Safe and effective algaecides are needed to control agriculturally and environmentally significant algal species. Four series (6, 10, 17, and 21) of 29 novel 4-aminopyrimidine derivatives were rationally designed and synthesized. A part of 10, 17, and 21 displayed potent inhibition of Escherichia coli pyruvate dehydrogenase complex E1 (E. coli PDHc-E1) (IC50 = 2.12–18.06 μM) and good inhibition of Synechocystis sp. PCC 6803 (EC50 = 0.7–7.1 μM) and Microcystis sp. FACH 905 (EC50 = 3.7–7.6 μM). The algaecidal activity of these compounds positively correlated with their inhibition of E. coli PDHc-E1. In particular, 21l and 10b exhibited potent algaecidal activity against PCC 6803 (EC50 = 0.7 and 0.8 μM, respectively), values that were 2-fold increased compared to that of copper sulfate (EC50 = 1.8 μM), and showed the best inhibition of cyanobacterium PDHc-E1 (IC50 = 5.10 and 6.06 μM, respectively). 17h and 21e, the best inhibitors of E. coli PDHc-E1, were studied by molecular docking, site-directed mutagenesis, and enzymatic assays. These results revealed that the improved inhibition of novel inhibitors compared with that of the lead compound I was due to the formation of a new hydrogen bond with Leu264 at the active site of E. coli PDHc-E1. The results proved the great potential to obtain effective algaecides via the rational design of PDHc-E1 inhibitors.

Safe and effective algaecides are needed to control agriculturally and environmentally significant algal species. Four series (6, 10, 17, and 21) of 29 novel 4-aminopyrimidine derivatives were rationally designed and synthesized. A part of 10, 17, and 21 displayed potent inhibition of Escherichia coli pyruvate dehydrogenase complex E1 (E. coli PDHc-E1) (IC50 = 2.12–18.06 μM) and good inhibition of Synechocystis sp. PCC 6803 (EC50 = 0.7–7.1 μM) and Microcystis sp. FACH 905 (EC50 = 3.7–7.6 μM). The algaecidal activity of these compounds positively correlated with their inhibition of E. coli PDHc-E1. In particular, 21l and 10b exhibited potent algaecidal activity against PCC 6803 (EC50 = 0.7 and 0.8 μM, respectively), values that were 2-fold increased compared to that of copper sulfate (EC50 = 1.8 μM), and showed the best inhibition of cyanobacterium PDHc-E1 (IC50 = 5.10 and 6.06 μM, respectively). 17h and 21e, the best inhibitors of E. coli PDHc-E1, were studied by molecular docking, site-directed mutagenesis, and enzymatic assays. These results revealed that the improved inhibition of novel inhibitors compared with that of the lead compound I was due to the formation of a new hydrogen bond with Leu264 at the active site of E. coli PDHc-E1. The results proved the great potential to obtain effective algaecides via the rational design of PDHc-E1 inhibitors.

•Four fluorine-containing cyclophosphonates derivatives and twenty eight fluorine-containing alkylphosphonates were synthesized.•Further study the relationship of structure-herbicidal activity.•Some target compounds exhibited high herbicidal activity at 75 g ai/ha.•Compounds III-3, III-4 and III-8 were selected for a broad spectrum test.•Compounds III-4 and III-8 were comparable with glyphosate against all of the tested weeds at a rate of 75 g ai/ha.Based on our previous work on the structural modification of the lead compound I, three series of novel fluorine-containing phosphonates derivatives (II, III and IV) were designed and synthesized. Their post-emergence herbicidal activities against some species of weeds were evaluated in a green house. The compounds II were synthesized by introducing of two methylene into the structure I. Compared with the commercial herbicidal clacyfos, compounds II showed moderate herbicidal activity with 60–85% inhibition effect against chingma abutilon (Abutilon theophrasti), common amaranth (Amaranthus retroflexus) and white eclipta (Eclipta prostrate) at a rate of 150 g ai/ha. The compounds III were designed by introducing open-chain phosphonates, which displayed notable herbicidal activity. Especially, the compounds III-1–III-4, III-6, III-8, III-11 and III-12 exhibited significant herbicidal activity (80–100%) comparing to the clacyfos against all tested broadleaf weeds, while compounds IV with five carbon atoms in the carboxylic acid chain were inactive against all of the tested weeds. Structure-activity relationship analyses indicated that the length of the carbon chain had a great effect on the herbicidal activity. Furthermore, a broad spectrum test confirmed that compounds III-4 and III-8 were comparable with glyphosate against all of the tested weeds at a rate of 75 g ai/ha.Three series of novel fluorine-containing phosphorus derivatives were designed and synthesized based on the structural modification of compound I. The results of bioassay showed that some of the target compounds were comparable with glyphosate against all of the tested weeds at a rate of 75 g ai/ha.

On the basis of our work on the modification of alkylphosphonates 1, a series of α-(substituted phenoxybutyryloxy or valeryloxy)alkylphosphonates (4–5) and 2-(substituted phenoxybutyryloxy)alkyl-5,5-dimethyl-1,3,2-dioxaphosphinan-2-one (6) were designed and synthesized. The bioassay results indicated that 14 of title compounds 4 exhibited significant postemergence herbicidal activity against velvetleaf, common amaranth, and false daisy at 150 g ai/ha. Compounds 5 were inactive against all tested weeds. Compounds 6 exhibited moderate to good inhibitory effect against the tested dicotyledonous weeds. Structure–activity relationship (SAR) analyses showed that the length of the carbon chain as linking bridge had a great effect on the herbicidal activity. Broad-spectrum tests of compounds 4-1, 4-2, 4-9, 4-30, and 4-36 were carried out at 75 g ai/ha. Especially, 4-1 exhibited 100% inhibition activity against the tested dicotyledonous weeds, which was higher than that of glyphosate.Keywords: crop selectivity; herbicide; modification; phosphonate; structure−activity relationship; synthesis;

A series of potassium methyl 1-(substituted phenoxyacetoxy)alkylphosphonates(9a–9o) was designed and synthesized. The results of preliminary bioassays indicate that most of the title compounds possess excellent pre-emergence and post-emergence herbicidal activities against Brassica napus, Amaranthus mangostanus, Medicago sativa, Echinochloa crusgalli, and Digitaria sanguinalis at a dosage of 1500 g/ha(1 ha=10000 m2). Especially, potassium methyl 1-(2,4-dichlorophenoxyacetoxy)-1-(4-methylphenyl)methylphosphonate(9g) and potassium methyl 1-(2,4-dichlorophenoxyacetoxy)-1-(furan-2-yl)methylphosphonate(9j) show the best herbicidal activity against five tested weeds with more than 85% inhibitory rate in pre-emergence.

A series of 2-(substituted phenoxyacetoxy)alkyl-5,5-dimethyl-1,3,2-dioxaphosphinan-2-ones IIa–s were designed and synthesized on the basis of the previous work for the modification of alkylphosphonates I, and their structures were confirmed by 1H NMR, 31P NMR, 13C NMR, IR, MS, and elemental analysis. Their herbicidal activities against seven species of weeds were evaluated in a greenhouse. A part of the title compounds such as IIa–g, IIk, IIo, and IIr exhibited significant postemergence herbicidal activity against Abutilon theophrasti, Brassica juncea, Amaranthus retroflexus, and Eclipta prostrate at a dosage of 150 g ai/ha. Structure–activity relationship analyses indicated that the introduction of a phosphorus-containing heterocyclic ring had a favorable effect on herbicidal activity, and their herbicidal activity could be further increased by a reasonable combination of X, Y, and R in parent structure II. It could be found that the title compounds IIa 2-[(2,4-dichlorophenoxy)acetoxy](methyl)methyl-5,5-dimethyl-1,3,2-dioxaphosphinan-2-one and IIr 2-[(4-chloro-2-methyl-phenoxy)acetoxy](methyl)methyl-5,5-dimethyl-1,3,2-dioxaphosphinan-2-one possess high activity and a broad spectrum against all of the test broadleaf weeds with 70–100% inhibition effect at a dosage of 75 g ai/ha, and the title compounds IIa and IIr are safe for corn and wheat at a dosage of 150 g ai/ha. Furthermore, the title compound IIa possesses low rat toxicity. These results suggest that the title compounds IIa and IIr could be potential and selective postemergence herbicides for further development.

A series of novel 2-(substituted phenoxyacetoxy)alkyl-5,5-dimethyl-1,3,2-dioxaphosphinan-2-one bearing fluorine 5a-n and fluorine free 5o-q were designed and synthesized. The results of bioassay showed that some of the target compounds exhibited excellent herbicidal activities to Abutilon theophrasti, Brassica juncea, Amaranthus retroflexus and Eclipta prostrata in post-emergence treatment at a dosage of 150 g ai/ha. It could be found that the type and position of fluorine-containing group as X or Y on benzene ring had a very important effect on herbicidal activity. Compound 5l 2-[(2-chloro-4-fluorophenoxy)acetoxy](methyl)methyl-5,5-dimethyl-1,3,2-dioxaphosphinan-2-one showed notable herbicidal activity, with 100% inhibition against A. theophrasti and A. retroflexus; and compound 5m 2-(3-trifluoromethylphenoxyacetoxy)(methyl)methyl-5,5-dimethyl-1,3,2-dioxaphosphinan-2-one with 100% inhibition against A. theophrasti even at a dosage of 75 g ai/ha. Additional crop selectivity testing showed that compounds 5g 2-(3-trifluoromethylphenoxyacetoxy)(phenyl)methyl-5,5-dimethyl-1,3,2-dioxaphosphinan-2-one and 5l are safe to rice, corn, cotton, rape and wheat.Graphical abstractA series of novel fluorine-containing cyclophosphonates derivatives were designed and synthesized. The results of bioassay showed that some of the target compounds display high herbicidal activity at a dosage of 75 g ai/ha.Highlights► Fourteen fluorine-containing cyclophosphonates derivatives were synthesized. ► Further study the relationship of structure-herbicidal activity. ► Some target compounds exhibited high herbicidal activity at 75 g ai/ha. ► Compounds 5g and 5l are safe to rice, corn, cotton, rape and wheat at 150 g ai/ha.

On the basis of the previous work for optimization of O,O-diethyl α-(substituted phenoxyacetoxy)alkylphosphonates, further extensive synthetic modifications were made to the substituents in alkylphosphonate and phenoxy moieties of the title compounds. New O,O-dimethyl α-(substituted phenoxyacetoxy)alkylphosphonates were synthesized as potential inhibitors of pyruvate dehydorogenase complex (PDHc). Their herbicidal activity and efficacy in vitro against PDHc were examined. Some of these compounds exhibited significant herbicidal activity and were demonstrated to be effective inhibitors of PDHc from three different plants. The structure−activity relationships of these compounds including previously reported analogous compounds were studied by examining their herbicidal activities. Both inhibitory potency against PDHc and herbicidal activity of title compounds could be increased greatly by optimizing substituent groups of the title compounds. O,O-Dimethyl α-(2,4-dichlorophenoxyacetoxy)ethylphosphonate (I-5), which acted as a competitive inhibitor of PDHc with much higher inhibitory potency against PDHc from Pisum sativum and Phaseolus radiatus than from Oryza sativa, was found to be the most effective compound against broadleaf weeds and showed potential utility as herbicide.