PMID- 30524149
OWN - NLM
STAT- MEDLINE
DCOM- 20181231
LR  - 20191001
IS  - 1095-9939 (Electronic)
IS  - 0048-3575 (Print)
IS  - 0048-3575 (Linking)
VI  - 151
DP  - 2018 Oct
TI  - Select beta- and gamma-branched 1-alkylpyrazol-4-yl methylcarbamates exhibit high 
      selectivity for inhibition of Anopheles gambiae versus human 
      acetylcholinesterase.
PG  - 32-39
LID - 10.1016/j.pestbp.2018.02.003 [doi]
AB  - The widespread emergence of pyrethroid-resistant Anopheles gambiae has 
      intensified the need to find new contact mosquitocides for indoor residual 
      spraying and insecticide treated nets. With the goal of developing new 
      species-selective and resistance-breaking acetylcholinesterase (AChE)-inhibiting 
      mosquitocides, in this report we revisit the effects of carbamate substitution on 
      aryl carbamates, and variation of the 1-alkyl group on pyrazol-4-yl 
      methylcarbamates. Compared to aryl methylcarbamates, aryl dimethylcarbamates were 
      found to have lower selectivity for An. gambiae AChE (AgAChE) over human AChE 
      (hAChE), but improved tarsal contact toxicity to G3 strain An. gambiae. Molecular 
      modeling studies suggest the lower species-selectivity of the aryl 
      dimethylcarbamates can be attributed to a less flexible acyl pocket in AgAChE 
      relative to hAChE. The improved tarsal contact toxicity of the aryl 
      dimethylcarbamates relative to the corresponding methylcarbamates is attributed 
      to a range of complementary phenomena. With respect to the pyrazol-4-yl 
      methylcarbamates, the previously observed low An. gambiae-selectivity of 
      compounds bearing alpha-branched 1-alkyl groups was improved by employing beta- and 
      gamma-branched 1-alkyl groups. Compounds 22a (cyclopentylmethyl), 21a 
      (cyclobutylmethyl), and 26a (3-methylbutyl) offer 250-fold, 120-fold, and 96-fold 
      selectivity, respectively, for inhibition of AgAChE vs. hAChE. Molecular modeling 
      studies suggests the high species-selectivity of these compounds can be 
      attributed to the greater mobility of the W84 side chain in the choline-binding 
      site of AgAChE, compared to that of W86 in hAChE. Compound 26a has reasonable 
      contact toxicity to G3 strain An. gambiae (LC(50) = 269 mug/mL) and low 
      cross-resistance to Akron strain (LC(50) = 948 mug/mL), which bears the G119S 
      resistance mutation.
FAU - Carlier, Paul R
AU  - Carlier PR
AD  - Department of Chemistry and Virginia Tech Center for Drug Discovery, Virginia 
      Tech, Blacksburg, VA 24061 USA.
FAU - Chen, Qiao-Hong
AU  - Chen QH
AD  - Department of Chemistry and Virginia Tech Center for Drug Discovery, Virginia 
      Tech, Blacksburg, VA 24061 USA.
FAU - Verma, Astha
AU  - Verma A
AD  - Department of Chemistry and Virginia Tech Center for Drug Discovery, Virginia 
      Tech, Blacksburg, VA 24061 USA.
FAU - Wong, Dawn M
AU  - Wong DM
AD  - Department of Chemistry and Virginia Tech Center for Drug Discovery, Virginia 
      Tech, Blacksburg, VA 24061 USA.
FAU - Mutunga, James M
AU  - Mutunga JM
AD  - Emerging Pathogens Institute and Department of Entomology and Nematology, 
      University of Florida, Gainesville, FL 32610, USA.
AD  - Department of Entomology, Virginia Tech, Blacksburg, VA 24061 USA.
FAU - Muller, Jasmin
AU  - Muller J
AD  - Department of Chemistry and Virginia Tech Center for Drug Discovery, Virginia 
      Tech, Blacksburg, VA 24061 USA.
FAU - Islam, Rafique
AU  - Islam R
AD  - Emerging Pathogens Institute and Department of Entomology and Nematology, 
      University of Florida, Gainesville, FL 32610, USA.
FAU - Shimozono, Alex M
AU  - Shimozono AM
AD  - Department of Chemistry and Virginia Tech Center for Drug Discovery, Virginia 
      Tech, Blacksburg, VA 24061 USA.
FAU - Tong, Fan
AU  - Tong F
AD  - Department of Entomology, Virginia Tech, Blacksburg, VA 24061 USA.
FAU - Li, Jianyong
AU  - Li J
AD  - Department of Biochemistry, Virginia Tech, Blacksburg, VA 24061 USA.
FAU - Totrov, Max
AU  - Totrov M
AD  - Molsoft LLC, 11199 Sorrento Valley Road, San Diego, California 92121, USA.
FAU - Bloomquist, Jeffrey R
AU  - Bloomquist JR
AD  - Emerging Pathogens Institute and Department of Entomology and Nematology, 
      University of Florida, Gainesville, FL 32610, USA.
LA  - eng
GR  - R01 AI082581/AI/NIAID NIH HHS/United States
PT  - Journal Article
DEP - 20180213
PL  - United States
TA  - Pestic Biochem Physiol
JT  - Pesticide biochemistry and physiology
JID - 1301573
RN  - 0 (Carbamates)
RN  - 0 (Cholinesterase Inhibitors)
RN  - 0 (Insecticides)
RN  - EC 3.1.1.7 (Acetylcholinesterase)
SB  - IM
MH  - Acetylcholinesterase/metabolism
MH  - Animals
MH  - Anopheles/*drug effects/physiology
MH  - Carbamates/chemistry/*toxicity
MH  - Cholinesterase Inhibitors/chemistry/*toxicity
MH  - Female
MH  - Humans
MH  - Insecticide Resistance/genetics
MH  - Insecticides/chemistry/*toxicity
MH  - Models, Molecular
MH  - Mutation
PMC - PMC6277143
MID - NIHMS946904
COIS- Conflict of Interest: None of the authors have any conflict to report.
EDAT- 2018/12/14 06:00
MHDA- 2019/01/01 06:00
PMCR- 2019/10/01
CRDT- 2018/12/08 06:00
PHST- 2018/12/08 06:00 [entrez]
PHST- 2018/12/14 06:00 [pubmed]
PHST- 2019/01/01 06:00 [medline]
PHST- 2019/10/01 00:00 [pmc-release]
AID - 10.1016/j.pestbp.2018.02.003 [doi]
PST - ppublish
SO  - Pestic Biochem Physiol. 2018 Oct;151:32-39. doi: 10.1016/j.pestbp.2018.02.003. 
      Epub 2018 Feb 13.