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Compostos de Biginelli como potenciais inibidores da xantina oxidase
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Advisor(s)
Abstract(s)
A presente dissertação teve como objetivo o desenvolvimento e a avaliação de compostos com potencial atividade anti-hiperuricémica, visando a inibição da enzima xantina oxidase (XO) e a atividade antioxidante. Para isso, foi sintetizada uma série de compostos (série EF) e foram avaliadas três séries de compostos: (i) a série EF, composta por derivados de di-hidropirimidin-2(1H)-tionas obtidos através da reação de Biginelli; (ii) a série MM; e (iii) a série 7b, ambas formadas por análogos previamente sintetizados. Os compostos foram submetidos a ensaios in vitro de inibição da XO, utilizando o alopurinol como referência, e a ensaios de capacidade antioxidante pelo método do radical 2,2-difenil-1-picrilhidrazil. A série EF apresentou atividade limitada, com destaque para o composto EF11, que alcançou 10,59% de inibição da XO. Na avaliação antioxidante, todos os compostos EF apresentaram percentuais negativos de redução, sugerindo ausência de atividade antioxidante ou possível comportamento pró-oxidante. Por outro lado, as séries MM e 7b revelaram resultados significativamente superiores. Na primeira, os compostos MM74, MM35 e MM84 destacaram-se com inibição acima de 20%. A série 7b apresentou atividade maior, com o derivado 7.15b atingindo 39,01% de inibição da XO. A diversidade estrutural destas séries parece contribuir para uma maior afinidade com o sítio ativo da enzima, corroborando com o princípio de que pequenas variações estruturais impactam fortemente a bioatividade. Os resultados obtidos reforçam a importância da integração entre síntese racional, caracterização biológica e planeamento estrutural orientado, contribuindo para a identificação de novos candidatos terapêuticos direcionados particularmente à inibição da XO.
This dissertation aimed to develop and evaluate compounds with potential anti-hyperuricemic and antioxidant activity, specifically targeting the inhibition of the enzyme xanthine oxidase (XO). For this purpose, three series of compounds were investigated: (i) the EF series, consisting of 3,4-dihydropyrimidin-2-(1H)-thione derivatives synthesized via the Biginelli multicomponent reaction; (ii) the MM series, and (iii) the 7b series, composed of previously synthesized molecules based on pharmacophorically validated scaffolds. The compounds were subjected to in vitro assays to evaluate XO inhibition, using allopurinol as the reference drug, and to antioxidant activity tests employing the DPPH radical method. The EF series displayed limited activity, with EF11 being the most active (10.59% XO inhibition), while the remaining compounds exhibited minimal or even negative values. In the antioxidant assay, all EF compounds showed negative reduction percentages, suggesting a lack of effective radical scavenging or a potential pro-oxidant behavior. In contrast, the MM and 7b series exhibited significantly superior results. In the MM series, MM74, MM35, and MM84 stood out with inhibition values exceeding 20%. The 7b series showed the most promising performance, with compound 7.15b reaching 39.01% inhibition of XO. The structural diversity within these series appears to enhance their affinity for the enzyme's active site, supporting the notion that subtle structural variations can markedly influence bioactivity. The results obtained reinforce the importance of integrating rational synthesis, biological evaluation, and structure-based design strategies, contributing to the identification of novel therapeutic candidates targeting XO inhibition and the mitigation of oxidative stress.
This dissertation aimed to develop and evaluate compounds with potential anti-hyperuricemic and antioxidant activity, specifically targeting the inhibition of the enzyme xanthine oxidase (XO). For this purpose, three series of compounds were investigated: (i) the EF series, consisting of 3,4-dihydropyrimidin-2-(1H)-thione derivatives synthesized via the Biginelli multicomponent reaction; (ii) the MM series, and (iii) the 7b series, composed of previously synthesized molecules based on pharmacophorically validated scaffolds. The compounds were subjected to in vitro assays to evaluate XO inhibition, using allopurinol as the reference drug, and to antioxidant activity tests employing the DPPH radical method. The EF series displayed limited activity, with EF11 being the most active (10.59% XO inhibition), while the remaining compounds exhibited minimal or even negative values. In the antioxidant assay, all EF compounds showed negative reduction percentages, suggesting a lack of effective radical scavenging or a potential pro-oxidant behavior. In contrast, the MM and 7b series exhibited significantly superior results. In the MM series, MM74, MM35, and MM84 stood out with inhibition values exceeding 20%. The 7b series showed the most promising performance, with compound 7.15b reaching 39.01% inhibition of XO. The structural diversity within these series appears to enhance their affinity for the enzyme's active site, supporting the notion that subtle structural variations can markedly influence bioactivity. The results obtained reinforce the importance of integrating rational synthesis, biological evaluation, and structure-based design strategies, contributing to the identification of novel therapeutic candidates targeting XO inhibition and the mitigation of oxidative stress.
Description
Keywords
Xantina oxidase Di-hidropirimidinonas Reação de Biginelli Atividade antioxidante Inibição enzimática Xanthine oxidase Dihydropyrimidines