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Design, Synthesis and Pharmacological Evaluation of Novel Antiinflammatory and Analgesic O-Benzyloxime Compounds Derived From Natural Eugenol

[ Vol. 16 , Issue. 10 ]

Author(s):

Rodrigo César da Silva, Fabiano Veiga, Fabiana Cardoso Vilela, André Victor Pereira, Thayssa Tavares da Silva Cunha, Roberta Tesch, Claudio Viegas Jr., Danielle Ferreira Dias, Alexandre Giusti-Paiva, Marcia Paranho Veloso and Carlos Alberto Manssour Fraga*   Pages 1157 - 1166 ( 10 )

Abstract:


Background: A new series of O-benzyloximes derived from eugenol was synthesized and was evaluated for its antinociceptive and anti-inflammatory properties.

Methods: The target compounds were obtained in good global 25-28% yields over 6 steps, which led us to identify compounds (Z)-5,6-dimethoxy-2,2-dimethyl-2,3-dihydro-1H-inden-1-one-O-(4- (methylthio)benzyloxime (8b), (Z)-5,6-dimethoxy-2,2-dimethyl-2,3-dihydro-1H-inden-1-one-O-4- bromobenzyloxime (8d) and (Z)-5,6-dimethoxy-2,2-dimethyl-2,3-dihydro-1H-inden-1-one-O-4- (methylsulfonyl)benzyloxime (8f) as promising bioactive prototypes.

Results: These compounds have significant analgesic and anti-inflammatory effects, as evidenced by formalin-induced mice paw edema and carrageenan-induced mice paw edema tests. In the formalin test, compounds 8b and 8f evidenced both anti-inflammatory and direct analgesic activities and in the carrageenan-induced paw edema, with compounds 8c, 8d, and 8f showing the best inhibitory effects, exceeding the standard drugs indomethacin and celecoxib.

Conclusion: Molecular docking studies have provided additional evidence that the pharmacological profile of these compounds may be related to inhibition of COX enzymes, with slight preference for COX-1. These results led us to identify the new O-benzyloxime ethers 8b, 8d and 8f as orally bioactive prototypes, with a novel structural pattern capable of being explored in further studies aiming at their optimization and development as drug candidates.

Keywords:

O-benzyloxime, eugenol, indanone derivatives, anti-inflammatory, analgesic, drug design.

Affiliation:

Laboratório de Fitoquímica e Química Medicinal (LFQM), Universidade Federal de Alfenas, 37130-000, Alfenas, MG, Laboratório de Fitoquímica e Química Medicinal (LFQM), Universidade Federal de Alfenas, 37130-000, Alfenas, MG, Laboratório de Fisiologia, Universidade Federal de Alfenas, 37130-000, Alfenas, MG, Laboratório de Pesquisa em Química Farmacêutica (LQFar), Universidade Federal de Alfenas, 37130-000, Alfenas, MG, Laboratório de Avaliação e Síntese de Substâncias Bioativas (LASSBio), Instituto de Ciências Biomédicas, Universidade Federal do Rio de Janeiro, PO Box 68023, 21941-902, Rio de Janeiro, RJ, Laboratório de Avaliação e Síntese de Substâncias Bioativas (LASSBio), Instituto de Ciências Biomédicas, Universidade Federal do Rio de Janeiro, PO Box 68023, 21941-902, Rio de Janeiro, RJ, Programa de Pós-Graduação em Química, Universidade Federal de Alfenas, 37130-000, Alfenas, MG, Laboratório de Fitoquímica e Química Medicinal (LFQM), Universidade Federal de Alfenas, 37130-000, Alfenas, MG, Laboratório de Fisiologia, Universidade Federal de Alfenas, 37130-000, Alfenas, MG, Laboratório de Pesquisa em Química Farmacêutica (LQFar), Universidade Federal de Alfenas, 37130-000, Alfenas, MG, Laboratório de Avaliação e Síntese de Substâncias Bioativas (LASSBio), Instituto de Ciências Biomédicas, Universidade Federal do Rio de Janeiro, PO Box 68023, 21941-902, Rio de Janeiro, RJ

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