Synthesis and structure-activity relationships of novel biphenyl containing tetronamides with cyanobactericidal activity

Abstract

Currently, cyanobacterial bloom control relies on management strategies that involve the use of algaecides. Among these, copper salts and the herbicide diuron are the most commonly used, with negative impacts on the environment. Therefore, the discovery of new, more effective and environmentally safer algaecides is greatly desirable. Recently, we reported a series of novel tetronamides featuring the biphenyl moiety, which were designed based on natural substances from the rubrolide class. Herein, we further expanded on this discovery and described the synthesis of 20 new tetronamides prepared from mucohalogenic acids, and their evaluation on the growth of the model cyanobacterium Synechococcus elongatus. Six compounds (17, 19, 21, 26, 29, and 32) showed excellent cyanobactericidal activity, presenting an IC₅₀ of 2 μM. At a concentration of 10 μM, these compounds showed no significant inhibition of the photosynthetic electron transport chain, or impact on the growth of the model plant Raphanus sativus, indicating a selective action on cyanobacteria. QSAR studies shed light on the biphenyl, N-aryl and N-H moieties as crucial structural features associated to the cyanobactericidal activity of this class of compounds. In summary, our findings expanded the knowledge on the SAR of cyanobactericidal tetronamides and led to the discovery of novel biphenyl tetronamides as promising leads for the development of new algaecides.