Naturally and synthetically derived hybrid molecules are promising sources for new drug development due to their multiple modes of action and their ability to bypass systemic toxicities associated with traditional combination therapies. The rapid escalation of multifactorial diseases such as cancer, neurodegenerative disorders, and multidrug-resistant infections has exposed the limitations of traditional polypharmacy. To overcome these challenges, molecular hybridization has emerged as a cutting-edge paradigm in rational drug design, allowing the scientific community to report dozens of highly potent hybrids. This strategy involves the fusion of two or more distinct pharmacophores into a single multi-target directed ligand. Due to its unique α,β-unsaturated ketone framework, high conformational flexibility, and ease of synthesis, the chalcone scaffold represents a highly privileged template for building a hybrid scaffold as a bioactive agent. This review comprehensively explores the chemical architecture, synthetic methodologies (including green ionic liquid protocols), and profound biological potential of chalcone derivatives. We critically analyze the pharmacodynamic efficacy of various chalcone conjugates, including fluoroquinolone mutual prodrugs for antimicrobial resistance, benzimidazole and α-bromoacryloylamido hybrids for terminal cell cycle arrest in oncology, and sulfonamide chalcones as non-competitive α-glucosidase inhibitors for metabolic syndrome. Finally, we discuss the structure-activity relationship (SAR) profiles and the translational challenges of utilizing chalcone hybrids, highlighting the future integration of nanotechnology and artificial intelligence in overcoming pharmacokinetic barriers.
Keywords: Chalcone derivatives, Molecular hybridization, multi-target directed ligands, Claisen-Schmidt condensation, Drug design, Multifactorial diseases