Sultana Najma, Arayne M Saeed, Naz Asia, Mesaik M Ahmed
Department of Chemistry, University of Karachi, Karachi, Pakistan.
Chem Cent J. 2013 Jan 14;7(1):6. doi: 10.1186/1752-153X-7-6.
Seventeen 1,4-dihydroquinoline-3-carboxamide and 1,4-dihydroquinoline-3-carbohydrazide derivatives of gatifloxacin have been prepared with a facile one step synthesis aiming to improve antibacterial, antifungal and immunological activities. The methodology allows the introduction of a variety of substituents such as amines, alcohol, phenol, amides and alkyl halides into the core structure of gatifloxacin.
The analog N-(3-aminophenyl)-1-cyclopropyl-6-fluoro-8-methoxy-7-(3-methylpiperazin-1-yl)-4-oxo-1,4-dihydroquinoline-3-carboxamide has been identified as a potentially excellent anti-inflammatory agent, which exhibited highly potent effects on the oxidative burst activity of whole blood phagocytes (IC50 <12.5 μg mL-1), neutrophils (IC50 <0.1 μg mL-1) and macrophages phagocytes (IC50 <3.1 μg mL-1) as well as potent T-cell proliferation inhibitory effect (IC50 3.7 μg mL-1) while having comparable antibacterial activity to gatifloxacin. Another analog, 1-cyclopropyl-6-fluoro-8-methoxy-7-(3-methylpiperazin-1-yl)-4-oxo-N-phenyl-1,4-dihydroquinoline-3-carbohydrazide has tremendous T-cell proliferation inhibitory effect IC50 <3.1 μg mL-1 as compared to prednisolone, whereas, 3,5-dihydroxyphenyl1-cyclopropyl-6-fluoro-8-methoxy-7-(3-methylpiperazin-1-yl)-4-oxo-1,4-dihydroquinoline-3-carboxylate and 2-hydroxyphenyl-1-cyclopropyl-6-fluoro-8-methoxy-7-(3-methylpiperazin-1-yl)-4-oxo-1,4-dihydroquinoline-3-carboxylate envision good inhibitory activity on T-cells proliferation (IC50 6.8 & 8.8 μg mL-1 respectively).
The structural modification at carboxylic group has resulted in improved anti-inflammatory activities with comparable antibacterial activity to gatifloxacin. We believe that C3 structural modifications of gatifloxacin are definitely important in bringing major immunomodulatory changes in these compounds.
已通过简便的一步合成法制备了17种加替沙星的1,4 - 二氢喹啉 - 3 - 甲酰胺和1,4 - 二氢喹啉 - 3 - 碳酰肼衍生物，旨在提高其抗菌、抗真菌和免疫活性。该方法允许将多种取代基如胺、醇、酚、酰胺和卤代烃引入加替沙星的核心结构中。
类似物N - (3 - 氨基苯基)-1 - 环丙基 - 6 - 氟 - 8 - 甲氧基 - 7 - (3 - 甲基哌嗪 - 1 - 基)-4 - 氧代 - 1,4 - 二氢喹啉 - 3 - 甲酰胺已被鉴定为一种潜在的优秀抗炎剂，它对全血吞噬细胞（IC50 <12.5 μg mL-1）、中性粒细胞（IC50 <0.1 μg mL-1）和巨噬细胞吞噬细胞（IC50 <3.1 μg mL-1）的氧化爆发活性表现出高效作用，以及对T细胞增殖有强效抑制作用（IC50 3.7 μg mL-1），同时具有与加替沙星相当的抗菌活性。另一种类似物，1 - 环丙基 - 6 - 氟 - 8 - 甲氧基 - 7 - (3 - 甲基哌嗪 - 1 - 基)-4 - 氧代 - N - 苯基 - 1,4 - 二氢喹啉 - 3 - 碳酰肼与泼尼松龙相比具有巨大的T细胞增殖抑制作用（IC50 <3.1 μg mL-1），而3,5 - 二羟基苯基1 - 环丙基 - 6 - 氟 - 8 - 甲氧基 - 7 - (3 - 甲基哌嗪 - 1 - 基)-4 - 氧代 - 1,4 - 二氢喹啉 - 3 - 羧酸酯和2 - 羟基苯基 - 1 - 环丙基 - 6 - 氟 - 8 - 甲氧基 - 7 - (3 - 甲基哌嗪 - 1 - 基)-4 - 氧代 - 1,4 - 二氢喹啉 - 3 - 羧酸酯对T细胞增殖具有良好的抑制活性（分别为IC50 6.8和8.8 μg mL-1）。
羧酸基团的结构修饰导致抗炎活性提高，同时具有与加替沙星相当的抗菌活性。我们认为加替沙星的C3结构修饰对于在这些化合物中带来主要的免疫调节变化肯定是重要的。
