A multimodal caffeic acid-derived alkyl-amide antidiabetic agent: targeting α-glucosidase, α-amylase, oxidative stress, and protein glycation

Historically, natural products have been a primary source of new drugs and lead compounds. However, their direct application as therapeutic agents remains limited. Given the multifactorial nature of diabetes, therapeutic agents with multi-targeting properties offer a promising solution for effective management. Herein, we developed a library of seven lipophilic derivatives of caffeic acid (CA) and evaluated their multimodal antidiabetic activities. Among these, the most potent compound, CA14, showed an IC₅₀ of 1.94 μM, representing a 113-fold improvement over acarbose (IC₅₀ 219.70 μM). Further, compared to the parent compound CA (IC₅₀ 12 400 μM), CA14 was 6392 times more potent. Kinetic analysis revealed that CA14 acts as a competitive inhibitor of α-glucosidase. CA14 showed comparable α-amylase inhibition to that of acarbose, while CA showed no inhibition even at 500 μM. Additionally, CA14 exhibited antiglycation activity by inhibiting fructosamine and advanced glycation end products (AGEs). It also showed excellent antioxidant activity (IC₅₀ 13.98 μM), nearly twice as potent as Vitamin C. Notably, acarbose lacked any antioxidant activity. Intrinsic fluorescence quenching and FT-IR analyses further confirmed that CA14 disrupted substrate binding, reducing enzymatic activity. Of note, CA14 did not exhibit any significant cytotoxicity in 3T3-L1 fibroblasts, even at 50 μM. Molecular docking revealed good extent of interactions, while ADMET profiling predicted favorable druglikeness. CA14 was found to be stable under physiological conditions even after 10 days. In summary, CA derivatives demonstrated robust multifaceted antidiabetic potential by inhibiting α-glucosidase, α-amylase, and AGE formation, while also mitigating oxidative stress, which are key contributors to diabetes progression.