Synthesis of new tetronamides displaying inhibitory activity against bloom‐forming cyanobacteria

• Published in: Pest management science Vol. 76; no. 2; pp. 779 - 788
• Main Authors: Acosta, Jaime AM, Karak, Milandip, Barbosa, Luiz CA, Boukouvalas, John, Straforini, Andrea, Forlani, Giuseppe
• Format: Journal Article
• Language: English
• Published: Chichester, UK John Wiley & Sons, Ltd 01-02-2020; Wiley Subscription Services, Inc
• Subjects: Adducts; Aldehydes; Aliphatic compounds; Aquatic ecosystems; Aromatic compounds; Biological effects; Biological properties; Biphenyl; butenolides; Control methods; Cyanobacteria; cyanobactericidal activity; Dehydration; Domestic animals; Drinking water; Ecosystem; Electron transport; Electron transport chain; Herbicides; Hill reaction; Microorganisms; Natural products; Organic chemistry; Photosynthesis; Synechococcus; Synechococcus elongatus; tetronamides; Toxins; vinylogous aldol reaction; Water pollution; butenolides; tetronamides; cyanobactericidal activity; vinylogous aldol reaction; Synechococcus elongatus; Hill reaction
• ISSN: 1526-498X; 1526-4998
• DOI: 10.1002/ps.5580

BACKGROUND
The increasing frequency and intensity of cyanobacterial blooms pose a serious threat to aquatic ecosystems. These blooms produce potent toxins that can contaminate drinking water and endanger the life of wild and domestic animals as well as humans. Consequently, the development of effective methods for their control is a matter of high priority. We have previously shown that some γ‐benzylidenebutenolides, related to the rubrolide family of natural products, are capable of inhibiting the photosynthetic electron transport chain (Hill reaction), a target of commercial herbicides. Here we report the synthesis and biological properties of a new class of rubrolide‐inspired molecules featuring a tetronamide motif.
RESULTS
A total of 47 N‐aryl tetronamides, including 38 aldol adducts, were prepared bearing phenyl, biphenyl, naphthyl, aliphatic and heteroaromatic groups. Some of the aldol adducts were dehydrated to the corresponding γ‐benzylidenetetronamides, although satisfactory yields were obtained in only three cases (52–97%). None of the synthesized compounds were capable of blocking the Hill reaction. This notwithstanding, several aldol adducts equipped with a biphenyl substituent displayed excellent inhibitory activity against Synechococcus elongatus and other cyanobacterial strains (IC50 = 1–5 μM). Further, these tetronamides were found to be essentially inactive against eukaryotic microorganisms.
CONCLUSION
Several newly synthesized biphenyl‐containing tetronamides were shown to display potent and selective inhibitory activity against cyanobacteria. These compounds appear to exert their biological effects without interfering with the Hill reaction. As such, they represent novel leads in the search of environmentally benign agents for controlling cyanobacterial blooms. © 2019 Society of Chemical Industry
A series of synthetic tetronamides have been shown to inhibit the growth of bloom‐forming cyanobacteria.