Cellular Immunology and Experimental Therapeutics Laboratory, Department of Zoology, West Bengal State University, Barasat, North 24 Parganas, Pin-700126, West Bengal, India.
Department of Chemistry, University of Calcutta, Kolkata, Pin-700009 West Bengal, India.
J Med Chem. 2020 Dec 24;63(24):15621-15638. doi: 10.1021/acs.jmedchem.0c00690. Epub 2020 Dec 9.
Since inception, the magic bullets developed against leishmaniasis traveled a certain path and then dropped down due to either toxicity or the emergence of resistance. The route of administration is also an important concern. We developed a series of water-soluble ferrocenylquinoline derivatives, targeting , among which CQFC1 showed the highest efficacy even in comparison to other drugs, in use or used, both in oral and intramuscular routes. It did not induce any toxicity to splenocytes and on hematopoiesis, induced protective cytokines, and did not hamper the drug-metabolizing enzymes in hosts. It acts through the reduction and the inhibition of parasites' survival enzyme trypanothione reductase of replicating amastigotes in hosts' reticuloendothelial tissues. Unlike conventional drugs, this molecule did not induce the resistance-conferring genes in laboratory-maintained resistant lines. Experimentally, this easily bioavailable preclinical drug candidate overcame all of the limitations causing the discontinuation of the other conventional antileishmanial drugs.
自成立以来，针对利什曼病开发的“魔弹”由于毒性或耐药性的出现，走了一段路后就失败了。给药途径也是一个重要的关注点。我们开发了一系列水溶性二茂铁基喹啉衍生物，针对该途径进行了研究，其中 CQFC1 表现出最高的疗效，即使与其他正在使用或已使用的药物相比，无论是口服还是肌肉内途径，它都没有引起脾细胞毒性和造血毒性，诱导保护性细胞因子，也不干扰宿主的药物代谢酶。它通过还原和抑制寄生虫生存酶（复制的巨噬细胞内阿米巴）在宿主网状内皮组织中的还原型谷胱甘肽还原酶起作用。与传统药物不同，这种分子不会诱导实验室维持的耐药系中赋予耐药性的基因。在实验中，这种易于生物利用的临床前候选药物克服了导致其他传统抗利什曼病药物停药的所有限制。
