Synthesis of withaferin a derivatives and exploratory evaluation of weight reduction and fasting blood glucose in DIO mice.

Obesity and its cardiometabolic complications remain a major public-health burden. Leptin resistance is a common feature of hyperleptinemic obesity, but the molecular basis of leptin resensitization remains incompletely understood, making the rational optimization of leptin-sensitizing agents difficult. Withaferin A (1) has been reported to enhance leptin responsiveness and to reduce body weight and the fasting blood glucose in diet-induced obese (DIO) mice. In this study, a series of withaferin A derivatives (2-15) bearing modifications in the A/B-ring region and the C-27 side-chain/lactone moiety was synthesized and evaluated in DIO mice. The compounds were administered intraperitoneally at 1.2 mg kg-1 once daily for 21 days. Withaferin A produced sustained reductions in body weight, cumulative food intake, and fasting blood glucose. Most derivatives showed weaker or less consistent responses, although compounds 2, 6, 10, and 12 significantly reduced body weight relative to the vehicle group at day 21. Overall, withaferin A (1) showed the most consistent response across the measured endpoints. These results suggest that structural modifications in either the A/B-ring region or the C-27 side-chain/lactone moiety affect the in vivo phenotypic responses of withaferin A. This study provides preliminary phenotype-level in vivo SAR information for withaferin A derivatives and may assist the design of compounds for further evaluation.