Department of Zoology, Visva-Bharati University, Santiniketan, 731 235, India.
Department of Chemistry, Syamsundar College, Shyamsundar, 713 424, India.
Sci Rep. 2018 Aug 13;8(1):12073. doi: 10.1038/s41598-018-30610-7.
Search of potent antifilarial drugs has been a major thrust area in tropical medicine research over the decades. Herein, we report 4,7-dimethyl-3,4,7,8-tetrahydro-3λ-[1,2]thiazino[4,3-f]quinoline-3,3,8-trione (8l) as a new class of antifilarial agent which is extremely potent, with lethality against all the developmental stages (oocyte, microfilaria and adult) of the filarial parasite Setaria cervi. Molecular investigation on its mode of action revealed that 8l is a typical inducer of reactive oxygen species that triggers oxidative stress inside the filarid and further signals induction of apoptosis by activating both intrinsic and extrinsic pathways. Moreover, 8l is also active against Wolbachia, the essential endosymbiont of several human infectious filarids. Selective toxicity against filarial parasites and non-toxic nature in rat model were found as unique traits of 8l to be a future medicine. Taken en masse, this maiden report on a novel quinolone fused cyclic sulfonamide presents a promising therapeutic lead for lymphatic filariasis in future.
几十年来，寻找有效的抗丝虫药物一直是热带医学研究的主要重点。在此，我们报告了 4,7-二甲基-3,4,7,8-四氢-3λ-[1,2]噻嗪[4,3-f]喹啉-3,3,8-三酮（8l）作为一种新型的抗丝虫药物，对丝状寄生虫马氏血吸虫的所有发育阶段（卵母细胞、微丝蚴和成虫）都具有极强的杀伤力。对其作用机制的分子研究表明，8l 是一种典型的活性氧诱导剂，它在丝虫内部引发氧化应激，通过激活内在和外在途径进一步发出诱导细胞凋亡的信号。此外，8l 对几种人类感染性丝虫的必需共生体沃尔巴克氏体也有活性。在大鼠模型中，对丝虫的选择性毒性和非毒性被认为是 8l 成为未来药物的独特特征。总的来说，这是关于新型喹诺酮融合环状磺酰胺的首次报告，为未来的淋巴丝虫病提供了有希望的治疗靶点。
