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Open Access Bivalent Carbamates as Novel Control Agents of the Malaria Mosquito, Anopheles gambiae

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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.
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Keywords: ANTICHOLINESTERASE; CATALYTIC SITE; MOLECULAR DOCKING; PERIPHERAL SITE

Document Type: Research Article

Affiliations: 1: 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 2: Department of Chemistry, Virginia Tech Blacksburg, VA 24061, USA 3: Molsoft LLC 11199 Sorrento Valley Road San Diego, CA 92121, USA 4: Department of Biochemistry, Virginia Tech Blacksburg, VA 24061, USA 5: Department of Entomology and Nematology Emerging Pathogens Institute University of Florida, Gainesville, FL 32610, USA 6: Department of Entomology and Nematology Emerging Pathogens Institute University of Florida, Gainesville, FL 32610, USA. [email protected]

Publication date: October 1, 2016

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  • International Journal for Chemistry and Official Membership Journal of the Swiss Chemical Society (SCS) and its Divisions

    CHIMIA, a scientific journal for chemistry in the broadest sense, is published 10 times a year and covers the interests of a wide and diverse readership. Contributions from all fields of chemistry and related areas are considered for publication in the form of Review Articles and Notes. A characteristic feature of CHIMIA are the thematic issues, each devoted to an area of great current significance.

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