Structural Investigation of Anti-Trypanosoma cruzi 2-Iminothiazolidin-4-ones Allows the Identification of Agents with Efficacy in Infected Mice

Abstract

We modified the thiazolidinic ring at positions N3, C4, and C5, yielding compounds 6-24. Compounds with a phenyl at position N3, 15-19, 22-24, exhibited better inhibitory properties for cruzain and against the parasite than 2-iminothiazolidin-4-one 5. We were able to identify one high-efficacy trypanocidal compound, 2-minothiazolidin-4-one 18, which inhibited the activity of cruzain and the proliferation of epimastigotes and was cidal for trypomastigotes but was not toxic for splenocytes. Having located some of the structural determinants of the trypanocidal properties, we subsequently wished to determine if the exchange of the thiazolidine for a thiazole ring leaves the functional properties unaffected. We therefore tested thiazoles 26-45 and observed that they did not inhibit cruzain, but they exhibited trypanocidal effects. Parasite development was severely impaired when treated with 18, thus reinforcing the notion that this class of heterocycles can lead to useful cidal agents for Chagas disease.

Evaluation of the Anti-Schistosoma mansoni Activity of Thiosemicarbazones and Thiazoles

“…The compounds 2-(1-phenoxypropan-2-ylideno)thiosemicarbazide (LpQM-01), 2-(1-phenoxypropan-2-ylideno)-4-phenylthiosemicarbazide (LpQM-02), and 2-(1-phenoxypropan-2-ylideno)-4-methylthiosemicarbazide (LpQM-03) were prepared as described by Moreira et al (39)…”

Structural Design, Synthesis and Structure–Activity Relationships of Thiazolidinones with Enhanced Anti‐Trypanosoma cruzi Activity

“…[35][36][37][38] After screening the activity of 60 thiazolidinic derivatives, we previously identified a potent anti-T. cruzi thiazolidinone (18). [24] This compound selectively inhibited the trypanosomal protease cruzain but not its mammalian homologous cathepsin L. Of note, compound 18 achieved inhibitory property against cruzain without exhibiting nonspecific and promiscuous binding properties, a characteristic observed for thiazolidinones of very low molecular weight. [39] Moreover, this compound presented low cytotoxicity towards host cells, no apparent toxicity in mice and reduced blood parasitemia in mice when administrated orally.…”

“…[17,18] Based on this, our research group has been investigating cruzain-inhibiting hydrazones to obtain novel and potent anti-T. cruzi agents. At least five distinct classes were investigated: thiosemicarbazones, [19] N-acylhydrazones, [20,21] thiazolidinones [22][23][24] and their transition metal complexes. [25] Within the thiazolidinone class of compounds, we identified compound 18 after examining the importance of modifications at every atom of the thiazolidinic ring ( Figure 1).…”

“…However, thiazolidinone 18 was less efficient in reducing blood parasitemia in T. cruzi-infected mice than benznidazole. [24] To identify new anti-T. cruzi thiazolidinones with enhanced in vivo efficacy, we reasoned that some molecular modifications in this class of compounds are necessary.…”

“…Previously, it was observed that thiazolidinone 18 inhibits cruzain activity but not its homologous in mammalian cells (cathepsin L). [24] However, it was several times less potent than KB2, a high-efficient cruzain inhibitor. [13] A comparison of cruzain docking between 18 and KB2 has revealed that the major difference is that KB2 assumes a T-shaped conformation.…”