Heteroatom modified carbohydrate scaffolds in drug discovery

Abstract Carbohydrate-derived heteroatom scaffolds have emerged as versatile frameworks in modern drug discovery due to their inherent stereochemical diversity, biocompatibility, and ability to engage biological targets through multiple noncovalent interactions. These include iminosugars, in which nitrogen take the place of the ring oxygen, represent a particularly promising class, exhibiting potent glycosidase inhibition, chaperone activity, and antiviral properties. Recent advances in synthetic methodologies, including heteroatom substitution, Prins cyclization, and metal-catalyzed C-glycoside formation, have enabled efficient access to structurally diverse analogues and glycohybrids. Concurrently, the integration of computational methods like molecular dynamics simulations, molecular docking, and ADMET profiling has enhanced rational design, enabling prediction of binding affinities, conformational stability, and pharmacokinetic properties. Hybrid scaffolds that combine carbohydrate motifs with heterocycles (e.g., triazoles, pyridazines, coumarins, isatins) have demonstrated multifunctional biological processes, such as anti-inflammatory, anticancer, antibacterial, and antidiabetic effects. Case scrutiny on diazaspiro-iminosugars, pyrrolidine derivatives, azetidine analogues, and fluorinated iminosugars illustrate how structural modifications fine-tune enzyme selectivity and potency, supported by strong correlations between in vitro assays and in silico docking results. Collectively, these trends highlight the growing potential of carbohydrate-derived heteroatom scaffolds, particularly iminosugars, as next-generation therapeutic agents positioned at the intersection of synthetic innovation and computational drug design.