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.

Disruption of protein-protein interactions of essential oligomeric enzymes by small molecules represents a significant challenge. We recently reported some linear and cyclic peptides derived from an α-helical region present in the homodimeric interface of Leishmania infantum trypanothione reductase (Li-TryR) that showed potent effects on both dimerization and redox activity of this essential enzyme. Here we describe our first steps towards the design of non-peptidic small-molecule Li-TryR dimerization disruptors using a proteomimetic approach. The pyrrolopyrimidine and the 5-6-5 imidazole-phenyl-thiazole α-helix-mimetic scaffolds were suitably decorated with substituents that could mimic three key residues (K, Q and I) of the linear peptide prototype (PKIIQSVGIS-Nle-K-Nle). Extensive optimization of previously described synthetic methodologies was required. A library of 15 compounds bearing different hydrophobic alkyl and aromatic substituents was synthesized. The imidazole-phenyl-thiazole-based analogues outperformed the pyrrolopyrimidine-based derivatives in both inhibiting the enzyme and killing extracellular and intracellular parasites in cell culture. The most active imidazole-phenyl-thiazole compounds 3e and 3f inhibit Li-TryR and prevent growth of the parasites at low micromolar concentrations similar to those required by the peptide prototype. The intrinsic fluorescence of these compounds inside the parasites visually demonstrates their good permeability in comparison with previous peptide-based Li-TryR dimerization disruptors.

4H-Pyranylidene-containing push-pull chromophores built around a bithiophene (BT) π relay or a rigidified thiophene-based unit, namely cyclopenta[1,2-b:3,4-b']dithiophene (CPDT) or dithieno[3,2-b:2',3'-d]pyrrole (DTP), have been synthesized and characterized. The effect of these different relays on the polarization and the second-order nonlinear optical (NLO) properties has been studied. For the sake of comparison, the corresponding reported dithieno[3,2-b:2',3'-d]thiophene (DTT) derivatives have also been included in the discussion. Replacement of the BT core by a rigidified unit (CPDT, DTP) leads to more polarized systems. Calculated NBO charges and electrochemical measurements show that dithienopyrrole has a remarkable donor character that allows an important charge transfer between the donor and the acceptor. The influence of the rigidification of the BT relay on the NLO responses depends on the acceptor strength. For the weakest acceptor used (thiobarbituric acid), passing from the BT relay to the rigidified units always involves an increase in the μβ0 figure of merit. Nevertheless, for the strongest acceptor (2-dicyanomethylene-3-cyano-4,5,5-trimethyl-2,5-dihydrofuran (TCF)), a slight increase in μβ0 with respect to the BT chromophore is only observed for the DTP derivative. Thus, rigidification of the BT core is not enough to improve the second-order nonlinearity and the incorporation of a DTP moiety has proven to be the most efficient approach for this purpose.

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