دورية أكاديمية
Structural design, synthesis and structure-activity relationships of thiazolidinones with enhanced anti-Trypanosoma cruzi activity.
| العنوان: | Structural design, synthesis and structure-activity relationships of thiazolidinones with enhanced anti-Trypanosoma cruzi activity. |
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| المؤلفون: | Moreira DR; Universidade Federal de Pernambuco (UFPE), Departamento de Química Fundamental, 50670-901, Recife, PE (Brazil); Fundação Oswaldo Cruz (Fiocruz), Centro de Pesquisas Gonçalo Moniz, CEP 40296-710, Salvador, BA (Brazil). diogollucio@gmail.com., Leite AC, Cardoso MV, Srivastava RM, Hernandes MZ, Rabello MM, da Cruz LF, Ferreira RS, de Simone CA, Meira CS, Guimaraes ET, da Silva AC, dos Santos TA, Pereira VR, Soares MB |
| المصدر: | ChemMedChem [ChemMedChem] 2014 Jan; Vol. 9 (1), pp. 177-88. Date of Electronic Publication: 2013 Nov 07. |
| نوع المنشور: | Journal Article; Research Support, Non-U.S. Gov't |
| اللغة: | English |
| بيانات الدورية: | Publisher: Wiley-VCH Country of Publication: Germany NLM ID: 101259013 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1860-7187 (Electronic) Linking ISSN: 18607179 NLM ISO Abbreviation: ChemMedChem Subsets: MEDLINE |
| أسماء مطبوعة: | Original Publication: Weinheim, Germany : Wiley-VCH, c2006- |
| مواضيع طبية MeSH: | Drug Design*, Hydrazines/*chemical synthesis , Thiazolidinediones/*chemical synthesis , Thiazolidines/*chemistry , Trypanocidal Agents/*chemical synthesis, Animals ; Cells, Cultured ; Crystallography, X-Ray ; Cysteine Endopeptidases/metabolism ; Endoplasmic Reticulum/drug effects ; Female ; Golgi Apparatus/drug effects ; Hydrazines/chemistry ; Hydrazines/pharmacology ; Macrophages/drug effects ; Mice ; Mice, Inbred BALB C ; Molecular Conformation ; Molecular Docking Simulation ; Protein Structure, Tertiary ; Protozoan Proteins/antagonists & inhibitors ; Protozoan Proteins/metabolism ; Spleen/cytology ; Spleen/drug effects ; Structure-Activity Relationship ; Thiazolidinediones/chemistry ; Thiazolidinediones/pharmacology ; Thiazolidines/chemical synthesis ; Thiazolidines/pharmacology ; Trypanocidal Agents/chemistry ; Trypanocidal Agents/pharmacology ; Trypanosoma cruzi/drug effects |
| مستخلص: | 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. (Copyright © 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.) |
| فهرسة مساهمة: | Keywords: Trypanosoma cruzi; antiprotozoal agents; biological activity; hydrazones; medicinal chemistry; thiazolidinones |
| المشرفين على المادة: | 0 ((2-(2-Phenoxy-1-(4-bromophenyl)ethylidene)hydrazono)-5-ethylthiazolidin-4-one) 0 (Hydrazines) 0 (Protozoan Proteins) 0 (Thiazolidinediones) 0 (Thiazolidines) 0 (Trypanocidal Agents) EC 3.4.22.- (Cysteine Endopeptidases) EC 3.4.22.- (cruzain, Trypanosoma cruzi) |
| تواريخ الأحداث: | Date Created: 20131109 Date Completed: 20140811 Latest Revision: 20131230 |
| رمز التحديث: | 20221213 |
| DOI: | 10.1002/cmdc.201300354 |
| PMID: | 24203393 |
| قاعدة البيانات: | MEDLINE |
Full Text Finder | تدمد: | 1860-7187 |
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| DOI: | 10.1002/cmdc.201300354 |