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

• Published in: European journal of medicinal chemistry 2023-06, Vol.254, p.115310-115310, Article 115310
• Main Authors: Conceição, Juliana Maria da, Santos, Aline Caroline da Silva, Brayner, Fabio André, Alves, Luiz Carlos, Pinto, Aline Ferreira, Brondani, Graziella Leite, Oliveira Filho, Gevânio Bezerra de, Bedor, Danilo Cesar Galindo, Silva, José Wellithom Viturino da, Sales Junior, Policarpo Ademar, Cavalcante, Marton Kaique de Andrade, Silva, Elis Dionísio da, Pereira, Valéria Rêgo Alves, Leite, Ana Cristina Lima
• Format: Article
• Language: English
• Subjects: Antiparasitic Agents - pharmacology; Chagas Disease - drug therapy; Humans; Leishmania amazonensis; Leishmania mexicana; Pyridine; Structure-Activity Relationship; Thiazolidinone; Trypanocidal Agents - chemistry; Trypanosoma cruzi; Trypanosomatina
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2023.115310

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. [Display omitted] •Piridyl-thiazolidinones with an anti-Trypanosomatidae profile.•Derivatives showing SI values better than benznidazole against amastigote form.•Compounds modulate IL-6 and IL-10 cytokines.•Compounds causes necrosis induction.•Compounds exhibited drug-likeness profiles.