Natural α-methylenelactam analogues: Design, synthesis and evaluation of α-alkenyl-γ and δ-lactams as potential antifungal agents against Colletotrichum orbiculare.

摘要: Abstract In our continued efforts to improve the potential utility of α-methylene-γ-lactone scaffold, 62 new and 59 known natural α-methylenelactam analogues including α-methylene-γ-lactams, α-arylidene-γ δ-lactams, 3-arylideneindolin-2-ones were synthesized as bioisosteric α-methylenelactone scaffold. The results antifungal cytotoxic activity indicated that among these derivatives compound (E)-1-(2, 6-dichlorobenzyl)-3-(2-fluorobenzylidene) pyrrolidin-2-one (Py51) possessed good selectivity with highest against Colletotrichum orbiculare IC50 = 10.4 μM but less IC50 = 141.2 μM (against HepG2 cell line) 161.2 μM human hepatic L02 cell line). Ultrastructural change studies performed by transmission electron microscope showed Py51 could cause important morphological changes in C. orbiculare, such plasma membrane detached from wall, wall thickening, mitochondria disruption, a dramatic increase vacuolation, eventually complete loss integrity organelles. Significantly, appeared one primary targets, confirmed their remarkably aberrant changes. Analysis structure–activity relationships revealed incorporation aryl group into α-exo-methylene N-benzyl substitution increased activity. Meanwhile, α-arylidene-γ-lactams have superiority over 3-arylideneindolin-2-ones. Based on results, substituted α-(2-fluorophenyl)-γ-lactam was identified most promising natural-based scaffold for further discovering developing improved crop-protection agents.