Diabetes mellitus remains a global health challenge, demanding innovative therapeutic solutions. Herein, we present the design, synthesis, and pharmacological evaluation of a novel series of carbazole-thiadiazole hybrids targeting key enzymes in carbohydrate metabolism. Among the synthesized compounds, 5l emerged as the most potent inhibitor of α-amylase, with an IC₅₀ value of 0.68 µM—far surpassing the efficacy of the standard drug acarbose (IC₅₀: 5.19 µM). Similarly, 5r exhibited exceptional dual activity against both α-amylase and α-glucosidase, with IC₅₀ values of 1.63 µM and 0.14 µM, respectively, highlighting its dual inhibitory potential. Biological assays demonstrated the compounds’ low cytotoxicity on hepatic stellate (LX-2) cells, affirming their safety for therapeutic use. Molecular docking studies provided mechanistic insights into their binding interactions, revealing strong hydrogen bonding and hydrophobic interactions with key active site residues. Density functional theory (DFT) and electrostatic potential (ESP) analyses further elucidated their electronic properties, offering a deeper understanding of their structure–activity relationships. Pharmacokinetic profiling via the BOILED-Egg model confirmed these derivatives’ excellent oral bioavailability and drug-likeness. Collectively, these findings establish carbazole-thiadiazole hybrids as promising candidates for next-generation antidiabetic therapies, warranting further investigation in preclinical and clinical settings.

Title

Bioorganic Chemistry

Publisher

Elsevier

Publisher Country

United States of America

Indexing

Thomson Reuters

Impact Factor

4.5

Publication Type

Prtinted only

Volume

49

Year

2025

Pages

1-25