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Design and Synthesis of Triazole-Phthalimide Hybrids with Anti-inflammatory Activity

2019; Pharmaceutical Society of Japan; Volume: 67; Issue: 2 Linguagem: Inglês

10.1248/cpb.c18-00607

1347-5223

Shalom Pôrto de Oliveira Assis, Moara T. da Silva, Filipe Torres da Silva, Mirella P. Sant’Anna, Carolina M. B. de Albuquerque Tenório, Caroline F. Brito dos Santos, Caíque Silveira Martins da Fonseca, Gustavo Seabra, Vera Lúcia de Menezes Lima, Ronaldo N. de Oliveira,

Synthesis and Biological Evaluation

Phthalimido-alkyl-1H-1,2,3-triazole derivatives 3a–d and 4a–d were efficiently synthesized using 1,3-dipolar cycloaddition reaction. Anti-inflammatory activity and toxicity studies were performed. The results demonstrated that all the tested compounds reduced carrageenan-induced paw edema and indicated no lethality for toxicity against Artemia salina and acute toxicity in vivo (LD50 up to 1 g kg −1). Furthermore, the structure of phthalimide linked to phenyl group proved to be more active than the compounds containing benzothiazole moiety. Structural modifications such as removal of the phthalimide group and subsequent acetylation, to exemplify a non-cyclic amide, demonstrate that the phthalimide and triazole moieties are important for design of potent candidates with anti-inflammatory drug proprieties. Docking into the cyclooxygenase-2 (COX-2) confirms the importance of the phthalimide and triazole groups in the anti-inflammatory activity. The histopathological studies showed that the compounds 3a–d and 4a–d did not cause serious pathological lesions liver or kidneys.