title: 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.
authors.affiliation: 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.
authors.forename: Diogo Rodrigo Magalhães
authors.initials: DR
authors.lastname: Moreira
authors.forename: Ana Cristina Lima
authors.initials: AC
authors.lastname: Leite
authors.forename: Marcos Verissimo Oliveira
authors.initials: MV
authors.lastname: Cardoso
authors.forename: Rajendra Mohan
authors.initials: RM
authors.lastname: Srivastava
authors.forename: Marcelo Zaldini
authors.initials: MZ
authors.lastname: Hernandes
authors.forename: Marcelo Montenegro
authors.initials: MM
authors.lastname: Rabello
authors.forename: Luana Faria
authors.initials: LF
authors.lastname: da Cruz
authors.forename: Rafaela Salgado
authors.initials: RS
authors.lastname: Ferreira
authors.forename: Carlos Alberto
authors.initials: CA
authors.lastname: de Simone
authors.forename: Cássio Santana
authors.initials: CS
authors.lastname: Meira
authors.forename: Elisalva Teixeira
authors.initials: ET
authors.lastname: Guimaraes
authors.forename: Aline Caroline
authors.initials: AC
authors.lastname: da Silva
authors.forename: Thiago André Ramos
authors.initials: TA
authors.lastname: dos Santos
authors.forename: Valéria Rêgo Alves
authors.initials: VR
authors.lastname: Pereira
authors.forename: Milena Botelho Pereira
authors.initials: MB
authors.lastname: Soares
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D018360:Crystallography, X-Ray; D003546:Cysteine Endopeptidases / Q000378:metabolism; D015195:Drug Design; D004721:Endoplasmic Reticulum / Q000187:drug effects; D005260:Female; D006056:Golgi Apparatus / Q000187:drug effects; D006834:Hydrazines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D008264:Macrophages / Q000187:drug effects; D051379:Mice; D008807:Mice, Inbred BALB C; D008968:Molecular Conformation; D062105:Molecular Docking Simulation; D017434:Protein Structure, Tertiary; D015800:Protozoan Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D013154:Spleen / Q000166:cytology / Q000187:drug effects; D013329:Structure-Activity Relationship; D045162:Thiazolidinediones / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D053778:Thiazolidines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D014344:Trypanocidal Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D014349:Trypanosoma cruzi / Q000187:drug effects
chemical_list: C000590414:(2-(2-Phenoxy-1-(4-bromophenyl)ethylidene)hydrazono)-5-ethylthiazolidin-4-one; D006834:Hydrazines; D015800:Protozoan Proteins; D045162:Thiazolidinediones; D053778:Thiazolidines; D014344:Trypanocidal Agents; D003546:Cysteine Endopeptidases; C074032:cruzain, Trypanosoma cruzi
keywords: Trypanosoma cruzi; antiprotozoal agents; biological activity; hydrazones; medicinal chemistry; thiazolidinones