Novel 5-(1-aryl-1H-pyrazol-3-yl)-1H-tetrazoles as glycogen phosphorylase inhibitors: An in vivo antihyperglycemic activity study.

In this study, we report the ring transformation of 3-arylsydnone into 1-aryl-1H-pyrazole-3-carbonitriles via [3 + 2] cycloaddition with acrylonitrile. 1-Aryl-1H-pyrazole-3-carbonitrile underwent [2 + 3] cycloaddition with sodium azide to afford 5-(1-aryl-1H-pyrazol-3-yl)-1H-tetrazoles which were further subjected to N-alkylation with aryl/heteroaryl alkyl halides to afford 1,5- and 2,5-disubstituted tetrazoles. Furthermore, the title compounds were screened for in vivo antihyperglycemic activity using albino Wistar rats of either sex. Compounds 4a, 6b, 7a, 7b, 8b, and 9b showed maximum fall in the blood glucose levels in streptozotocin-induced diabetic rats after 5-7 days of administration. In support of antidiabetic activity, we also performed the experimental in vivo studies, namely, effect of compounds on enzymes (serum glutamic oxaloacetic transaminase, serum glutamic-pyruvic transaminase, creatinine, urea, and total protein), antihyperlipidemic, and histopathology. Moreover, the molecular docking study has been performed for potent molecules among the series with glycogen phosphorylase as target enzyme, and this study corroborated the experimental in vivo results.