Sriram Dharmarajan, Aubry Alexandra, Yogeeswari Perumal, Fisher L M
Medicinal Chemistry Research Laboratory, Pharmacy Group, Birla Institute of Technology and Science, Pilani-333031, India.
Bioorg Med Chem Lett. 2006 Jun 1;16(11):2982-5. doi: 10.1016/j.bmcl.2006.02.065. Epub 2006 Mar 22.
Sixteen 7-substituted gatifloxacin derivatives were synthesized and evaluated for antimycobacterial activity in vitro and in vivo against Mycobacterium tuberculosis H37Rv (MTB) and multi-drug resistant M. tuberculosis (MDR-TB), and also tested for the ability to inhibit the supercoiling activity of DNA gyrase from M. tuberculosis. Among the synthesized compounds, 1-cyclopropyl-6-fluoro-8-methoxy-7-[[[N4-[1'-(5-isatinyl-beta-semicarbazo)]methyl]3-methyl]N1-piperazinyl]-4-oxo-1,4-dihydro-3-quinoline carboxylic acid (3d) was found to be the most active compound in vitro with an MIC of 0.0125 microg/mL against MTB and MTR-TB. In the in vivo animal model 3d decreased the bacterial load in lung and spleen tissues with 3.62- and 3.76-log10 protections, respectively. Compound 3d was also found to be equally active as gatifloxacin in the inhibition of the supercoiling activity of wild-type M. tuberculosis DNA gyrase with an IC50 of 3.0 microg/mL. The results demonstrate the potential and importance of developing new quinolone derivatives against mycobacterial infections.
合成了16种7-取代加替沙星衍生物，并对其针对结核分枝杆菌H37Rv（MTB）和耐多药结核分枝杆菌（MDR-TB）的体外和体内抗分枝杆菌活性进行了评估，还测试了它们抑制结核分枝杆菌DNA促旋酶超螺旋活性的能力。在所合成的化合物中，1-环丙基-6-氟-8-甲氧基-7-[[[N4-[1'-(5-异吲哚基-β-氨基脲)]甲基]3-甲基]N1-哌嗪基]-4-氧代-1,4-二氢-3-喹啉羧酸（3d）被发现是体外活性最强的化合物，对MTB和MTR-TB的MIC为0.0125μg/mL。在体内动物模型中，3d分别使肺和脾组织中的细菌载量降低了3.62和3.76个对数10级的保护水平。还发现化合物3d在抑制野生型结核分枝杆菌DNA促旋酶超螺旋活性方面与加替沙星具有同等活性，IC50为3.0μg/mL。结果证明了开发新型喹诺酮衍生物用于抗分枝杆菌感染的潜力和重要性。
