Withanolide Scaffold in Drug Discovery: A Review of Structural Modifications, Structure-Activity Relationships, and Pharmacological Targets

Withanolides are C-28 polyoxygenated steroidal lactones that are characterised by a pair of C2-C3 enones and an α,β-unsaturated d-lactone held in fixed space geometry by a rigid ergostane tetracyclic core. The architecture allows specific covalent interaction with nucleophilic cysteine targets in the protein of interest of mechanobiological interest and has been utilised in a polypharmacology profile of anticancer, anti-inflammatory, neuroprotective, and immunomodulatory activities. A pre-existing SAR dataset of significant chemical depth in more than 1,200 natural analogues spread out in 15 genera in the Solanaceae provides a basis that is further extended by emerging semi-synthetic literature. This review critically discusses the medicinal chemistry-based analysis of withanolide scaffold modification as structural changes at the A-ring enone, lactone ring, peripheral hydroxyl positions and C-17 side chain translate into defined biological outcomes at molecular targets of validated structure requirements that are defined as pharmacophoric elements. Cytotoxic, anti-inflammatory and neuroprotective phages, with their structural separability being a key feature, are is the new opportunities in chemoproteomics-mediated target discovery, biosynthetic engineering and targeted covalent drug design