Targeting the Trypanothione Reductase of Tissue-Residing Leishmania in Hosts’ Reticuloendothelial System: A Flexible Water-Soluble Ferrocenylquinoline-Based Preclinical Drug Candidate

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.

Exploration of potential inhibitors for autophagy‐related protein 8 as antileishmanial agents

“…Polyphenols are well‐known pharmacologically active compounds with immunomodulatory activities (Kujawska & Jodynis‐Liebert, 2020). Several natural and synthetic compounds, as well as their derivatives, have been reported to exhibit target‐specific antileishmanial effects (Mukherjee et al, 2020; Thompson et al, 2021). Urolithins belong to the ellagitannin class of polyphenol, which are combinations of coumarin and isocoumarin.…”

“…Several target‐specific naturals, and lead and derivative molecules having antileishmanial effects had been reported yet (Mukherjee et al, 2020; Thompson et al, 2021). Urolithins are the derivatives of dibenzopyran‐6‐one with different hydroxyl substitutions formed in the gut microbiota from ellagic acid by successive removal of the hydroxyls and by the eliminating one out of two lactones present in ellagic acid (Cerdá et al, 2005).…”

Toward New Antileishmanial Compounds: Molecular Targets for Leishmaniasis Treatment

“…Various chemical structures were reported with TR inhibitor activity and leishmaniacidal activity to the literature: Ag(0) nanoparticles encapsulated by ferritin molecules [89], Cu(II) diketonates [90], oxabicyclo[3.3.1]nonanones [73], azole-based compounds -e. pyrrole [91], β-carboline-quinazolinone hybrid [92], phenothiazine and phenoxazine derived chloroacetamides [93], selenocyanates and diselenide compounds [94,95], iminodibenzyl derivatives with ethylenediamine, ethanolamine and diethylenetriamine and their copper(II) complexes [96], diaryl sulfide derivatives [97], ammonium trichloro [1,2-ethanediolato-O,O′]-tellurat [98], all-hydrocarbon stapled peptides [99] chalcone derivatives [100], thiophene derivatives [101], imidazole-phenyl-thiazole compounds [102], isothiocyanate derivatives [103], (phenylthio)pyrimidin-4-amine derivatives [104], ferrocenylquinoline derivatives [105], triazole-phenyl-thiazoles derivatives [106], fluorene derivatives [107], adamantan derivatives, and their gold complexes [108] and natural products [109,110] (Figure 6).…”

Deletion of Glutamine Synthetase Gene Disrupts the Survivability and Infectivity of Leishmania donovani

“…They were kept at 25°C ± 2°C and subjected to a 12 h light dark cycle. They were fed ad libitum (Mukherjee et al, 2020). The experimental groups (5 animals in each group; 4-6 weeks age; weighing approximately 20g) were infected, i.v., with 2 × 10 7 promastigotes of LdGS (+/+) , LdGS (+/−) , LdGS (+/−/+) , LdGS (−/−) , LdGS (−/−/+) , LdGS (++/++) , and Ld: psp (Vc).…”