Design, synthesis, high algicidal potency, and putative mode of action of new 2-cyclopropyl-4-aminopyrimidine hydrazones

Control of cyanobacteria harmful algal blooms remains a global challenge. In the present study, a series of novel 2-cyclopropyl-4-aminopyrimidine hydrazones were designed and synthesized as potential algicides. Compounds 4a, 4b, 4h, 4j, 4k, 4l, and 4m showed potent inhibition against Synechocystis sp. PCC6803 (median effective concentration, EC50 = 1.1 to 1.7 μM) and Microcystis aeruginosa FACHB905 (EC50 = 1.2 to 2.0 μM), more potent than, or comparably with, copper sulfate (PCC6803, EC50 = 1.8 μM; FACHB905, EC50 = 2.2 μM) and prometryne (PCC6803, EC50 = 12.3 μM; FACHB905, EC50 = 7.2 μM). Compound 4k exhibited algicidal activity in an expanded culture system, and was less toxic than copper sulfate to zebrafish. Electron microscope analyses showed that 4k damaged cyanobacterial cells and decreased the number of thylakoid lamellae. Transcriptomic and qPCR analyses suggest that 4k interfered photosynthesis-related pathways. Treatment with 4k significantly decreased the maximum quantum yield of photosystem II and the photosynthetic electron transfer rate, and the resulting reactive oxygen species damaged thylakoid membranes and photosystem I. The results suggest that 4k is a potential lead for further development of effective and safe algicides.