Identification of Novel Zika Virus Inhibitors: A Screening using Thiosemicarbazones and Thiazoles Templates.

BACKGROUND: Zika virus (ZIKV) remains an important cause of congenital infection, fetal microcephaly, and Guillain-Barré syndrome in the population. In 2016, WHO declared a cluster of microcephaly cases and other neurological disorders reported as a global public health emergency in Brazil. There is still no specific treatment for Zika virus fever, only palliative care. Therefore, there is a need for new therapies against this disease. According to the literature, thiosemicarbazone, phthalimide and thiazole are privileged structures with several biological activities, including antiviral activity against various viruses. OBJECTIVE: Based on this, this work presents an antiviral screening using previously synthesized compounds derived from thiosemicarbazone, phthalimide, and thiazole as new hits active against ZIKV. METHODS: After synthesis and characterization, all compounds were submitted to Cytotoxicity by MTT and Antiviral activity against ZIKV assays. RESULTS: Compounds 63, 64, 65, and 73 exhibited major reductions in the ZIKV title from this evaluation. Compounds 63 (99.74%), 64 (99.77%), 65 (99.92%), and 73 (99.21%) showed a higher inhibition than the standard 6MMPr (98.74%) at the CC20 dose. These results revealed new chemical entities with anti-ZIKV activity. CONCLUSION: These derivatives are promising candidates for further assays. In addition, the current approach brings a new privileged scaffolding, which may drive future drug discovery for ZIKV.

Structural improvement of new thiazolyl-isatin derivatives produces potent and selective trypanocidal and leishmanicidal compounds.

Neglected diseases are a group of transmissible diseases that occur mostly in countries in tropical climates. Among this group, Chagas disease and leishmaniasis stand out, considered threats to global health. Treatment for these diseases is limited. Therefore, there is a need for new therapies against these diseases. In this sense, our proposal consisted of developing two series of compounds, using a molecular hybridization of the heterocyclic isatin and thiazole. The isatin and thiazole ring are important scaffold for several biological disorders, including antiparasitic ones. Herein, thiazolyl-isatin has been synthesized from respective thiosemicarbazone or phenyl-thiosemicarbazone, being some of these new thiazolyl-isatin toxic for trypomastigotes without affecting macrophages viability. From this series, compounds 2e (IC50 = 4.43 µM), 2j (IC50 = 2.05 µM), 2l (IC50 = 4.12 µM) and 2m (1.72 µM) showed the best anti-T. cruzi activity for trypomastigote form presenting a selectivity index higher than Benznidazole (BZN). Compounds 2j, 2l and 2m were able to induce a significantly labelling compatible with necrosis in trypomastigotes. Analysis by scanning electron microscopy showed that T. cruzi trypomastigote cells treated with the compound 2m from IC50 concentrations, promoted changes in the shape, flagella and surface of body causing of the parasite dead. Concerning leishmanicidal evaluation against L. amazonensis and L. infantum, compounds 2l (IC50 = 7.36 and 7.97 µM, respectively) and 2m (6.17 and 6.04 µM, respectively) showed the best activity for promastigote form, besides showed a higher selectivity than Miltefosine. Thus, compounds 2l and 2m showed dual in vitro trypanosomicidal and leishmanicidal activities. A structural activity relationship study showed that thiazolyl-isatin derivatives from phenyl-thiosemicarbazone (2a-m) were, in general, more active than thiazolyl-isatin derivatives from thiosemicarbazone (1a-g). Crystallography studies revealed a different configuration between series 1a-g and 2a-m. The configuration and spatial arrangement divergent between the two sub-series could explain the improved biological activity profile of 2a-m sub-series.

The design, synthesis, and in vitro trypanocidal and leishmanicidal activities of 1,3-thiazole and 4-thiazolidinone ester derivatives.

Chagas and leishmaniasis are both neglected tropical diseases, whose inefficient therapies have made them remain the cause for millions of deaths worldwide. Given this, we synthesized 27 novel 1,3-thiazoles and 4-thiazolidinones using bioisosteric and esterification strategies to develop improved and safer drug candidates. After an easy, rapid and low-cost synthesis with satisfactory yields, compounds were structurally characterized. Then, in vitro assays were performed, against Leishmania infantum and Leishmania amazonensis promastigotes, Trypanosoma cruzi trypomastigotes and amastigotes, for selected compounds to determine IC50 and SI, with cytotoxicity on LLC-MK2 cell lines. Overall, 1,3-thiazoles exhibited better trypanocidal activity than 4-thiazolidinones. The compound 1f, an ortho-bromobenzylidene-substituted 1,3-thiazole (IC50 = 0.83 µM), is the most potent of them all. In addition, compounds had negligible cytotoxicity in mammalian cells (CC50 values > 50 µM). Also noteworthy is the examination of the cell death mechanism of T. cruzi, which showed that compound 1f induced necrosis and apoptosis in the parasite. Scanning electron microscopy analysis demonstrated that the treatment of Trypanosoma cruzi trypomastigote cells with the compound 1f at different IC50 concentrations promoted alterations in the shape, flagella and body surface, inducing parasite death. Together, our data revealed a novel series of 1,3-thiazole structure-based compounds with promising activity against Trypanosoma cruzi and Leishmania spp., broadening ways for scaffold optimization.