Efficient Dimerization Disruption of Leishmania infantum Trypanothione Reductase by Triazole-phenyl-thiazoles

Abstract

Inhibition of Leishmania infantum trypanothione disulfide reductase ( Li TryR) by disruption of its homodimeric interface has proved to be an alternative and unexploited strategy in the search for novel antileishmanial agents. Proof of concept was first obtained by peptides and peptidomimetics. Building on previously reported dimerization disruptors containing an imidazole-phenyl-thiazole scaffold, we now report a new 1,2,3-triazole-based chemotype that yields noncompetitive, slow-binding inhibitors of Li TryR. Several compounds bearing (poly)aromatic substituents dramatically improve the ability to disrupt Li TryR dimerization relative to reference imidazoles. Molecular modeling studies identified an almost unexplored hydrophobic region at the interfacial domain as the putative binding site for these compounds. A subsequent structure-based design led to a symmetrical triazole analogue that displayed even more potent inhibitory activity over Li TryR and enhanced leishmanicidal activity. Remarkably, several of these novel triazole-bearing compounds were able to kill both extracellular and intracellular parasites in cell cultures.

Small Molecule–Peptide Conjugates as Dimerization Inhibitors of Leishmania infantum Trypanothione Disulfide Reductase

“…Structural cavities in Li TryR dimer and monomer were calculated using the Computed Atlas of Surface Topography of proteins (CASTp) web server [ 32 ] and a probe radius of 1.4 Å. Molecular dynamics simulations were run in the AMBER force field, as described previously for Li TryR dimer and complexes [ 22 , 23 , 24 , 25 , 26 , 27 , 28 ]. The molecular graphics program PyMOL (v. 1.8, Schrödinger, 2015) was employed for molecular editing, visualization, and figure preparation.…”

“… ( A ) An illustration of the Li TryR dimer (PDB entry 6I7N [ 27 ]) showing the large channel (yellow) connecting the NADPH entry site to the interfacial cavity [ 28 ], as calculated by the CASTp web server [ 32 ]; ( B ) an illustration of a Li TryR monomer showing a similar channel (yellow, 2016 Å 2 , 2550 Å 3 ) plus a second one (green, 129 Å 2 , 125 Å 3 ) that makes up the putative target site for the dimer-disrupting peptides and SMPCs; ( C ) theoretical model of the complex between prototype peptide TRL38 (C atoms in grey) and a Li TryR monomer (rainbow-colored illustration, with N - and C-termini in blue and red, respectively). …”

“…All these peptides and peptidomimetics required attachment to cell-penetrating peptides to allow their cellular uptake and subsequent killing of the parasites in cell culture [ 25 , 26 ]. To overcome the unfavorable drug-like properties of these early prototypes, our efforts were then directed towards the design of small molecules (pyrrolopyrimidine-, imidazole-, and triazole-phenyl-thiazole scaffolds) endowed with high potency and more favorable pharmacokinetic characteristics [ 27 , 28 ]. Nonetheless, our interest in peptide-based compounds did not wane because these types of compounds are gaining momentum as innovative therapies against different diseases, including leishmaniasis [ 29 , 30 ], due to their biocompatibility, versatility, low toxicity, and concise synthesis [ 30 , 31 ].…”

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).…”

Metabolic Pathways of Leishmania Parasite: Source of Pertinent Drug Targets and Potent Drug Candidates

“…In comparison to reference imidazoles, certain compounds with (poly) aromatic substituents significantly improve the capacity to disrupt LiTR dimerization. Revuelto et al, recently revealed symmetrical triazole analogue with a much more potent inhibitory effect was able to kill both external and intracellular parasites [100]. The anti-leishmanial action of various resveratrol analogues (ResAn) was investigated utilizing molecular modeling, computational docking, and in vitro research, with a focus on their pro-oxidant effect.…”