Pyridine-containing antitumor agents: structure-oriented medicinal chemistry, structure–activity relationships, and ADMET liabilities

Pyridine is a common nitrogen-containing heteroaromatic motif in antitumor medicinal chemistry, but its design value is highly context dependent. Here, we synthesize structure-oriented medicinal chemistry principles that govern the use of pyridine-related motifs in antitumor drug design. We discuss pyridine-containing antitumor agents with emphasis on target recognition, scaffold organization, structure–activity relationship (SAR), drug metabolism and pharmacokinetics (DMPK), and absorption, distribution, metabolism, excretion, and toxicity (ADMET) liabilities. Representative approved drugs, antibody–drug conjugate (ADC) payloads, targeted degraders, and polypyridyl metal complexes are used to illustrate how pyridine-related motifs can support binding, property tuning, and modality adaptation. By grouping representative compounds according to the medicinal chemistry function of their pyridine-related motifs, this review provides a practical framework for future scaffold design. Overall, pyridine should not be viewed as a universally beneficial privileged scaffold; it is better treated as a context-dependent design module that requires validation through integrated structural, SAR, ADMET, and translational evidence. Pyridine motifs act as context-dependent medicinal chemistry modules rather than universally beneficial privileged scaffolds. Approved pyridine-containing antitumor agents illustrate roles in target recognition, scaffold organization, and ADMET tuning. Phenyl-to-pyridine replacement, pyridinone switching, AO metabolism, and hERG liability require scaffold-specific validation. Pyridine-related motifs may support targeted degraders, ADC payloads, and metal-complex design when evaluated at the modality level.