Design, Synthesis, and Potency of Pyruvate Dehydrogenase Complex E1 Inhibitors against Cyanobacteria

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.