Computer-aided nematicide design towards mitochondria-directed complex II inhibitors

Complex II inhibitors belonging to the benzamide family have recently drawn attention as novel nematicide compounds, particularly in agriculture.1 As benzamides molecular target is located in the inner mitochondrial membrane protruding into the mitochondrial matrix, a selective delivery of the compounds into this organelle could increase potency and decrease off-target interactions. Lipophilic cationic groups, such as triphenylphosphonium, have been used as mitochondria-targeting groups, as they accumulate in the electronegative mitochondrial matrix.2 With this rationale, we propose the hybridization of benzamide compounds (Wact family) with mitochondria-directing groups and the evaluation of this hybrids against Caenorhabditis elegans as a nematode model. The synthesis of derivatives benzamide 1 and 2 resulted in a loss of nematicide potency, confirming that benzamide ring B is essential. Apart from this structural requirement, in silico modeling suggests that a linker of at least 8 atoms from ring B is needed, thus informing the design of new hybrids.