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

Authors

  • 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. jbquist@epi.ufl.edu

DOI:

https://doi.org/10.2533/chimia.2016.704

Keywords:

Anticholinesterase, Catalytic site, Molecular docking, Peripheral site

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.

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Published

2016-10-26

Issue

Section

Scientific Articles

How to Cite

[1]
J. M. Mutunga, Q.-H. Chen, D. M. Wong, P. C.-H. Lam, J. Li, M. M. Totrov, A. D. Gross, P. R. Carlier, J. R. Bloomquist, Chimia 2016, 70, 704, DOI: 10.2533/chimia.2016.704.