Novel Pyrido[2′,1′:2,3]imidazo[4,5-<i>c</i>]quinoline Derivative Selectively Poisons <i>Leishmania donovani</i> Bisubunit Topoisomerase 1 to Inhibit the Antimony-Resistant <i>Leishmania</i> Infection <i>in Vivo</i>
Srijita Paul Chowdhuri, Shiv Dhiman, Subhendu Das, Neha Meena, Sonali Das, Anil Kumar, Benu Brata Das
Abstract
The unique bisubunit structure of Leishmania donovani topoisomerase 1B (LdTop1) is a potential drug target in the parasites unlike the monomeric Top1 from its human host counterpart. Here, we report the design, synthesis, and validation of a chimeric pyrido[2′,1′:2,3]imidazo[4,5- c ]quinoline derivative ( C17 ) as a novel antileishmanial agent that poisons topoisomerase 1-DNA covalent complexes (LdTop1cc) inside the parasites and inhibits Top1 religation activity both in the drug sensitive and antimony-resistant L. donovani clinical isolates. Importantly, the human Top1 is not sensitive to C17 . Further, C17 overcomes the chemical instability of camptothecin (CPT) by generating persistent LdTop1cc-induced DNA breaks inside the parasites even after 12 h of drug removal. Intraperitoneal administration of C17 results in marked reduction of the Leishmania amastigotes from the infected spleen and liver of BALB/c mice. C17 confers a host protective immune-response up-regulating the Th1 cytokines facilitating parasite clearance which can be exploited for treating drug-resistant leishmaniasis.