Current advances in drug discovery for Chagas disease

Scarim, Cauê Benito; Jornada, Daniela Hartmann; Chelucci, Rafael Consolin; Almeida, Letícia de; Santos, Jean Leandro dos; Chin, Chung Man

doi:10.1016/j.ejmech.2018.06.040

Cited by 81 publications

(66 citation statements)

References 119 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…First-line treatment of Chagas disease is performed with benznidazole, whose success depends on the stage of the disease, the patient's age, and on biochemical characteristics of the strain (10). T. cruzi strains show great discrepancy in susceptibility to chemotherapy, being resistance detected on wild-type strains or after prolonged treatment (11)(12)(13).…”

Section: Introductionmentioning

confidence: 99%

Thiol efflux mediated by an ABCC-like transporter participates forTrypanosoma cruziadaptation to environmental and chemotherapeutic stresses

Costa

et al. 2020

Preprint

View full text Add to dashboard Cite

The protozoan Trypanosoma cruzi is the etiologic agent for Chagas disease, which affects 6-7 million people worldwide. The parasite presents high biological diversity, reflecting on the inefficiency of benznidazole in chronic or older patients. ABC superfamily proteins contain active transporters involved in the xenobiotic and endobiotic efflux and overexpressed in MDR cells. An ABCC-like transport was identified in the T. cruzi Y strain, being able to extrude thiol-conjugated compounds. As non-protein thiols represent prime line of defense towards reactive species, ABCC-like activity could participate in the regulation of mediators implicated in responses to cellular stress arising from a variety of stimuli, as environmental or chemotherapeutic. This study shows that T. cruzi ABCC-like protein transports GSH, GSSG and ceramides, all implicated in cellular stress. Hemin, representative from the hematophagous feeding of the vector, was transported as well, suggesting a role for ABCC as a metal-thiol transporter. In addition, all strains evaluated showed ABCC-like activity, while no ABCB1-like activity was detected. Also, results suggest that ABCC-like does not associate to natural resistance to benznidazole, considering that the sensitive strains CL Brener and Berenice showed higher ABCC-like activity than the resistant strains Y and Colombiana. Instead, ABCC-like efflux increased after continuous exposure of Y strain to benznidazole. Moreover, ABCC does not perform direct efflux of drug and its participation in the machinery of protection against stress depends on the efflux of metabolites in conjugation to or in cotransport with thiol.

show abstract

Section: Introductionmentioning

confidence: 99%

Thiol efflux mediated by an ABCC-like transporter participates forTrypanosoma cruziadaptation to environmental and chemotherapeutic stresses

Costa

et al. 2020

Preprint

View full text Add to dashboard Cite

show abstract

“…Effective drugs with a wide margin of safety and low cost are vital to combat this parasitosis . Several studies have focused on the search for antichagasic small molecules . Mannich bases have demonstrated this parasitic activity .…”

Section: Discussion and Resultsmentioning

confidence: 99%

Antichagasic profile of a Series of Mannich Base‐Type Derivatives: Design, Synthesis, in vitro Evaluation, and Computational Studies Involving Iron Superoxide Dismutase

et al. 2019

View full text Add to dashboard Cite

Chagas disease is a silent disease that continues to endanger millions of people and, due to its insufficient current chemotherapy, urgently requires the development of more effective drugs. With this objective, twenty‐six Mannich base derivatives were synthesized, and their in vitro activity was evaluated against Trypanosoma cruzi. Three out of the twenty‐six compounds showed interesting results, including IC50 values<10 μM and a selectivity index >20 in amastigote forms of Arequipa and SN3 T. cruzi strains. In addition, these compounds showed similar infection rates in Vero cells compared to those of benznidazole at 50 μM. Finally, some studies were performed to investigate the possible mechanism of action; moreover, computational studies proposed a binding mode of these derivatives to Fe‐SOD. This new series of compounds has an encouraging antichagasic profile with a simplified structure and synthetic routes. Therefore, the most active compounds should be considered as leads for further optimization of the antichagasic activity.

show abstract

“…One of the directions for the design of new antitrypanosomal agents using a molecular hybridization approach is the utilization of hydrazone fragments (Figure 9) as the linker group for the connection of the thiazole/4-thiazolidinone scaffold with the other molecular fragments [117,[141][142][143][144][145][146][147].…”

Section: -Thiazolidinone Frame In the Design Of Antitrypanosomalsmentioning

confidence: 99%

Thiazolidinone-Related Heterocyclic Compounds as Potential Antitrypanosomal Agents

Kryshchyshyn¹,

Kaminskyy²,

Grellier³

et al. 2021

Azoles - Synthesis, Properties, Applications and Perspectives

View full text Add to dashboard Cite

Human African trypanosomiasis (HAT) and Chagas disease are neglected tropical diseases (NTDs) due to parasite protists from the Trypanosoma genus transmitted by insect vectors. Trypanosomiases affect mostly poor populations in the developing countries, and the development of new antitrypanosomal drugs is underinvested by governments and the pharmaceutical industry. In this chapter, we described the development of 4-thiazolidinone and thiazole derivatives with heterocyclic fragments which exhibit good inhibition of trypanosome growth and might constitute potential candidates for the development of new drugs against trypanosomiasis. Antitrypanosomal design, mainly within structure-based design, led to the synthesis of 5-ene-4-thiazolidinone-3-alkanecarboxylic acids; 2,3-disubstituted 4-thiazolidinones; thiazolidinone-pyrazoline, phenylindole-thiazolidinone, and imidazothiadiazole-thiazolidinone hybrids; as well as 4-thiazolidinone-based fused heterocycles, especially thiopyrano[2,3-d]thiazoles, and non-thiazolidinone compounds-namely, isothiocoumarine derivatives. Moreover, antitrypanosomal 4-thiazolidinones are of special interest in the search for new antimalarial and antileishmanial agents. Also many active anticancer agents among the abovementioned 4-thiazolidinones have been discovered.

show abstract

Current advances in drug discovery for Chagas disease

Cited by 81 publications

References 119 publications

Thiol efflux mediated by an ABCC-like transporter participates forTrypanosoma cruziadaptation to environmental and chemotherapeutic stresses

Thiol efflux mediated by an ABCC-like transporter participates forTrypanosoma cruziadaptation to environmental and chemotherapeutic stresses

Antichagasic profile of a Series of Mannich Base‐Type Derivatives: Design, Synthesis, in vitro Evaluation, and Computational Studies Involving Iron Superoxide Dismutase

Thiazolidinone-Related Heterocyclic Compounds as Potential Antitrypanosomal Agents

Contact Info

Product

Resources

About