ABSTRACT
Natural products have routinely been used both as sources of and inspiration for new crop protection active ingredients. The natural product UK-2A has potent anti-fungal activity but lacks key attributes for field translation. Post-fermentation conversion of UK-2A to fenpicoxamid resulted in an active ingredient with a new target site of action for cereal and banana pathogens. Here we demonstrate the creation of a synthetic variant of fenpicoxamid via identification of the structural elements of UK-2A that are needed for anti-fungal activity. Florylpicoxamid is a non-macrocyclic active ingredient bearing two fewer stereocenters than fenpicoxamid, controls a broad spectrum of fungal diseases at low use rates and has a concise, scalable route which is aligned with green chemistry principles. The development of florylpicoxamid represents the first example of using a stepwise deconstruction of a macrocyclic natural product to design a fully synthetic crop protection active ingredient.
Subject(s)
Antifungal Agents/pharmacology , Biological Products/pharmacology , Drug Discovery , Macrocyclic Compounds/pharmacology , Pyridines/pharmacology , Antifungal Agents/chemical synthesis , Antifungal Agents/chemistry , Ascomycota/drug effects , Biological Products/chemical synthesis , Biological Products/chemistry , Dose-Response Relationship, Drug , Macrocyclic Compounds/chemical synthesis , Macrocyclic Compounds/chemistry , Microbial Sensitivity Tests , Molecular Structure , Pyridines/chemical synthesis , Pyridines/chemistry , Structure-Activity RelationshipABSTRACT
Herein, we report the discovery of novel, proline-based factor Xa inhibitors containing a neutral P1 chlorophenyl pharmacophore. Through the additional incorporation of 1-(4-amino-3-fluoro-phenyl)-1H-pyridin-2-one 22, as a P4 pharmacophore, we discovered compound 7 (PD 0348292). This compound is a selective, orally bioavailable, efficacious FXa inhibitor that is currently in phase II clinical trials for the treatment and prevention of thrombotic disorders.
