Re-engineering aryl methylcarbamates to confer high selectivity for inhibition of Anopheles gambiae versus human acetylcholinesterase.
To identify potential human-safe insecticides against the malaria mosquito we undertook an investigation of the structure-activity relationship of aryl methylcarbamates inhibitors of acetylcholinesterase (AChE). Compounds bearing a β-branched 2-alkoxy or 2-thioalkyl group were found to possess good selectivity for inhibition of Anopheles gambiae AChE over human AChE; up to 530-fold selectivity was achieved with carbamate 11d. A 3D QSAR model is presented that is reasonably consistent with log inhibition selectivity of 34 carbamates. Toxicity of these compounds to live Anopheles gambiae was demonstrated using both tarsal contact (filter paper) and topical application protocols.
Department of Chemistry, Virginia Tech, Blacksburg, VA 24061, USA.
Joshua A
JA
Hartsel
Dawn M
DM
Wong
James M
JM
Mutunga
Ming
M
Ma
Troy D
TD
Anderson
Ania
A
Wysinski
Rafique
R
Islam
Eric A
EA
Wong
Sally L
SL
Paulson
Jianyong
J
Li
Polo C H
PC
Lam
Maxim M
MM
Totrov
Jeffrey R
JR
Bloomquist
Paul R
PR
Carlier
D000110:Acetylcholinesterase / Q000378:metabolism*; D000818:Animals; D000852:Anopheles / Q000187:drug effects / Q000201:enzymology*; D002219:Carbamates; D002800:Cholinesterase Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D006801:Humans; D008958:Models, Molecular; D015394:Molecular Structure; D021281:Quantitative Structure-Activity Relationship
D002219:Carbamates; D002800:Cholinesterase Inhibitors; C036868:methyl carbamate; D000110:Acetylcholinesterase