Design and synthesis of fosmidomycin analogs containing aza‐linkers and their biological activity evaluation

Abstract

BackgroundThe enzymes involved in the MEP pathway are attractive targets of new mode of action for developing anti‐infective drugs and herbicides, and the inhibitors against IspC, the second key enzyme in the pathway, have been intensively investigated, however, few works are reported regarding the IspC inhibitors designed for new herbicide discovery.ResultsA series of fosmidomycin (FOS) analogs with nitrogen‐containing linkers replacing the trimethylene linker between the two active substructures of FOS, phosphonic acid and hydroxamic acid, were designed, and the synthesis was carried out by a facile three‐step route of sequential aza‐Michael addition of α‐amino acids to dibenzyl vinylphosphonate, amidation of the amino acid carboxyl with O‐benzyl hydroxylamine, and simultaneous removal of the benzyl protective groups. Biological activity evaluation on IspC and model plants revealed that some compounds had moderate enzyme and model plant growth inhibition effects, but in particular, compound 10g that has a N‐(4‐fluorophenylethyl) nitrogen‐containing linker exhibited the best plant inhibition activities, superior to the control FOS against the model plants Arabidopsis thaliana, Brassica napus L., Amaranthus retroflexus, and Echinochloa crus‐galli. The dimethylallyl pyrophosphate rescue assay on Arabidopsis thaliana validated that both 10g and FOS exert their herbicidal activity by blocking the MEP pathway, a result consistent with the molecular docking that confirmed 10g and FOS binding to the IspC active site in a similar way.ConclusionCompound 10g has excellent herbicidal activity and represents the first herbicide lead structure of new mode of action that targets IspC enzyme in the MEP pathway.This article is protected by copyright. All rights reserved.

Hydroxamate-Containing Bisphosphonates as Fosmidomycin Analogues: Design, Synthesis, and Proherbicide Activity

“…To validate the possible mode of action of the active compounds in this work, a DMAPP rescue assay was conducted by treating Arabidopsis with the compound pair 8m/15m and the control FOS, with the supplement of DMAPP, the product of the MEP pathway, according to a reported procedure. 28 The underlying logic of DMAPP rescue is that if the Arabidopsis growth inhibition is caused by inhibition of the DXR enzyme, adding exogenous DMAPP as a downstream product of the MEP pathway should restore the growth of Arabidopsis. As shown in Figure 5A, the bleaching and growth inhibition of Arabidopsis by 8m were effectively rescued by DMAPP, just as what happens in the case with FOS treatment.…”

“…On the other hand, FOS as a herbicide-active compound was tested on Arabidopsis thaliana ( Arabidopsis ) two decades ago, demonstrating the effects of bleaching and developmental arrest of wild-type Arabidopsis seedlings through inhibiting DXR. , However, their analogues for herbicide development are rarely reported. In recent years, our group reported that several aza-linker-containing FOS analogues have promising herbicidal activities and may act through targeting the DXR enzyme . These early studies provide an avenue to finding FOS analogues as novel herbicides with a new mode of action.…”

“…In recent years, our group reported that several aza-linker-containing FOS analogues have promising herbicidal activities and may act through targeting the DXR enzyme. 28 These early studies provide an avenue to finding FOS analogues as novel herbicides with a new mode of action.…”

“…However, their analogues for herbicide development are rarely reported. In recent years, our group reported that several aza-linker-containing FOS analogues have promising herbicidal activities and may act through targeting the DXR enzyme 28. These early studies provide an avenue to finding FOS analogues as novel herbicides with a new mode of action.In this context, two series of hydroxamate-containing bisphosphonates as FOS analogues were designed in this work, and their general structures are shown in Figure2B.…”

Design, Synthesis and Bioactivity Evaluation of Heterocycle-Containing Mono- and Bisphosphonic Acid Compounds

“…The second enzyme in this pathway, 1-deoxy-D-xylulose 5-phosphate reductoisomerase, shortly named DXR and also known as IspC, which catalyzes the isomerization and reduction of 1-deoxy-D-xylulose 5-phosphate (DXP) to produce MEP [6], is the most encouraging target for the development of novel antibacterial and antimalarial drugs because two naturally occurring products, fosmidomycin (FOS) and FR900098 (FR), have been found active in targeting this enzyme, and the inhibition mechanism has been well documented [7,8]. Although DXR has been considered a promising target for herbicides [9,10], the research focusing on the herbicide discovery based on DXR is rather limited, making the development of DXR inhibitors as herbicidal lead compounds a work of great significance. The two natural products, FOS and FR, originally isolated from Streptomyces species [11,12], are structurally composed of three parts, namely phosphonic acid, hydroxamate and the trimethylene linker, as shown in Figure 2A.…”