In vitro and in silico analysis of imatinib analogues as anti-Trypanosoma cruzi drug candidates

Abstract

Chagas disease (CD) is a neglected tropical disease caused by the intracellular protozoan Trypanosoma cruzi that remains a serious public health issue affecting more than 6 million people worldwide. The available treatment includes 2 nitro derivatives, benznidazole (BZ) and nifurtimox, that lack in efficacy in the later chronic phase and when administered against the several naturally resistant parasite strains and present several side-effects, demanding new therapeutic options. One strategy is based on repurposing by testing drugs already used for other illness that may share similar targets. In this context, our previous data on imatinib (IMB) and derivatives motivated the screening of 8 new IMB analogues. Our findings showed that all except 1 were active against bloodstream trypomastigotes reaching drug concentration capable of inducing a 50% of parasite lysis (EC50) values < 12 μm after 2 h while BZ was inactive. After 24 h, all derivatives were more potent than BZ, exhibiting EC50 values 1.5–5.5 times lower. Against intracellular forms, 7 out of 8 derivatives presented high activity, with EC50 values ≤ BZ. LS2/89 stood out as one of the most promising, reaching EC90 values of 1.68 and 4.9 μm on intracellular and trypomastigote forms, respectively, with the best selectivity index (>60) towards the proliferative forms. Physicochemical parameters as well as the absorption, distribution, metabolism, excretion and toxicity properties were predicted to be acceptable and with good chance of a favourable oral bioavailability. The promising results motivate further studies such as in vivo and combinatory assays aiming to contribute for a novel safer and effective therapy for CD.

Navigating drug repurposing for Chagas disease: advances, challenges, and opportunities

“…An additive effect was observed in the combination of imatinib 21 + BZN 1, in fixed-ratio proportions. Similarly, by using this drug as a pharmacophore in a hit-to-lead strategy, a promising synthetic analogue was developed: LS2/89 22 (Nesic de Freitas et al, 2023). Although not a repurposed compound, this analogue demonstrated significantly improved potency, with antiparasitic activities more than 100-times lower against the intracellular form (EC 50 of 0.19 μM) and 10-times lower against the trypomastigote form (EC 50 of 2.67 μM), compared to imatinib 21.…”