title: Natural α-methylenelactam analogues: Design, synthesis and evaluation of α-alkenyl-γ and δ-lactams as potential antifungal agents against Colletotrichum orbiculare.
abstract: In our continued efforts to improve the potential utility of the α-methylene-γ-lactone scaffold, 62 new and 59 known natural α-methylenelactam analogues including α-methylene-γ-lactams, α-arylidene-γ and δ-lactams, and 3-arylideneindolin-2-ones were synthesized as the bioisosteric analogues of the α-methylenelactone scaffold. The results of antifungal and cytotoxic activity indicated that among these derivatives compound (E)-1-(2, 6-dichlorobenzyl)-3-(2-fluorobenzylidene) pyrrolidin-2-one (Py51) possessed good selectivity with the highest antifungal activity against Colletotrichum orbiculare with IC50= 10.4 μM but less cytotoxic activity with IC50= 141.2 μM (against HepG2 cell line) and 161.2 μM (against human hepatic L02 cell line). Ultrastructural change studies performed by transmission electron microscope showed that Py51 could cause important cell morphological changes in C. orbiculare, such as plasma membrane detached from cell wall, cell wall thickening, mitochondria disruption, a dramatic increase in vacuolation, and eventually a complete loss in the integrity of organelles. Significantly, mitochondria appeared one of the primary targets, as confirmed by their remarkably aberrant morphological changes. Analysis of structure-activity relationships revealed that incorporation of the aryl group into the α-exo-methylene and the N-benzyl substitution increased the activity. Meanwhile, the α-arylidene-γ-lactams have superiority in selectivity over the 3-arylideneindolin-2-ones. Based on the results, the N-benzyl substituted α-(2-fluorophenyl)-γ-lactam was identified as the most promising natural-based scaffold for further discovering and developing improved crop-protection agents.
authors.affiliation: Research & Development Center of Biorational Pesticide, Key Laboratory of Plant Protection Resources and Pest Management of Ministry of Education, Northwest A&F University, Yangling 712100, China.
authors.forename: Wang
authors.initials: W
authors.lastname: Delong
authors.affiliation: Research & Development Center of Biorational Pesticide, Key Laboratory of Plant Protection Resources and Pest Management of Ministry of Education, Northwest A&F University, Yangling 712100, China; College of Environment and Plant Protection, Hainan University, Haikou, Hainan, 570228, China.
authors.forename: Wang
authors.initials: W
authors.lastname: Lanying
authors.affiliation: Research & Development Center of Biorational Pesticide, Key Laboratory of Plant Protection Resources and Pest Management of Ministry of Education, Northwest A&F University, Yangling 712100, China.
authors.forename: Wu
authors.initials: W
authors.lastname: Yongling
authors.affiliation: Research & Development Center of Biorational Pesticide, Key Laboratory of Plant Protection Resources and Pest Management of Ministry of Education, Northwest A&F University, Yangling 712100, China.
authors.forename: Song
authors.initials: S
authors.lastname: Shuang
authors.affiliation: Research & Development Center of Biorational Pesticide, Key Laboratory of Plant Protection Resources and Pest Management of Ministry of Education, Northwest A&F University, Yangling 712100, China. Electronic address: fengjt@nwafu.edu.cn.
authors.forename: Feng
authors.initials: F
authors.lastname: Juntao
authors.affiliation: Research & Development Center of Biorational Pesticide, Key Laboratory of Plant Protection Resources and Pest Management of Ministry of Education, Northwest A&F University, Yangling 712100, China.
authors.forename: Zhang
authors.initials: Z
authors.lastname: Xing
mesh_terms: D000935:Antifungal Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D045744:Cell Line, Tumor; D048430:Cell Shape / Q000187:drug effects; D020231:Colletotrichum / Q000187:drug effects*; D015195:Drug Design; D005658:Fungi / Q000187:drug effects / Q000648:ultrastructure; D056945:Hep G2 Cells; D006801:Humans; D020128:Inhibitory Concentration 50; D007769:Lactams / Q000138:chemical synthesis / Q000494:pharmacology*; D013045:Species Specificity; D013329:Structure-Activity Relationship
chemical_list: D000935:Antifungal Agents; D007769:Lactams
keywords: Antifungal activity; Structure–activity relationships; Ultrastructural changes studies; α-Methylenelactam