovery of this lead may have a positive impact on anti-TB drug discovery.
一系列三取代的吲唑类似物是通过基于片段的方法设计的，旨在抑制分枝杆菌烯酰基辅酶 A 还原酶。通过 Resazurin 微量板测定法对所鉴定的化合物进行抗结核（TB）筛选，结果表明吲唑核的第二个位置的乙基基团在 5.5 和 11.3 μg/mL 的浓度下分别对敏感和耐多药结核分枝杆菌菌株具有活性。还进行了分子对接研究以评估活性化合物的稳定性，并且在吲唑核的第二个位置具有乙基取代的化合物显示出最高的自由结合能 ΔG -24.11（kcal/mol），低碰撞评分 3.04 和高脂评分-13.33。具有乙基取代的吲唑类似物显示出分子力学/广义 Born 表面面积（-23.85 kcal/mol）。进行了两项分子动力学研究（100 ps 和 50 ns），以计算活性抗 TB 化合物的势能和动能与时间和温度之间的关系。这一先导化合物的发现可能对抗结核药物的发现产生积极影响。
