Medicinal Chemistry & Antimycobacterial Research Laboratory, Pharmacy Group, Birla Institute of Technology & Science - Pilani, Hyderabad Campus, Jawahar Nagar, Hyderabad - 500 078, Andhra Pradesh, India.
Chem Biol Drug Des. 2010 Apr;75(4):381-91. doi: 10.1111/j.1747-0285.2010.00947.x. Epub 2010 Feb 8.
Twenty four novel 2-[3-(4-bromo-2-fluorobenzyl)-4-oxo-3,4-dihydro-1-phthalazinyl]acetic acid amides were synthesized from phthalic anhydride and were subjected to in vitro and in vivo evaluation against log- and starved phase of mycobacterial species and Mycobacterium tuberculosis isocitrate lyase enzyme inhibition studies. Among the compounds screened, 2-(2-(4-bromo-2-fluorobenzyl)-1,2-dihydro-1-oxophthalazin-4-yl)-N-(2,6-dimethylphenyl)acetamide (5j) inhibited all eight mycobacterial species with MIC's ranging from 0.08 to 5.05 microm and was non-toxic to Vero cells till 126.43 microm. Four compounds were tested against starved culture of Mycobacterium tuberculosis and they inhibited with MIC's ranging from 3.78 to 23.2 microm. Some compounds showed 40-66% inhibition against Mycobacterium tuberculosis isocitrate lyase enzyme at 10 microm. The docking studies also confirmed the binding potential of the compounds at the isocitrate lyase active site. In the in vivo animal model, 5j reduced the mycobacterial load in lung and spleen tissues with 1.38 and 2.9-log10 protections, respectively, at 25 mg/kg body weight dose.
合成了 24 种新型 2-[3-(4-溴-2-氟苄基)-4-氧代-3,4-二氢-1-酞嗪基]乙酸酰胺，对对数期和饥饿期的分枝杆菌属和结核分枝杆菌异柠檬酸裂解酶进行了体外和体内评价。在筛选的化合物中，2-(2-(4-溴-2-氟苄基)-1,2-二氢-1-氧代酞嗪-4-基)-N-(2,6-二甲基苯基)乙酰胺(5j)抑制了所有 8 种分枝杆菌属，MIC 值范围为 0.08 至 5.05 微米，对 Vero 细胞的毒性直到 126.43 微米才显现。四种化合物对结核分枝杆菌饥饿培养进行了测试，MIC 值范围为 3.78 至 23.2 微米。一些化合物在 10 微米时对结核分枝杆菌异柠檬酸裂解酶的抑制率达到 40-66%。对接研究也证实了化合物在异柠檬酸裂解酶活性部位的结合潜力。在体内动物模型中，5j 在 25mg/kg 体重剂量下，分别在肺部和脾脏组织中使分枝杆菌负荷减少了 1.38 和 2.9 个对数。
