Noncovalent Inhibitors of Mosquito Acetylcholinesterase 1 with Resistance-Breaking Potency

Knutsson, Sofie; Engdahl, Cecilia; Kumari, Rashmi; Forsgren, Nina; Lindgren, Cecilia M.; Kindahl, Tomas; Kitur, Stanley; Wachira, Lucy; Kamau, Luna; Ekström, Fredrik; Linusson, Anna

doi:10.1021/acs.jmedchem.8b01060

Cited by 15 publications

(25 citation statements)

References 62 publications

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“…For instance, larvicidal inhibitors have the ability to bind to sterol carrier protein-2 [56], juvenile hormone-binding protein [57], D7r4 a salivary biogenic amine-binding protein [58], calcium-dependent protein kinase-1 [59], or purine nucleoside phosphorylase targets [60]. The binding investigation of the dihydroquinazolines against the above-mentioned molecular targets allowed us to identify AChE as the most plausible molecular target which corroborated with the predicted brain cell permeability [51][52][53][54][55][56][57][58][59][60]. No crystal structures of Anopheles arabienesis AChE from mosquito are deposited in the Protein Data Bank (PDB) so far.…”

Section: Molecular Modelingsupporting

confidence: 52%

“…On the basis of the preliminary structure-activity relationship of the 2,3-dihydroquinazolin-4(1H)-one derivatives, we explored a variety of enzyme molecular targets in an attempt to identify the mode of action via which the compounds exert their larvicidal effect. It is well known that AChE represents the main molecular target of insecticides [51][52][53][54][55] and can be associated with the larvicidal action of our compounds. However, some insecticide enzyme targets other than AChE were reported.…”

Section: Molecular Modelingmentioning

confidence: 99%

“…This mutation does not appear to perturb the other amino acids in the catalytic site. Knutsson et al reported the synthesis and the larvicidal activity of some phenoxyacetamide derivatives [55]. An enzymatic assay of these derivatives was conducted against four AChE1 enzymes (Anopheles gambiae mosquito, G119S mutation Anopheles gambiae mosquito, mouse, and human), and it demonstrated good selectivity in favor of both mosquito AChE1 enzymes as compared to that of human AChE.…”

Section: Molecular Modelingmentioning

confidence: 99%

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Larvicidal Activities of 2-Aryl-2,3-Dihydroquinazolin -4-ones against Malaria Vector Anopheles arabiensis, In Silico ADMET Prediction and Molecular Target Investigation

et al. 2020

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Malaria, affecting all continents, remains one of the life-threatening diseases introduced by parasites that are transmitted to humans through the bites of infected Anopheles mosquitoes. Although insecticides are currently used to reduce malaria transmission, their safety concern for living systems, as well as the environment, is a growing problem. Therefore, the discovery of novel, less toxic, and environmentally safe molecules to effectively combat the control of these vectors is in high demand. In order to identify new potential larvicidal agents, a series of 2-aryl-1,2-dihydroquinazolin-4-one derivatives were synthesized and evaluated for their larvicidal activity against Anopheles arabiensis. The in silico absorption, distribution, metabolism, excretion, and toxicity (ADMET) properties of the compounds were also investigated and most of the derivatives possessed a favorable ADMET profile. Computational modeling studies of the title compounds demonstrated a favorable binding interaction against the acetylcholinesterase enzyme molecular target. Thus, 2-aryl-1,2-dihydroquinazolin-4-ones were identified as a novel class of Anopheles arabiensis insecticides which can be used as lead molecules for the further development of more potent and safer larvicidal agents for treating malaria.

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Section: Molecular Modelingsupporting

confidence: 52%

Section: Molecular Modelingmentioning

confidence: 99%

Section: Molecular Modelingmentioning

confidence: 99%

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Larvicidal Activities of 2-Aryl-2,3-Dihydroquinazolin -4-ones against Malaria Vector Anopheles arabiensis, In Silico ADMET Prediction and Molecular Target Investigation

et al. 2020

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“…We also investigated the binding pose of the 4‐methyl‐3‐nitrobenzamide scaffold by determining the X‐ray crystal structure of the complex between 1 a and Mus musculus AChE ( m AChE) at a resolution of 2.3 Å (Table S2). h AChE and m AChE are very similar in sequence and 3D structure, and studies have shown similar inhibition kinetics [66,67] . Also, binary OPNA‐AChE complex structures determined in both species are similar [12,13,15,16] .…”

Section: Resultsmentioning

confidence: 75%

Broad‐Spectrum Antidote Discovery by Untangling the Reactivation Mechanism of Nerve‐Agent‐Inhibited Acetylcholinesterase

Lindgren

Forsgren

Hoster

et al. 2022

Chemistry A European J

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Reactivators are vital for the treatment of organophosphorus nerve agent (OPNA) intoxication but new alternatives are needed due to their limited clinical applicability. The toxicity of OPNAs stems from covalent inhibition of the essential enzyme acetylcholinesterase (AChE), which reactivators relieve via a chemical reaction with the inactivated enzyme. Here, we present new strategies and tools for developing reactivators. We discover suitable inhibitor scaffolds by using an activity-independent competition assay to study non-covalent interactions with OPNA-AChEs and transform these inhibitors into broad-spectrum reactivators. Moreover, we identify determinants of reactivation efficiency by analysing reactivation and pre-reactivation kinetics together with structural data. Our results show that new OPNA reactivators can be discovered rationally by exploiting detailed knowledge of the reactivation mechanism of OPNAinhibited AChE.

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“…In addition, PyrimidineTrione Furan-substituted (PTF) compounds have been observed to preferentially bind mutated G119S AChE [223]. Knutsson et al [224] designed, synthesized and evaluated the biological activity of phenoxyacetamide-based inhibitors of AgAChE and observed that these inhibitors were highly selective for AgAChE compared to hAChE. Also, these inhibitors were effective towards AgAChE with G119S mutation.…”

Section: Generation Of Organism-target Specific and Selective Insectimentioning

confidence: 99%

Anopheles metabolic proteins in malaria transmission, prevention and control: a review

et al. 2020

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The increasing resistance to currently available insecticides in the malaria vector, Anopheles mosquitoes, hampers their use as an effective vector control strategy for the prevention of malaria transmission. Therefore, there is need for new insecticides and/or alternative vector control strategies, the development of which relies on the identification of possible targets in Anopheles. Some known and promising targets for the prevention or control of malaria transmission exist among Anopheles metabolic proteins. This review aims to elucidate the current and potential contribution of Anopheles metabolic proteins to malaria transmission and control. Highlighted are the roles of metabolic proteins as insecticide targets, in blood digestion and immune response as well as their contribution to insecticide resistance and Plasmodium parasite development. Furthermore, strategies by which these metabolic proteins can be utilized for vector control are described. Inhibitors of Anopheles metabolic proteins that are designed based on target specificity can yield insecticides with no significant toxicity to non-target species. These metabolic modulators combined with each other or with synergists, sterilants, and transmission-blocking agents in a single product, can yield potent malaria intervention strategies. These combinations can provide multiple means of controlling the vector. Also, they can help to slow down the development of insecticide resistance. Moreover, some metabolic proteins can be modulated for mosquito population replacement or suppression strategies, which will significantly help to curb malaria transmission.

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Noncovalent Inhibitors of Mosquito Acetylcholinesterase 1 with Resistance-Breaking Potency

Cited by 15 publications

References 62 publications

Larvicidal Activities of 2-Aryl-2,3-Dihydroquinazolin -4-ones against Malaria Vector Anopheles arabiensis, In Silico ADMET Prediction and Molecular Target Investigation

Larvicidal Activities of 2-Aryl-2,3-Dihydroquinazolin -4-ones against Malaria Vector Anopheles arabiensis, In Silico ADMET Prediction and Molecular Target Investigation

Broad‐Spectrum Antidote Discovery by Untangling the Reactivation Mechanism of Nerve‐Agent‐Inhibited Acetylcholinesterase

Anopheles metabolic proteins in malaria transmission, prevention and control: a review

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