Design, Synthesis, and Evaluation of Novel Thiazole-Containing Algicides Inspired by Bacillamide A.

Abstract

The pursuit of highly effective, low-toxicity, and eco-friendly algicides for controlling and eradicating harmful algal blooms (HABs) is of paramount importance. The natural allelochemical bacillamide A has displayed impressive algicidal activity against harmful algae with favorable safety profiles. However, the poor synthetic efficiency and large dose requirements of bacillamide A limit its further application. In this paper, 17 thiazole-containing bacillamide derivatives (BDs) were designed and synthesized in three linear steps as potential algicides. Eight compounds (6a, 6c, 6j, 7b, 7c, 7d, 7e, and 7g) displayed potent inhibitory effects against Prorocentrum minimum, Skeletonema costatum, and Alexandrium pacificum, and they had similar or better activity than the positive control (CuSO₄) and bacillamide A. Compound 6a exhibited the most potent algicidal activity against S. costatum (half-maximal effective concentration [EC₅₀] = 0.11 μg/mL), being 23-fold more potent than bacillamide A, 28-fold more potent than CuSO₄, and 39-fold more potent than Diuron. Compound 6j exhibited significant algicidal activity against the toxic dinoflagellates P. minimum (EC₅₀ = 1.0 μg/mL) and A. pacificum (EC₅₀ = 0.47 μg/mL), being 3-5-fold more potent than natural bacillamide A, Diuron, and CuSO₄. Micrographs and SEM images revealed that 6j induced cell wall rupture and cellular content leakage. Biochemical and physiological studies indicated that 6j might partially disrupt the antioxidant and photosynthetic systems in algal cells, resulting in morphological changes, cell wall rupture, and inclusion leakage. Our work suggests that 6j has a distinct mode of action from CuSO₄ and provides a promising candidate for the development of new algicides, worthy of further investigation.