title: Bivalent Carbamates as Novel Control Agents of the Malaria Mosquito, Anopheles gambiae.
abstract: Widespread pyrethroid resistance has caused an urgent need to develop new insecticides for control of the malaria mosquito, Anopheles gambiae. Insecticide discovery efforts were directed towards the construction of bivalent inhibitors that occupy both the peripheral and catalytic sites of the mosquito acetylcholinesterase (AChE). It was hypothesized that this approach would yield a selective, high potency inhibitor that would also circumvent known catalytic site mutations (e.g. G119S) causing target site resistance. Accordingly, a series of bivalent phthalimide-pyrazole carbamates were prepared having an alkyl chain linker of varying length, along with other modifications. The most active compound was (1-(3-(1,3-dioxoisoindolin-2-yl)propyl)-1H-pyrazol-4-yl methylcarbamate, 8a), which has a chain length of three carbons, good mosquito anticholinesterase activity, and ca. 5-fold selectivity compared to human AChE. Moreover, this compound was toxic to mosquitoes by topical application (LD50= 63 ng/female) with only 6-fold cross resistance in the Akron strain of Anopheles gambiae that showed 50- to 60-fold resistance to conventional carbamate insecticides. However, contact lethality in the WHO paper assay was disappointing. The implications of these results for design of new mosquitocides are discussed.
authors: Department of Entomology and Nematology Emerging Pathogens Institute University of Florida, Gainesville, FL 32610, USA; Human Health Division International Centre of Insect Physiology and Ecology (ICIPE) P.O. Box 30772-00100, Nairobi, Kenya.
authors: James M
authors: JM
authors: Mutunga
authors: Department of Chemistry, Virginia Tech Blacksburg, VA 24061, USA.
authors: Qiao-Hong
authors: QH
authors: Chen
authors: Department of Chemistry, Virginia Tech Blacksburg, VA 24061, USA.
authors: Dawn M
authors: DM
authors: Wong
authors: Molsoft LLC 11199 Sorrento Valley Road San Diego, CA 92121, USA.
authors: Polo C-H
authors: PC
authors: Lam
authors: Department of Biochemistry, Virginia Tech Blacksburg, VA 24061, USA.
authors: Jianyong
authors: J
authors: Li
authors: Molsoft LLC 11199 Sorrento Valley Road San Diego, CA 92121, USA.
authors: Maxim M
authors: MM
authors: Totrov
authors: Department of Entomology and Nematology Emerging Pathogens Institute University of Florida, Gainesville, FL 32610, USA.
authors: Aaron D
authors: AD
authors: Gross
authors: Department of Chemistry, Virginia Tech Blacksburg, VA 24061, USA.
authors: Paul R
authors: PR
authors: Carlier
authors: Department of Entomology and Nematology Emerging Pathogens Institute University of Florida, Gainesville, FL 32610, USA. jbquist@epi.ufl.edu.
authors: Jeffrey R
authors: JR
authors: Bloomquist
mesh_terms: D000818:Animals; D000852:Anopheles; D002219:Carbamates / Q000494:pharmacology*; D002800:Cholinesterase Inhibitors / Q000494:pharmacology; D015195:Drug Design; D007305:Insecticide Resistance; D007306:Insecticides / Q000494:pharmacology*; D008288:Malaria / Q000517:prevention & control*; D009032:Mosquito Control / Q000379:methods*
chemical_list: D002219:Carbamates; D002800:Cholinesterase Inhibitors; D007306:Insecticides