Docking And Pharmacological Antioxidant And Anti-Diabetic Activity Of Pyrazole Derivatives

Abstract

The pyrazole is a privileged N-heterocycle that has enough structural flexibility to be used as enzyme inhibitors, radical scavengers and have good drug-like properties. This study reanalyzed compound-level data from open-access primary investigations to investigate whether pyrazole derivatives can be utilized to develop an effective dual approach to postprandial glucose control and oxidative-stress attenuation. The quantitative data included eleven acyl pyrazole sulfonamides tested against alpha-glucosidase and two pyrazole derivatives tested against alpha-glucosidase, alpha-amylase, five antioxidant endpoints, and molecular docking targets. The analytical unit was the reported compound-level mean IC50 or SC50 value as there were no observations of raw absorbance or concentration response. Descriptive statistics and Shapiro-Wilk, one-sample Wilcoxon signed-rank, exact sign testing, fold-potency estimation, bootstrapping, and exploratory rank-concordance analysis were performed. The median IC50 of the 11 compounds was 4.11 micromolar (interquartile range 3.03-13.55), while acarbose's median IC50 was 35.1 micromolar. All eleven compounds were more potent than the comparator; for this library level result (not replicate level) the one sided Wilcoxon test was significant (W=0, p=0.00049) but this is for exploratory purposes and not to replace replicate level inference. Acarbose showed 31.06-fold less activity than compound 5a, which was the most potent inhibitor with an IC50 of 1.13 micromolar. The results from DPPH assays, ABTS assays, FRAP assays, hydrogen-peroxide scavenging assays, and xanthine-oxidase assays are shown in the following comparisons: In all five comparisons, the inhibitory concentrations of Pyz-2 were lower than that of Pyz-1 (exact sign-test p=0.031); in all comparisons except for hydrogen-peroxide scavenging, Pyz-2 exhibited an inhibitory concentration that was either equal to or lower than that of another Pyz-3 group, indicating a conservative improvement of 1.00 to 1.98-fold. Docking rankings were shown to be in agreement with alpha-glucosidase activity but not in a consistent manner with alpha-amylase activity, thus suggesting that docking ought not to supplant the pharmacologic testing. The evidence is that the combined data sets suggest that acyl-pyrazole sulfonamides and triazole-thiol pyrazole hybrids are potential lead classes and that it is important to have consistent assays, toxicity studies, mammalian enzyme models, and in vivo validation.