https://orcid.org/0000-0002-3899-8772
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.
Graphical Abstract
Acknowledgments
The authors thank QFI Z M Ramos-Perez for the reference drugs and their time, and J Ontiveros-Rodriguez for obtaining NMR spectroscopy.
Financial & competing interests disclosure
This work was supported financially by CONACyT CB222239, SIP 20196031–20202133 (scholarship no. 307263). The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.
No writing assistance was utilized in the production of this manuscript.