Bridging mechanism and design: modern medicinal chemistry approaches to thymidylate synthase inhibitors.

ABSTRACT: Thymidylate synthase (TS) is a folate-dependent enzyme essential for DNA synthesis and cell proliferation, making it one of the most enduring and clinically validated targets in anticancer chemotherapy. This review provides a comprehensive overview of TS structure, catalytic mechanism, and inhibition modes, emphasizing its central role in the action of classical antimetabolites such as fluoropyrimidines and antifolates. Despite decades of clinical success, drug resistance, toxicity, and limited tumor selectivity continue to challenge TS-targeted therapy. Recent advances in medicinal chemistry have introduced novel heterocyclic scaffolds, particularly oxadiazoles, pyrimidines, and their hybrid analogs, exhibiting improved TS inhibition, cytotoxic selectivity, and multitarget potential. Stru

SUBMITTER: Al-Karmalawy AA 

PROVIDER: S-EPMC12809673 | biostudies-literature | 2026 Jan

REPOSITORIES: biostudies-literature