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© 2024 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.

Abstract

Background: Leishmaniasis, caused by Leishmania protozoa and transmitted by vectors, presents varied clinical manifestations based on parasite species and host immunity. The lack of effective vaccines or treatments has prompted research into new therapies, including thiourea derivatives, which have demonstrated antiprotozoal activities. Methods: We synthesized two series of N,N′-disubstituted thiourea derivatives through the reaction of isothiocyanates with amines. These compounds were evaluated in vitro against promastigote and amastigote forms of L. amazonensis, alongside cytotoxicity assessments on macrophages. In silico studies were conducted to analyze structure–activity relationships (SARs) and drug-likeness. Results: A total of fifty thiourea derivatives were synthesized and tested. Compound 3e from the first generation exhibited significant anti-leishmanial activity with an IC50 of 4.9 ± 1.2 µM and over 80-fold selectivity compared to that of miltefosine (IC50 = 7.5 ± 1.2 µM). The introduction of a piperazine ring in the second-generation thioureas enhanced potency and selectivity, with compound 5i achieving an IC50 of 1.8 ± 0.5 µM and a selectivity index of approximately 70. Pharmacokinetic predictions indicated favorable profiles for the active compounds. Conclusions: SAR and ADMET analyses identified compound 5i as the most promising candidate for further preclinical evaluation, suggesting that piperazine thiourea derivatives represent a novel class of anti-leishmanial agents.

Details

Title
Synthesis and Structure–Activity Relationship of Thiourea Derivatives Against Leishmania amazonensis
Author
Gil Mendes Viana 1 ; Edézio Ferreira da Cunha-Junior 2   VIAFID ORCID Logo  ; Paloma Wetler Meireles Carreiros Assumpção 1 ; Marianne Grilo Rezende 1 ; Yago Sousa dos Santos Emiliano 3 ; Laiza Maria da Silva Soares 3 ; Gabriel Rodrigues Coutinho Pereira 4 ; Carlos Rangel Rodrigues 4 ; Lucio Mendes Cabral 1 ; Torres-Santos, Eduardo Caio 3   VIAFID ORCID Logo 

 Laboratório de Tecnologia Industrial Farmacêutica, Faculdade de Farmácia, Universidade Federal do Rio de Janeiro, Rio de Janeiro 21941-590, Brazil; [email protected] (G.M.V.); [email protected] (P.W.M.C.A.); [email protected] (M.G.R.) 
 Laboratório de Imunoparasitologia, Unidade Integrada de Pesquisa em Produtos Bioativos e Biociências, Centro Multidisciplinar UFRJ-Macaé, Universidade Federal do Rio de Janeiro, Macaé 27970-000, Brazil; [email protected] 
 Laboratório de Bioquímica de Tripanosomatídeos, Instituto Oswaldo Cruz, Fundação Oswaldo Cruz, Rio de Janeiro 21040-900, Brazil; [email protected] (Y.S.d.S.E.); [email protected] (L.M.d.S.S.) 
 Laboratório ModMolQSAR, Faculdade de Farmácia, Universidade Federal do Rio de Janeiro, Rio de Janeiro 21941-590, Brazil; [email protected] (G.R.C.P.); [email protected] (C.R.R.) 
First page
1573
Publication year
2024
Publication date
2024
Publisher
MDPI AG
e-ISSN
14248247
Source type
Scholarly Journal
Language of publication
English
ProQuest document ID
3149748245
Copyright
© 2024 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.