Bivalent Carbamates as Novel Control Agents of the Malaria Mosquito, Anopheles gambiae
James M. Mutunga,
Qiao-Hong Chen,
Dawn M. Wong,
Polo C-H. Lam,
Jianyong Li,
Maxim M. Totrov,
Aaron D. Gross,
Paul R. Carlier,
Jeffrey R. Bloomquist
Affiliations
James M. Mutunga
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
Qiao-Hong Chen
Department of Chemistry, Virginia Tech Blacksburg, VA 24061, USA
Dawn M. Wong
Department of Chemistry, Virginia Tech Blacksburg, VA 24061, USA
Polo C-H. Lam
Molsoft LLC 11199 Sorrento Valley Road San Diego, CA 92121, USA
Jianyong Li
Department of Biochemistry, Virginia Tech Blacksburg, VA 24061, USA
Maxim M. Totrov
Molsoft LLC 11199 Sorrento Valley Road San Diego, CA 92121, USA
Aaron D. Gross
Department of Entomology and Nematology Emerging Pathogens Institute University of Florida, Gainesville, FL 32610, USA
Paul R. Carlier
Department of Chemistry, Virginia Tech Blacksburg, VA 24061, USA
Jeffrey R. Bloomquist
Department of Entomology and Nematology Emerging Pathogens Institute University of Florida, Gainesville, FL 32610, USA. [email protected]
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.
