Targeting the Trypanothione Reductase of Tissue-Residing <i>Leishmania</i> in Hosts’ Reticuloendothelial System: A Flexible Water-Soluble Ferrocenylquinoline-Based Preclinical Drug Candidate
Debarati Mukherjee, Md Yousuf, Somaditya Dey, Sondipon Chakraborty, Ankur Chaudhuri, Vinay Kumar, Biswajyoti Sarkar, Supriya Nath, Aabid Hussain, Aritri Dutta, Tanushree Mishra, Biswajit Roy, Sushma Singh, Sibani Chakraborty, Susanta Adhikari, Chiranjib Pal
Abstract
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 Leishmania donovani, 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 L. donovani lines. Experimentally, this easily bioavailable preclinical drug candidate overcame all of the limitations causing the discontinuation of the other conventional antileishmanial drugs.