Factorial design in the optimization and study 'in combo' of derivatives of imidazo[1,2-a]azines in the COX´s isoforms inhibition.

Abstract

Background: Imidazo[1,2-a]azines with an acid group decrease inflammatory processes in murine models, and the effect has been attributed to the inhibition of COX enzymes. Results: The optimization of a series of imidazo[1,2-a]azines was performed using the reduced factorial design 23-1. The inhibitory effects of five acid derivatives of imidazo[1,2-a]azines and the standard drugs ibuprofen and indomethacin were evaluated in vitro on COX isoforms. It was observed that the different substituents provided different inhibition profiles, highlighting that the imidazo[1,2-a]pyridines are more active than the bioisosteric imidazo[1,2-a]pyrimidines. These results were analyzed using in silico docking to recognize the structural elements necessary for the inhibition of the targets. The IC50 values for COX1 and COX2 for the various compounds were as follows. COX1: 4a = 2.72 μM, 4b = 3.94 μM, 5a = 7.29μM, 5b = 63.26 μM, 6a = 12.93 μM, indomethacin = 0.13 μM, ibuprofen = 0.2 μM; COX 2: 4a = 1.89 μM, 4b = 2.39 μM, 5a = 8.08 μM, 5b = 41.15 μM, 6a = 5.86 μM, indomethacin = 0.09 μM, ibuprofen = 0.125 μM. Conclusion: Through factorial design it was possible to optimize the inhibitory response on therapeutic targets, obtaining molecule 4a as a result of factorial analysis.