The protein tyrosine phosphatases (PTPase) are a group of regulatory enzymes that are critically important to a wide variety of cellular functions. PTPase 1B has recently been implicated in the pathogenesis of diabetes, neuronal disease, and autoimmune diseases. A number of these PTPase that act as negative regulators of the insulin signaling cascade have been identified as novel targets for the therapeutic enhancement of insulin action in insulin-resistant disease states like type II diabetes. Therefore, in the present work we describes a study of the synthesis and structure–activity relationship (SAR) of chromene and 2,4-dimethoxy benzaldehyde-based isoxazolines, which are structurally related to potent PTPase inhibitors. Compounds 5–7 and 10–19 were synthesized via 1,3-dipolar cycloaddition reaction and evaluated against PTPase enzyme in vitro. Compounds 10, 14, and 19 displayed significant inhibitory activity with IC50 values of 69, 88, and 62.7 lM, respectively. Active compounds 10, 11, 14–16, and 19 were also tested in the STZ-S in vivo assay model, and compounds 10, 14, and 19 were found to be active.