Indenoquinoxaline-phenylacrylohydrazide Hybrids As Promising Drug Candidates for the Treatment of Type 2 Diabetes: in Vitro and in Silico Evaluation of Enzyme Inhibition and Antioxidant Activity.

Existing drugs that are being used to treat type -2 diabetes mellitus are associated with several side effects; thus, exploring potential drug candidates is still an utter need these days. Hybrids of indenoquinoxaline and hydrazide have never been explored as antidiabetic agents. In this study, a series of new indenoquinoxalinephenylacrylohydrazide hybrids ( 130 ) were synthesized, structurally characterized, and evaluated for alpha-amylase and alpha-glucosidase inhibitory activities, as well as for their antioxidant properties. All scaffolds exhibited varying degrees of inhibitory activity against both enzymes, with IC 50 values ranging from 2.34 to 61.12 mu M for alpha-amylase and 0.42 to 54.72 mu M for alpha-glucosidase. Particularly, compounds 10 , 16 , 17 , 18 , 24 , and 25 demonstrated the highest efficacy in inhibiting alpha-amylase, while compounds 6 , 7 , 8 , 10 , 12 , 14 , 13 , 16 , 17 , 18 , 24 , and 25 were the most effective alpha-glucosidase inhibitors, compared to standard acarbose. Moreover, most of these compounds displayed substantial antioxidant potential compared to standard butylated hydroxytoluene (BHT). Kinetics studies revealed competitive inhibition modes by compounds. Furthermore, a comprehensive in silico study and toxicity prediction were also conducted, further validating these analogs as potential drug candidates. The structured compounds demonstrated enhanced profiles, underscoring their potential as primary candidates in drug discovery.