Design and synthesis of aminol- and phenylamide-containing phosphonic acids and their biological activity evaluation

Abstract

Inhibitor design based on the natural product fosmidomycin (FOS) as a lead structure is a promising strategy in search of herbicidally active compounds that may target the DXR enzyme in the MEP pathway. Herein, two metal ion chelating groups, aminol and amide, were used to replace the hydroxamate moiety of FOS, and two types of non-hydroxamate FOS analogs, namely aminol- (5a ∼ n and 6a ∼ o) and phenylamide-containing (10a ∼ v) phosphonic acids were designed and synthesized by establishing facile routes involving the Michaelis-Arbuzov reaction, epoxide ring-opening, acrylamidation, Michael addition, and phosphonate hydrolysis. In the pre-emergency bioactivity screening several compounds demonstrated herbicidal activities superior to FOS, including 5c, 5 h, 10a, 10d, 10e, etc. In particular, 10e showed an 18.7-fold inhibition activity against Arabidopsis thaliana and 16.1- and 10.8-fold activities against the root and stalk of Echinochloa crus-galli, respectively, in comparison with that of FOS. In the post-emergency assay, 10e also displayed 1.9- and 2.1-fold inhibition activities against E. crus-galli and Amaranthus retroflexus. Enzyme inhibition assay revealed the inhibition activities of some compounds to the DXR enzyme far below that of FOS, while the plant growth rescue failed from the inhibition by 5c and 10e by adding dimethylallyl pyrophosphate (DMAPP), a downstream product of the MEP pathway, both suggesting that some targets instead of the DXR enzyme might be involved in the inhibition by the active compounds. Nevertheless, this work demonstrated that using bioisosteric replacement based on the lead structure FOS is an effective strategy for developing highly herbicidal active compounds.