Uncontrolled diabetes can lead to hyperglycemia, which causes neuropathy, heart attacks, retinopathy, and nervous system damage over time, therefore, controlling hyperglycemia using potential drug target inhibitors is a promising strategy. This work focused on synthesizing new derivatives via the diazo group, using a hybridization strategy involving two approved drugs, paracetamol and several sulfonamides. The newly designed diazo-paracetamols 5-12 were fully characterized and then screened for in vitro α-amylase and α-glucosidase activities and exhibited inhibitory percentages (IP) = 92.5-96.5 % and 91.0-95.7 % compared to Acarbose IP = 96.5 and 95.8 %, respectively at 100 μg/mL. The ICvalues of the synthesized derivatives were evaluated against α-amylase and α-glucosidase enzymes, and the results demonstrated moderate to potent activity. Among the tested diazo-paracetamols, compound 11 was found to have the highest potency activity against α-amylase with ICvalue of 0.98 ± 0.015 μM compared to Acarbose IC = 0.43 ± 0.009 μM, followed by compound 10 (IC = 1.55 ± 0.022 μM) and compound 9 (IC = 1.59 ± 0.023 μM). On the other hand, for α-glucosidase, compound 10 with pyrimidine moiety demonstrated the highest inhibitory activity with IC = 1.39 ± 0.021 μM relative to Acarbose IC = 1.24 ± 0.029 μM and the order of the most active derivatives was 10 > 9 (IC = 2.95 ± 0.046 μM) > 11 (IC = 5.13 ± 0.082 μM). SAR analysis confirmed that the presence of 4,5-dimethyl-isoxazole or pyrimidine nucleus attached to the sulfonyl group is important for activity. Finally, the docking simulation was achieved to determine the mode of binding interactions for the most active derivatives in the enzyme's active site. 50 50 50 50 50 50 50 50 50
