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Structural design, synthesis, and anti-Trypanosomatidae profile of new Pyridyl-thiazolidinones. 2023

Juliana Maria da Conceição, and Aline Caroline da Silva Santos, and Fabio André Brayner, and Luiz Carlos Alves, and Aline Ferreira Pinto, and Graziella Leite Brondani, and Gevânio Bezerra de Oliveira Filho, and Danilo Cesar Galindo Bedor, and José Wellithom Viturino da Silva, and Policarpo Ademar Sales Junior, and Marton Kaique de Andrade Cavalcante, and Elis Dionísio da Silva, and Valéria Rêgo Alves Pereira, and Ana Cristina Lima Leite
Laboratory of Planning in Medicinal Chemistry, Department of Pharmaceutical Sciences, Center for Health Sciences, Federal University of Pernambuco, 50740-535, Recife, PE, Brazil.

The present work reports the synthesis of a novel series of pyridine-thiazolidinones with anti-Trypanosoma cruzi and leishmanicidal activities (compounds 10-27), derived from 2 or 4-pyridine thiosemicarbazones (1-9). The in vitro assays were performed with Trypanosoma cruzi trypomastigotes and amastigotes, as well as with Leishmania amazonensis promastigotes and amastigotes. The cytotoxicity profile was evaluated using the cell line RAW 264.7. From the 18 pyridine-thiazolidinones, 5 were able to inhibit trypomastigotes. Overall, all compounds inhibited amastigotes, highlighting compounds 15 (0.60 μM), 18 (0.64 μM), 17 (0.81 μM), and 27 (0.89 μM). Compounds 15 and 18 were able to induce parasite cell death through necrosis induction. Analysis by scanning electron microscopy showed that T. cruzi trypomastigotes treated with compounds 15 and 18 induced morphological changes such as shortening, retraction and curvature of the parasite body and leakage of internal content. Regarding the antiparasitic evaluation against Leishmania amazonensis, only compound 27 had a higher selectivity compared to Miltefosine against the amastigote form (IC50 = 5.70 μM). Our results showed that compound 27 presented an antiparasitic activity for both Trypanosoma cruzi and Leishmania amazonensis. After in silico evaluation, it was suggested that the new pyridine-thiazolidinones had an appropriate drug-likeness profile. Our results pointed out a new chemical frame with an anti-Trypanosomatidae profile. The pyridine-thiazolidinones presented here for the first time could be used as a starting point for the development of new antiparasitic agents.

UI MeSH Term Description Entries
D007894 Leishmania mexicana A parasitic hemoflagellate of the subgenus Leishmania leishmania that infects man and animals including rodents. The Leishmania mexicana complex causes both cutaneous (LEISHMANIASIS, CUTANEOUS) and diffuse cutaneous leishmaniasis (LEISHMANIASIS, DIFFUSE CUTANEOUS) and includes the subspecies amazonensis, garnhami, mexicana, pifanoi, and venezuelensis. L. m. mexicana causes chiclero ulcer, a form of cutaneous leishmaniasis (LEISHMANIASIS, CUTANEOUS) in the New World. The sandfly, Lutzomyia, appears to be the vector. Leishmania (Leishmania) mexicana,Leishmania mexicana amazonensis,Leishmania mexicana mexicana,Leishmania leishmania mexicana,Leishmania leishmania mexicanas,Leishmania mexicana amazonenses,Leishmania mexicana mexicanas,Leishmania mexicanas,amazonenses, Leishmania mexicana,amazonensis, Leishmania mexicana,leishmania mexicana, Leishmania,mexicana amazonensis, Leishmania,mexicana mexicana, Leishmania,mexicana mexicanas, Leishmania,mexicana, Leishmania,mexicana, Leishmania leishmania,mexicana, Leishmania mexicana,mexicanas, Leishmania leishmania
D006801 Humans Members of the species Homo sapiens. Homo sapiens,Man (Taxonomy),Human,Man, Modern,Modern Man
D000977 Antiparasitic Agents Drugs used to treat or prevent parasitic infections. Antiparasitic,Antiparasitic Agent,Antiparasitic Drug,Parasiticide,Parasiticides,Antiparasitic Drugs,Antiparasitics,Agent, Antiparasitic,Agents, Antiparasitic,Drug, Antiparasitic,Drugs, Antiparasitic
D013329 Structure-Activity Relationship The relationship between the chemical structure of a compound and its biological or pharmacological activity. Compounds are often classed together because they have structural characteristics in common including shape, size, stereochemical arrangement, and distribution of functional groups. Relationship, Structure-Activity,Relationships, Structure-Activity,Structure Activity Relationship,Structure-Activity Relationships
D014344 Trypanocidal Agents Agents destructive to the protozoal organisms belonging to the suborder TRYPANOSOMATINA. Trypanocidal Drugs,Trypanocides,Trypanosomicidal Agents,Trypanosomicides,Agents, Trypanocidal,Agents, Trypanosomicidal,Drugs, Trypanocidal
D014349 Trypanosoma cruzi The agent of South American trypanosomiasis or CHAGAS DISEASE. Its vertebrate hosts are man and various domestic and wild animals. Insects of several species are vectors. Trypanosoma cruzus,cruzi, Trypanosoma
D014351 Trypanosomatina A suborder of monoflagellate parasitic protozoa that lives in the blood and tissues of man and animals. Representative genera include: Blastocrithidia, Leptomonas, CRITHIDIA, Herpetomonas, LEISHMANIA, Phytomonas, and TRYPANOSOMA. Species of this suborder may exist in two or more morphologic stages formerly named after genera exemplifying these forms - amastigote (LEISHMANIA), choanomastigote (CRITHIDIA), promastigote (Leptomonas), opisthomastigote (Herpetomonas), epimastigote (Blastocrithidia), and trypomastigote (TRYPANOSOMA). Blastocrithidia,Herpetomonas,Leptomonas,Trypanosomatidae,Blastocrithidias,Herpetomona,Leptomona,Trypanosomatinas
D014355 Chagas Disease Infection with the protozoan parasite TRYPANOSOMA CRUZI, a form of TRYPANOSOMIASIS endemic in Central and South America. It is named after the Brazilian physician Carlos Chagas, who discovered the parasite. Infection by the parasite (positive serologic result only) is distinguished from the clinical manifestations that develop years later, such as destruction of PARASYMPATHETIC GANGLIA; CHAGAS CARDIOMYOPATHY; and dysfunction of the ESOPHAGUS or COLON. Trypanosomiasis, South American,American Trypanosomiasis,Chagas' Disease,Trypanosoma cruzi Infection,Infection, Trypanosoma cruzi,Infections, Trypanosoma cruzi,South American Trypanosomiasis,Trypanosoma cruzi Infections,Trypanosomiasis, American

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