Simplifying nature: Towards the design of broad spectrum kinetoplastid inhibitors, inspired by acetogenins

Abstract

The need for new treatments for the neglected tropical diseases African sleeping sickness, Chagas disease and Leishmaniasis remains urgent with the diseases widespread in tropical regions, affecting the world's very poorest. We have previously reported bis-tetrahydropyran 1,4-triazole analogues designed as mimics of the annonaceous acetogenin natural product chamuvarinin, which maintained trypanocidal activity. Building upon these studies, we here report related triazole compounds with pendant heterocycles, mimicking the original butenolide of the natural product. Analogues were active against T. brucei, with a nitrofuran compound displaying nanomolar trypanocidal activity. Several analogues also showed strong activity against T. cruzi and L. major. Importantly, select compounds gave excellent selectivity over mammalian cells with a furan-based analogue highly selective while remaining active against all three cell lines, thus representing a potential lead for a new broad spectrum kinetoplastid inhibitor.

Bioprospecting of Nitrogenous Heterocyclic Scaffolds with Potential Action for Neglected Parasitosis: A Review

“…The same work of Gould et al (2017) [77], evaluated anti-Trypanosoma brucei activity of the chamuvarinin (Figure 12) analogs, where, of the whole series of triazole compounds obtained, only compound 31 (Figure 12) demonstrated an increase in the anti-T. brucei activity, when compared to chamuvirinin, with IC50 of 0.037±0.003 µM, not being cytotoxic in HeLa cells, but with an EC50 value of [80] reported the azole action as a binder to DNA minor grooves, which inhibits the protein-DNA interaction, being of useful application in parasite infections treatment, among others diseases [81], by inducing apoptosis of invasive cells. Distamycin, a polyamide natural product which act as binder to DNA minor groves, was used as base for prepare a series of analogs, where five derivatives (Figure 14) demonstrated anti-Trypanosoma brucei activity in the nanomolar range (IC50 > 40 nM).…”

“…INSERT FIGURE 11 HERE Gould et al (2017) [77] have reported bis-tetrahydropyran 1,4-triazole analogs drawn as mimics of the annonaceous acetogenin natural product chamuvarinin (Figure 12), which maintained trypanocidal activity. This acetogenin compounds are polyketides found in Annonaceae spp [78].…”

An Overview of the Chemical Characteristics, Bioactivity and Achievements Regarding the Therapeutic Usage of Acetogenins from Annona cherimola Mill.

“…However, the original squamocin molecule was drastically denatured, since it had its characteristic γ-butyrolactone final ring and the ether groups removed. The most remarkable point in the mimic structure produced by Gould is the tetrahidropyrane core connected to the triazole ring, that replaces the bis-THF of squamocin [ 85 ]. Similar approaches were implemented by Ichimaru et al, where bullatacin mimics were synthesized employing piperazine core.…”

Design and Synthesis of Broad Spectrum Trypanosomatid Selective Inhibitors

“…19 We also report extended phenotypic screening of the related kinetoplastids T. cruzi, L. major and L. donovani. 20 Furthermore, as part of efforts to identify the protein target and establish the mode of action, we have adapted our core inhibitor scaffold to incorporate both a photo-reactive diazirine unit and an orthogonal reporter alkyne tag to produce photo-affinity labelling inhibitors. 21 Direct incorporation of a small photo-affinity label was viewed as advantageous in terms of minimising disruption of ligand-protein binding interactions in vitro, and reducing non-specific labelling by retaining the structural features identified by phenotypic screening, thereby increasing the likelihood of successful target protein labelling.…”

“…maintained activity when compared to 27. Inhibition activity is only moderately reduced with a bulky n-octyl substituent(20). The potency in other parasitic cell lines (insect forms of T. brucei, T. cruzi and L. major) were more sensitive to alkyl ether chain length.…”