Cholic acid, a primary bile acid, has emerged as a versatile scaffold for novel therapeutic design due to its unique amphiphilic structure, which imparts both hydrophilic and hydrophobic characteristics. These properties not only enable cholic acid to play essential roles in lipid absorption and cellular signaling via various receptors but also allow extensive chemical modifications that can be harnessed for drug development. Recent advances in medicinal chemistry have demonstrated that cholic acid derivatives and their conjugates can be engineered to enhance drug delivery, improve anticancer efficacy, and overcome antimicrobial resistance. The hydrophobic steroid nucleus of cholic acid, combined with its hydrophilic hydroxyl and carboxyl groups, plays essential role in the production of a broad array of conjugates and hybrid molecules. For example, cholic acid has been conjugated with cytotoxic agents such as cytarabine and tamoxifen, resulting in prodrugs with superior liver-targeting capabilities and enhanced anticancer activity against diverse cell lines, including HL-60, HCT116, MCF-7, and MDA-MB-231. In addition, linkage with platinum drugs, organotin compounds, and artemisinin analogues has yielded compounds that not only exhibit potent cytotoxicity but also overcome multidrug resistance in cancer cells. Beyond oncology, the inherent properties of cholic acid have been exploited to develop effective antimicrobial therapies. Cholic acid-based hybrids have demonstrated significant activity against drug-resistant pathogens, while innovative delivery systems—such as thiomeric micelles encapsulating metallic nanoparticles—have further advanced targeted drug delivery and controlled release. Collectively, these studies underscore the promise of cholic acid as a multifaceted platform in drug design. By fine-tuning chemical linkers and conjugation strategies, researchers have developed a new generation of prodrugs and hybrid molecules that improve therapeutic efficacy while minimizing adverse effects. This review synthesizes current findings on the structure–activity relationships of cholic acid derivatives, addresses challenges in their synthesis and clinical translation, and outlines promising future directions in the field of cholic acid-based therapeutics.
Muhammad Hassan Butt, Kanwal Rehman, Shagufta Kamal, Amjad Hussain
and Muhammad Sajid Hamid Akash