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 2^3-1. 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.

Keywords: COX inhibition; drug optimization; factorial design; imidazo[1,2-a]pyridine; imidazo[1,2-a]pyrimidine.