Sriram Dharmarajan, Senthilkumar Palaniappan, Dinakaran Murugesan, Yogeeswari Perumal, China Arnab, Nagaraja Valakunja
Medicinal Chemistry Research Laboratory, Pharmacy group, Birla Institute of Technology and Science, Pilani 333031, India.
J Med Chem. 2007 Nov 29;50(24):6232-9. doi: 10.1021/jm700999n. Epub 2007 Oct 26.
Fifty-one 1-(cyclopropyl/tert-butyl/4-fluorophenyl)-1,4-dihydro-6-nitro-4-oxo-7-(substituted secondary amino)-1,8-naphthyridine-3-carboxylic acids were synthesized and evaluated for antimycobacterial in vitro and in vivo against Mycobacterium tuberculosis H37Rv (MTB), multi-drug-resistant Mycobacterium tuberculosis (MDR-TB) and Mycobacterium smegmatis (MC2) and also tested for the ability to inhibit the supercoiling activity of DNA gyrase from M. smegmatis. Among the synthesized compounds, 1-tert-butyl-1,4-dihydro-7-(4,4-dimethyloxazolidin-3-yl)-6-nitro-4-oxo-1,8-naphthyridine-3-carboxylic acid (10q) was found to be the most active compound in vitro with an MIC of 0.1 microM against MTB and MDR-TB and was 3 and 455 times more potent than isoniazid against MTB and MDR-TB, respectively. In the in vivo animal model 10q decreased the bacterial load in lung and spleen tissues with 2.39 and 3.89-log10protections respectively at the dose of 50 mg/kg body weight.
合成了51种1-(环丙基/叔丁基/4-氟苯基)-1,4-二氢-6-硝基-4-氧代-7-(取代仲氨基)-1,8-萘啶-3-羧酸，并对其进行了体外和体内抗结核分枝杆菌活性评价，受试菌株包括结核分枝杆菌H37Rv(MTB)、耐多药结核分枝杆菌(MDR-TB)和耻垢分枝杆菌(MC2)，同时测试了这些化合物抑制耻垢分枝杆菌DNA回旋酶超螺旋活性的能力。在合成的化合物中，1-叔丁基-1,4-二氢-7-(4,4-二甲基恶唑烷-3-基)-6-硝基-4-氧代-1,8-萘啶-3-羧酸(10q)被发现是体外活性最强的化合物，对MTB和MDR-TB的MIC为0.1μM，分别比对MTB和MDR-TB的异烟肼强3倍和455倍。在体内动物模型中，10q在50mg/kg体重剂量下，使肺和脾组织中的细菌载量分别下降了2.39和3.89个对数10。
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