Srivastava S K, Chauhan P M, Bhaduri A P, Fatima N, Chatterjee R K
Divisions of Medicinal Chemistry and Parasitology, Central Drug Research Institute, Lucknow 226001, India.
J Med Chem. 2000 Jun 1;43(11):2275-9. doi: 10.1021/jm990438d.
Quinolones have been discovered in our laboratory as a new class of antifilarial agents. This has led to the design, synthesis, and antifilarial evaluation of a number of N-substituted quinol-4(1H)-one-3-carboxamide derivatives 4-6. The macrofilaricidal activity of the target compounds was initially evaluated in vivo against Acanthoeilonema viteae by oral administration of 200 mg/kg x 5 days. Among all the synthesized compounds, 13 displayed activity, with the most potent compound (4a) exhibiting 100% macrofilaricidal and 90% microfilaricidal activities. Compound 4e elicited significant macrofilaricidal (80%) response while compound 5c showed 100% sterilization of female worms. Finally, the two most potent macrofilaricidal compounds, namely 4a and 4e, have been screened for their potency against DNA topoisomerase II, and it has been observed that both have the capability to interfere with this enzyme at 10 micromol/mL concentration. The structure-activity relationship (SAR) associated with position-3 and aryl ring substituents is discussed.
喹诺酮类化合物是我们实验室发现的一类新型抗丝虫药物。这促使我们设计、合成并评估了一系列N-取代喹啉-4(1H)-酮-3-甲酰胺衍生物4-6的抗丝虫活性。通过口服给予200mg/kg，连续5天，初步在体内评估了目标化合物对棘唇旋尾线虫的杀成虫活性。在所有合成化合物中，有13种表现出活性，其中最有效的化合物（4a）表现出100%的杀成虫活性和90%的杀微丝蚴活性。化合物4e引起了显著的杀成虫（80%）反应，而化合物5c显示对雌虫有100%的绝育作用。最后，对两种最有效的杀成虫化合物4a和4e进行了抗DNA拓扑异构酶II活性筛选，结果发现它们在10μmol/mL浓度下均有干扰该酶的能力。讨论了与3位和芳环取代基相关的构效关系（SAR）。
