PMID- 25684426
OWN - NLM
STAT- MEDLINE
DCOM- 20151124
LR  - 20240322
IS  - 1464-3391 (Electronic)
IS  - 0968-0896 (Print)
IS  - 0968-0896 (Linking)
VI  - 23
IP  - 6
DP  - 2015 Mar 15
TI  - 3-Oxoisoxazole-2(3H)-carboxamides and isoxazol-3-yl carbamates: 
      Resistance-breaking acetylcholinesterase inhibitors targeting the malaria 
      mosquito, Anopheles gambiae.
PG  - 1321-40
LID - S0968-0896(15)00042-5 [pii]
LID - 10.1016/j.bmc.2015.01.026 [doi]
AB  - To identify potential selective and resistance-breaking mosquitocides against the 
      African malaria vector Anopheles gambiae, we investigated the 
      acetylcholinesterase (AChE) inhibitory and mosquitocidal properties of 
      isoxazol-3-yl dimethylcarbamates (15), and the corresponding 
      3-oxoisoxazole-2(3H)-dimethylcarboxamide isomers (14). In both series, compounds 
      were found with excellent contact toxicity to wild-type susceptible (G3) strain 
      and multiply resistant (Akron) strain mosquitoes that carry the G119S resistance 
      mutation of AChE. Compounds possessing good to excellent toxicity to Akron strain 
      mosquitoes inhibit the G119S mutant of An. gambiae AChE (AgAChE) with ki values 
      at least 10- to 600-fold higher than that of propoxur, a compound that does not 
      kill Akron mosquitoes at the highest concentration tested. On average, 
      inactivation of WT AgAChE by dimethylcarboxamides 14 was 10-20 fold faster than 
      that of the corresponding isoxazol-3-yl dimethylcarbamates 15. X-ray 
      crystallography of dimethylcarboxamide 14d provided insight into that reactivity, 
      a finding that may explain the inhibitory power of structurally-related 
      inhibitors of hormone-sensitive lipase. Finally, human/An. gambiae AChE 
      inhibition selectivities of these compounds were low, suggesting the need for 
      additional structural modification.
CI  - Copyright (c) 2015 Elsevier Ltd. All rights reserved.
FAU - Verma, Astha
AU  - Verma A
AD  - Department of Chemistry, Virginia Tech, Blacksburg, VA 24061, USA.
FAU - Wong, Dawn M
AU  - Wong DM
AD  - Department of Chemistry, Virginia Tech, Blacksburg, VA 24061, USA.
FAU - Islam, Rafique
AU  - Islam R
AD  - Department of Entomology and Nematology, Emerging Pathogens Institute, University 
      of Florida, Gainesville, FL 32610, USA.
FAU - Tong, Fan
AU  - Tong F
AD  - Department of Entomology and Nematology, Emerging Pathogens Institute, University 
      of Florida, Gainesville, FL 32610, USA.
FAU - Ghavami, Maryam
AU  - Ghavami M
AD  - Department of Chemistry, Virginia Tech, Blacksburg, VA 24061, USA.
FAU - Mutunga, James M
AU  - Mutunga JM
AD  - Department of Entomology and Nematology, Emerging Pathogens Institute, University 
      of Florida, Gainesville, FL 32610, USA.
FAU - Slebodnick, Carla
AU  - Slebodnick C
AD  - Department of Chemistry, Virginia Tech, Blacksburg, VA 24061, USA.
FAU - Li, Jianyong
AU  - Li J
AD  - Department of Biochemistry, Virginia Tech, Blacksburg, VA 24061, USA.
FAU - Viayna, Elisabet
AU  - Viayna E
AD  - Department of Chemistry, Virginia Tech, Blacksburg, VA 24061, USA.
FAU - Lam, Polo C-H
AU  - Lam PC
AD  - Molsoft LLC, 11199 Sorrento Valley Road, San Diego, CA 92121, USA.
FAU - Totrov, Maxim M
AU  - Totrov MM
AD  - Molsoft LLC, 11199 Sorrento Valley Road, San Diego, CA 92121, USA.
FAU - Bloomquist, Jeffrey R
AU  - Bloomquist JR
AD  - Department of Entomology and Nematology, Emerging Pathogens Institute, University 
      of Florida, Gainesville, FL 32610, USA.
FAU - Carlier, Paul R
AU  - Carlier PR
AD  - Department of Chemistry, Virginia Tech, Blacksburg, VA 24061, USA. Electronic 
      address: pcarlier@vt.edu.
LA  - eng
GR  - R01 AI082581/AI/NIAID NIH HHS/United States
GR  - AI082581/AI/NIAID NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
DEP - 20150122
PL  - England
TA  - Bioorg Med Chem
JT  - Bioorganic & medicinal chemistry
JID - 9413298
RN  - 0 (Carbamates)
RN  - 0 (Cholinesterase Inhibitors)
RN  - 0 (Isoxazoles)
RN  - EC 3.1.1.7 (Acetylcholinesterase)
SB  - IM
MH  - Acetylcholinesterase/genetics/*metabolism
MH  - Animals
MH  - Anopheles/*drug effects/*enzymology
MH  - Carbamates/chemical synthesis/chemistry/*pharmacology
MH  - Cholinesterase Inhibitors/chemical synthesis/chemistry/*pharmacology
MH  - Dose-Response Relationship, Drug
MH  - Humans
MH  - Isoxazoles/chemical synthesis/chemistry/*pharmacology
MH  - *Malaria/transmission
MH  - Molecular Structure
MH  - Structure-Activity Relationship
PMC - PMC4346421
MID - NIHMS657978
OTO - NOTNLM
OT  - Acetylcholinesterase
OT  - Anopheles gambiae
OT  - Carbamate
OT  - Carboxamide
OT  - Malaria
EDAT- 2015/02/17 06:00
MHDA- 2015/12/15 06:00
PMCR- 2016/03/15
CRDT- 2015/02/17 06:00
PHST- 2014/11/20 00:00 [received]
PHST- 2015/01/07 00:00 [revised]
PHST- 2015/01/15 00:00 [accepted]
PHST- 2015/02/17 06:00 [entrez]
PHST- 2015/02/17 06:00 [pubmed]
PHST- 2015/12/15 06:00 [medline]
PHST- 2016/03/15 00:00 [pmc-release]
AID - S0968-0896(15)00042-5 [pii]
AID - 10.1016/j.bmc.2015.01.026 [doi]
PST - ppublish
SO  - Bioorg Med Chem. 2015 Mar 15;23(6):1321-40. doi: 10.1016/j.bmc.2015.01.026. Epub 
      2015 Jan 22.