Pandeya S N, Sriram D, Nath G, De Clercq E
Department of Pharmaceutics, Institute of Technology, Banaras Hindu University, Varanasi, India.
Eur J Med Chem. 2000 Feb;35(2):249-55. doi: 10.1016/s0223-5234(00)00125-2.
Mannich bases of norfloxacin were synthesized by reacting them with formaldehyde and several isatin derivatives. Their chemical structures have been confirmed by means of their IR, 1H-NMR data and by elemental analysis. Investigation of in vitro antimicrobial activity of compounds was done by the agar dilution method against 28 pathogenic bacteria, eight pathogenic fungi and anti-HIV activity against replication of HIV-1 (III B) in MT-4 cells. The in vivo antibacterial efficacy of selected derivatives was determined using a mouse infection model. All the synthesized compounds are more active than norfloxacin against the 13 bacteria tested. The compounds are also more active than the standard drug clotrimazole against Histoplasma capsulatum. Two compounds S-8 and S-9 have shown inhibition against HIV-1 (III B) with EC(50) values of 11.3 and 13.9 microgram/mL, respectively. In the mouse protection test, two compounds S-4 (ED(50): 1.25 mg/kg) and S-9 (ED(50): 1.62 mg/kg) are more active than norfloxacin (ED(50): 6mg/kg). Among the compounds tested, 1-ethyl-6-fluoro-1, 4-dihydro-4-oxo-7[[N(4)-[5'-bromo-3'-(4'-amino-5'-trimethoxybenzylpyr imidin-2'-yl]-imino-1'-isatinyl]methyl]N(1)-piperazinyl]-3-q uinoline carboxylicacid (S-9) showed promising activity in all the three tests.
诺氟沙星的曼尼希碱是通过使其与甲醛和几种异吲哚酮衍生物反应合成的。它们的化学结构已通过红外光谱、1H-核磁共振数据和元素分析得以证实。采用琼脂稀释法对28种病原菌、8种致病真菌进行了化合物的体外抗菌活性研究，并对其在MT-4细胞中抗HIV-1（III B）复制的抗HIV活性进行了研究。使用小鼠感染模型测定了所选衍生物的体内抗菌效果。所有合成化合物对所测试的13种细菌的活性均高于诺氟沙星。这些化合物对荚膜组织胞浆菌的活性也高于标准药物克霉唑。两种化合物S-8和S-9对HIV-1（III B）表现出抑制作用，其半数有效浓度（EC50）值分别为11.3和13.9微克/毫升。在小鼠保护试验中，两种化合物S-4（半数有效剂量（ED50）：1.25毫克/千克）和S-9（ED50：1.62毫克/千克）比诺氟沙星（ED50：6毫克/千克）更具活性。在所测试的化合物中，1-乙基-6-氟-1,4-二氢-4-氧代-7[[N(4)-[5'-溴-3'-(4'-氨基-5'-三甲氧基苄基嘧啶-2'-基]-亚氨基-1'-异吲哚酮基]甲基]N(1)-哌嗪基]-3-喹啉羧酸（S-9）在所有三项试验中均显示出有前景的活性。
