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

Abstract

Chagas disease is a parasitic infection caused by protozoan Trypanosoma cruzi that affects approximately 6-7 million people worldwide. Benznidazole is the only drug approved for treatment during the acute and asymptomatic chronic phases; however, its efficacy during the symptomatic chronic phase is controversial. The present work reports the synthesis and anti-T. cruzi activities of a novel series of phthalimido-thiazoles. Some of these compounds showed potent inhibition of the trypomastigote form of the parasite at low cytotoxicity concentrations in spleen cells, and the resulting structure-activity relationships are discussed. We also showed that phthalimido-thiazoles induced ultrastructural alterations on morphology, flagellum shortening, chromatin condensation, mitochondria swelling, reservosomes alterations and endoplasmic reticulum dilation. Together, these data revealed, for the first time, a novel series of phthalimido-thiazoles-structure-based compounds with potential effects against T. cruzi and lead-like characteristics against Chagas disease.

Dual Parasiticidal Activities of Phthalimides: Synthesis and Biological Profile against Trypanosoma cruzi and Plasmodium falciparum

“…Indeed, hydrazine double-bond C2=N2 is commonly assigned as E configuration. [20,23,[25][26][27][28] Concerning the exocyclic double-bond N3=C3, we suggest that the predominant configuration is in Z configuration. [20,23,[28][29][30] Besides, a representative 1 H-NMR spectrum of compound 4 n is presented in Supplementary Material ( Figure S1).…”

“…[15][16][17][18][19][20][21][22] Our research group has explored the pharmacological properties of phthalimide derivatives, and as a result, phthalimido-thiazole derivatives were identified as building blocks to promising anti-T. cruzi candidates. [23] Here we performed the synthesis of 24 phthalimidothiosemicarbazones, (3 a-x), and 14 phthalimido-thiazoles (4 an) (Figure 1). In this synthetic strategy, a substructure-based compound library was used to choose different substituents around the phenyl ring attached in the thiosemicarbazone moiety, obtaining 3 a-x compounds.…”

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

“…Studies on 2,4-thiazolidinedione, rhodanine (2-thioxo-4-thiazolidinone), 2-alkyl(aryl)-substituted, and 2-R-amino(imino)-substituted 4-thiazolidinone subtypes were dedicated to the search for new antimicrobial, antidiabetic, anti-inflammatory and anticancer agents [10][11][12]. Recent investigations had proved 1,3-thiazoles as well as 4-thiazolidinone derivatives to be interesting and promising structures for the design of antitrypanosomal agents [2,13]. Thiazole core can be considered as a cyclic mimetic or bioisoster of the highly active antiTrypanosoma cruzi pharmacophore-thiosemicarbazone [14,15], which inhibits cruzain, an essential cysteine protease of Trypanosoma cruzi [16].…”

“…General Procedure for the Synthesis of 3-N-Substituted (5aR,8R,9aR)-5,5,8-trimethyl-3,5,5a,6,7,8,9,9aoctahydro-2H-isothiochromeno[4a,4-d][1,3]thiazol-2-ones(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13) Ethanol solution of potassium hydroxide (0.616 g, 0.011 mol) was added to the suspension of compound 1 (2.69 g, 0.01 mol) in 30 mL ethanol; after the mixture was intensively stirred, appropriate chloroacetamide (0.011 mol) and catalytically amount of KI (0.05 g) were added. Then the mixture wasCHMe 2 ), 4.28 (d, J = 18.0 Hz, 1H, CH 2 CO), 4.38 (d, J = 18.0 Hz, 1H, CH 2 CO), 7.18 (d, J = 8.4 Hz, 2H, arom.…”

Desing and synthesis of potent anti-Trypanosoma cruzi agents new thiazoles derivatives which induce apoptotic parasite death

“…In light of these findings, we turned our attention towards the structural optimization and further identification new anti-T. cruzi 2-(pyridin-2-yl)thiazoles. Structural modifications were performed by insertion of substituents on the N3 position of the thiazole ring due to previous results showing derivatives with phenyl or methyl groups in N3 as potent trypanocidal agents [15,17,23]. Here, we prepared twenty four new thiazoles.…”