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

Abstract

Pharmacological treatment of Chagas disease is based on benznidazole, which displays poor efficacy when administered during the chronic phase of infection. Therefore, the development of new therapeutic options is needed. This study reports on the structural design and synthesis of a new class of anti-Trypanosoma cruzi thiazolidinones (4 a-p). (2-[2-Phenoxy-1-(4-bromophenyl)ethylidene)hydrazono]-5-ethylthiazolidin-4-one (4 h) and (2-[2-phenoxy-1-(4-phenylphenyl)ethylidene)hydrazono]-5-ethylthiazolidin-4-one (4 l) were the most potent compounds, resulting in reduced epimastigote proliferation and were toxic for trypomastigotes at concentrations below 10 μM, while they did not display host cell toxicity up to 200 μM. Thiazolidinone 4 h was able to reduce the in vitro parasite burden and the blood parasitemia in mice with similar potency to benznidazole. More importantly, T. cruzi infection reduction was achieved without exhibiting mouse toxicity. Regarding the molecular mechanism of action, these thiazolidinones did not inhibit cruzain activity, which is the major trypanosomal protease. However, investigating the cellular mechanism of action, thiazolidinones altered Golgi complex and endoplasmic reticulum (ER) morphology, produced atypical cytosolic vacuoles, as well as induced necrotic parasite death. This structural design employed for the new anti-T. cruzi thiazolidinones (4 a-p) led to the identification of compounds with enhanced potency and selectivity compared to first-generation thiazolidinones. These compounds did not inhibit cruzain activity, but exhibited strong antiparasitic activity by acting as parasiticidal agents and inducing a necrotic parasite cell death.

Phthalimido-thiazoles as building blocks and their effects on the growth and morphology of Trypanosoma cruzi

“…Indeed, hydrazine double-bond C2¼N2 is commonly assigned as E configuration [4,23,28]. Concerning the exocyclic double-bond N3¼C3, we suggest that the predominant configuration is in Zconfiguration [7,29]. Besides, a representative 1 H-NMR spectrum of compound 6i is presented in Supplementary Material.…”

Isothiochromenothiazoles—A Class of Fused Thiazolidinone Derivatives with Established Anticancer Activity That Inhibits Growth of Trypanosoma brucei brucei

“…Moreover, some studies have showed that cyclization of thioureas/thiosemicarbazides into thiazole/thiazolidine derivatives is beneficial for Trypanosoma cruzi inhibition when compared to the antiparasitic activity of thiosemicarbazone derivatives [17]. 4-Thiazolidinone derivatives have been studied as potent trypanocidals since the 2000s, giving more active and less toxic lead compounds every year [18][19][20][21][22]. Our previous findings showed good antitrypanosomal activity of thiazolidinone-pyrazoline hybrids [23,24].…”

Trypanocidal Activity of Flavanone Derivatives

“…Flavanone derivatives were evaluated for anti-T. cruzi activity against the intracellular forms of the parasite. Although the use of epimastigotes present in the midgut vector may be utilized for initial screening [19,20], we have instead opted for the simultaneous use of trypomastigote and intracellular amastigotes forms that are present during both acute and chronic phases of the disease [21,22]. This approach is in accordance with the Drugs for Neglected Diseases Initiative guidelines (DNDi) [23].…”