Síntese de oxadiazol, oxadiazol-tiol, híbridos oxadiazol-triazol e hidrazidas-naftoquinonas a partir de hidrazidas aromáticas com potencial atividade biológica

• Ano de defesa: 2023
• Autor(a) principal: Rosane Dias Cezar
• Orientador(a): Denis Pires de Lima
• Tipo de documento: Tese
• Tipo de acesso: Acesso aberto
• Idioma: por
• Instituição de defesa: Fundação Universidade Federal de Mato Grosso do Sul
• País: Brasil
• Palavras-chave em Português: Síntese de Oxadiazol, Oxadiazol-tiol, Híbridos Oxadiazol e Triazol e Triazol a partir de Hidrazidas Aromáticas com Potencial Atividade Biológica
• Link de acesso: https://repositorio.ufms.br/handle/123456789/8303

Specific heterocyclic compounds are a broad class of organic molecules with diverse medicinal and industrial applications. Among them, we can mention 1,3,4-oxadiazoles and 1,2,3-triazoles with different biological activities associated with their structure. The present work aimed to develop new compounds that contain the aforementioned rings using the molecular hybridization strategy, in a multistep linear synthesis route. The experimental procedure consisted first of esterifying commercially obtained carboxylic acids to provide products 2a-2j (65-70%). In the second step, esters were transformed into acylhydrazides 3a-3j (50-56%); subsequently, these compounds were cyclized to generate 1,3,4-oxadiazoles 4a-4d (51-56%) and oxadiazol-thiols (7b-7j). Next, two methodologies were used for alkyne closure in parallel routes (5aC, 5aB, and 7b-7j) with varying yields. In the last step, the click protocol was applied to compound 5aC, resulting in the mixture of triazolo-oxadiazole isomers 5aC, 6aB, 9eB, 9gB, and 9hB with a yield of 3-92%. The evaluated route appeared promising for the development of these molecular hybrids. All compounds were characterized using ¹H NMR and ¹³C NMR analyses and will still be analyzed using complementary techniques such as a High-Resolution Mass Spectrometer. Finally, all prepared compounds will be subjected to biological evaluation tests available through our partnerships. In search of potential agents to treat Chagas disease and leishmaniasis, herein, following the molecular hybridization approach, we report the design, synthesis, and identification of four novel naphthoquinone hydrazide-based molecular hybrids resulting from the fusion of aromatic hydrazides and lawsone. The compounds were subjected to in vitro trypanocide and leishmanicidal activities. N'-(1,4-Dioxo-1,4-dihydronaphthalen-2-yl)-3,5-dimethoxybenzohydrazide (13) showed the best performance against Trypanosoma cruzi (IC50 1.83 µM) and Leishmania amazonensis (IC50 9.65 µM). 4-Bromo-N'-(1,4-dioxo-1,4-dihydronaphthalen-2-yl)benzohydrazide (16) exhibited leishmanicidal activity (IC50 12.16 µM). Regarding trypanocide activity, compound 13 was low cytotoxic to LLC-MK2 cells (SI = 95.28). Furthermore, through molecular modeling studies, the cysteine proteases cruzain, rhodesain, and CPB2.8 were identified as the potential biological target behind the antiparasitic effects. Analysis of intermolecular interactions supports understanding differences in the potency of tested compounds.