Tricyclic cyanoguanidines: synthesis, site of action and insecticidal activity of a novel class of reversible acetylcholinesterase inhibitors.
Bridged-tricyclic cyanoguanidines 1 were found to be active as insecticides. The preparation and structure-activity relationships of oxacyclic (X=O) and carbocyclic (X=CH(2)) analogues of 1 is described. Compounds 1 were found to inhibit acetylcholinesterase with IC(50) values comparable to the organophosphate Paraoxon. Unlike organophosphates, cyanoguanidines 1 were shown to reversibly bind acetylcholinesterase. This mode of action is shared by the structurally-related natural product Huperzine A.
Finkelstein
Bruce L
BL
DuPont Crop Protection, Stine-Haskell Research Center, PO Box 30, Newark, DE 19714, USA. bruce.l.finkelstein@usa.dupont.com
Benner
Eric A
EA
Hendrixson
Maura C
MC
Kranis
Kevin T
KT
Rauh
James J
JJ
Sethuraman
Maya R
MR
McCann
Stephen F
SF
D000110:Acetylcholinesterase / Q000187:drug effects / Q000378:metabolism; D000818:Animals; D002800:Cholinesterase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D006146:Guanidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D006575:Heterocyclic Compounds, 3-Ring / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D007313:Insecta / Q000187:drug effects / Q000201:enzymology; D007306:Insecticides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D007700:Kinetics; D008958:Models, Molecular; D011485:Protein Binding; D013329:Structure-Activity Relationship
D002800:Cholinesterase Inhibitors; D006146:Guanidines; D006575:Heterocyclic Compounds, 3-Ring; D007306:Insecticides; D000110:Acetylcholinesterase; C004711:dicyandiamido