Recent advances in natural and synthetic phosphonate therapeutics

Phosphonate and phosphinate compounds — both natural and synthetic — have given rise to major families of therapeutics and agricultural agents. The antibiotic fosfomycin, the antivirals foscarnet and tenofovir, the bisphosphonates, and the herbicides phosphinothricin and glyphosate all belong to this compound class. The carbon–phosphorus bonds that define these molecules enable chemical mimicry of essential phosphate ester and carboxylate metabolites within metabolism, which is the foundation for their bioactivity. Here, we review examples of C-P compounds in drug discovery. In the first half, we highlight the ongoing development of two phosphonate natural products, both of which were initially discovered as antibiotics: fosmidomycin, which has undergone clinical trials as an antimalarial, and SF-2312, derivatives of which are currently being explored as chemotherapeutics. In the second half, we summarize how the C-P moiety has inspired chemical synthesis of new antimicrobials, immunomodulators, and targeted protein degradation agents.