Re-engineering aryl methylcarbamates to confer high selectivity for inhibition of Anopheles gambiae versus human acetylcholinesterase

Hartsel, Joshua A.; Wong, Dawn M.; Mutunga, James M.; Ma, Ming; Anderson, Troy D.; Wysinski, Ania; Islam, Rafique; Wong, Eric A.; Paulson, Sally L.; Li, Jianyong; Lam, Polo C.‐H.; Totrov, Maxim; Bloomquist, Jeffrey R.; Carlier, Paul R.

doi:10.1016/j.bmcl.2012.05.103

Cited by 43 publications

(75 citation statements)

References 23 publications

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“…To search for compounds that might selectively inhibit Ag AChE, Carlier and co-workers prepared a series of 34 methylcarbamates derived from 2- and 3-substituted phenols [46]. Compounds of particular interest are depicted in Fig.…”

Section: Development Of Species-selective and Resistance-breaking mentioning

confidence: 99%

“…However, methylcarbamates with select γ -branched 2-substituents can offer excellent selectivity for inhibition of Ag AChE over h AChE. For example, compounds 11 and 13 (A = CH 2 and S, respectively) both offer greater than 100-fold selectivity, and analog 12 (A = O) offers greater than 500-fold selectivity for inhibition of Ag AChE relative to h AChE [46–48]. …”

Section: Development Of Species-selective and Resistance-breaking mentioning

confidence: 99%

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Discovery of Species-selective and Resistance-breaking Anticholinesterase Insecticides for the Malaria Mosquito

Carlier

Bloomquist

Totrov

et al. 2017

CMC

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Great reductions in malaria mortality have been accomplished in the last 15 years, in part due to the widespread roll-out of insecticide-treated bednets across sub-Saharan Africa. To date, these nets only employ pyrethroids, insecticides that target the voltage-gated sodium ion channel of the malaria vector, Anopheles gambiae. Due to the growing emergence of An. gambiae strains that are resistant to pyrethroids, there is an urgent need to develop new public health insecticides that engage a different target and possess low mammalian toxicity. In this review, we will describe efforts to develop highly species-specific and resistance-breaking inhibitors of An. gambiae acetylcholinesterase (AgAChE). These efforts have been greatly aided by advances in knowledge of the structure of the enzyme, and two major inhibitor design strategies have been explored. Since AgAChE possesses an unpaired Cys residue not present in mammalian AChE, a logical strategy to achieve selective inhibition involves design of compounds that could ligate that Cys. A second strategy involves the design of new molecules to target the catalytic serine of the enzyme. Here the challenge is not only to achieve high inhibition selectivity vs human AChE, but also to demonstrate toxicity to An. gambiae that carry the G119S resistance mutation of AgAChE. The advances made and challenges remaining will be presented. This review is part of the special issue “Insecticide Mode of Action: From Insect to Mammalian Toxicity.

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Section: Development Of Species-selective and Resistance-breaking mentioning

confidence: 99%

Section: Development Of Species-selective and Resistance-breaking mentioning

confidence: 99%

Discovery of Species-selective and Resistance-breaking Anticholinesterase Insecticides for the Malaria Mosquito

Carlier

Bloomquist

Totrov

et al. 2017

CMC

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“…gambiae AChE ( Ag AChE) vs human AChE ( h AChE). 7,8 These compounds bearing a γ -branched substituent exhibit up to 500-fold selectivity for Ag AChE over h AChE, and are toxic to wild-type (WT) An. gambiae (G3 strain, MR4, CDC).…”

Section: Introductionmentioning

confidence: 99%

“…9 Although we cannot yet point to specific residue substitutions that 5-7 exploit to achieve selective inhibition, we have developed a ligand-based selectivity model. 8 However, these compounds, like aryl methylcarbamates 1 - 4 , are not appreciably toxic to Akron strain An. gambiae (MR4, CDC).…”

Section: Introductionmentioning

confidence: 99%

3-Oxoisoxazole-2(3H)-carboxamides and isoxazol-3-yl carbamates: Resistance-breaking acetylcholinesterase inhibitors targeting the malaria mosquito, Anopheles gambiae

Verma

Wong

Islam

et al. 2015

Bioorganic & Medicinal Chemistry

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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.

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“…An additional structural feature that may contribute to inhibition of BChE is the carbamate group, as carbamates have been used as cholinesterase inhibitors (Verma et al 2015; Hartsel et al 2012; Wong et al 2013; Bar-On et al 2002). Nevertheless, several Fmoc-amino acids did not show an inhibitory effect under the conditions tested (e.g., Fmoc-Ala).…”

Section: Resultsmentioning

confidence: 99%

Evaluating Fmoc-amino acids as selective inhibitors of butyrylcholinesterase

2016

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Cholinesterases are involved in neuronal signal transduction, and perturbation of function has been implicated in diseases, such as Alzheimer’s and Huntington’s disease. For the two major classes of cholinesterases, such as acetylcholinesterase (AChE) and butyrylcholinesterase (BChE), previous studies reported BChE activity is elevated in patients with Alzheimer’s disease, while AChE levels remain the same or decrease. Thus, the development of potent and specific inhibitors of BChE have received much attention as a potential therapeutic in the alleviation of neurodegenerative diseases. In this study, we evaluated amino acid analogs as selective inhibitors of BChE. Amino acid analogs bearing a 9-fluorenylmethyloxycarbonyl (Fmoc) group were tested, as the Fmoc group has structural resemblance to previously described inhibitors. We identified leucine, lysine, and tryptophan analogs bearing the Fmoc group as selective inhibitors of BChE. The Fmoc group contributed to inhibition, as analogs bearing a carboxybenzyl group showed ~tenfold higher values for the inhibition constant (KI value). Inclusion of a t-butoxycarbonyl on the side chain of Fmoc tryptophan led to an eightfold lower KI value compared to Fmoc tryptophan alone suggesting that modifications of the amino acid side chains may be designed to create inhibitors with higher affinity. Our results identify Fmoc-amino acids as a scaffold upon which to design BChE-specific inhibitors and provide the foundation for further experimental and computational studies to dissect the interactions that contribute to inhibitor binding.

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Re-engineering aryl methylcarbamates to confer high selectivity for inhibition of Anopheles gambiae versus human acetylcholinesterase

Cited by 43 publications

References 23 publications

Discovery of Species-selective and Resistance-breaking Anticholinesterase Insecticides for the Malaria Mosquito

Discovery of Species-selective and Resistance-breaking Anticholinesterase Insecticides for the Malaria Mosquito

3-Oxoisoxazole-2(3H)-carboxamides and isoxazol-3-yl carbamates: Resistance-breaking acetylcholinesterase inhibitors targeting the malaria mosquito, Anopheles gambiae

Evaluating Fmoc-amino acids as selective inhibitors of butyrylcholinesterase

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