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Structure-Activity Relationships Reveal Beneficial Selectivity Profiles of Inhibitors Targeting Acetylcholinesterase of Disease-Transmitting Mosquitoes.

ABSTRACT: Insecticide resistance jeopardizes the prevention of infectious diseases such as malaria and dengue fever by vector control of disease-transmitting mosquitoes. Effective new insecticidal compounds with minimal adverse effects on humans and the environment are therefore urgently needed. Here, we explore noncovalent inhibitors of the well-validated insecticidal target acetylcholinesterase (AChE) based on a 4-thiazolidinone scaffold. The 4-thiazolidinones inhibit AChE1 from the mosquitoes Anopheles gambiae and Aedes aegypti at low micromolar concentrations. Their selectivity depends primarily on the substitution pattern of the phenyl ring; halogen substituents have complex effects. The compounds also feature a pendant aliphatic amine that was important for activity; little variation of this group is tolerated. Molecular docking studies suggested that the tight selectivity profiles of these compounds are due to competition between two binding sites. Three 4-thiazolidinones tested for in vivo insecticidal activity had similar effects on disease-transmitting mosquitoes despite a 10-fold difference in their in vitro activity.

SUBMITTER: Vidal-Albalat A

PROVIDER: S-EPMC10184127 | biostudies-literature | 2023 May

REPOSITORIES: biostudies-literature

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Structure-Activity Relationships Reveal Beneficial Selectivity Profiles of Inhibitors Targeting Acetylcholinesterase of Disease-Transmitting Mosquitoes.

Vidal-Albalat Andreu A Kindahl Tomas T Rajeshwari Rajeshwari R Lindgren Cecilia C Forsgren Nina N Kitur Stanley S Tengo Laura Sela LS Ekström Fredrik F Kamau Luna L Linusson Anna A

Journal of medicinal chemistry 20230424 9

Insecticide resistance jeopardizes the prevention of infectious diseases such as malaria and dengue fever by vector control of disease-transmitting mosquitoes. Effective new insecticidal compounds with minimal adverse effects on humans and the environment are therefore urgently needed. Here, we explore noncovalent inhibitors of the well-validated insecticidal target acetylcholinesterase (AChE) based on a 4-thiazolidinone scaffold. The 4-thiazolidinones inhibit AChE1 from the mosquitoes <i>Anophe ...[more]

PMID: 37094110

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Project description:BackgroundAntipsychotic medication remains the mainstay of treatment for schizophrenia and has been in use for a long time. As evidenced by ongoing research and partial effectiveness of the antipsychotics on cognitive and negative symptoms, the search is on for drugs that may improve these domains of functioning for someone suffering from schizophrenia. Acetylcholinesterase inhibitors have long been in use for treating cognitive symptoms of dementia.ObjectivesThe aim of the review was to evaluate the clinical effects, safety and cost effectiveness of acetylcholinesterase inhibitors for treating people with schizophreniaSearch methodsWe searched the Cochrane Schizophrenia Group's Register (February 2009), and inspected the references of all identified studies for further trials.Selection criteriaWe included all clinical randomised trials comparing acetylcholinesterase inhibitors with antipsychotics or placebo either alone, or in combination, for schizophrenia and schizophrenia-like psychoses.Data collection and analysisWe extracted data independently. For dichotomous data, we calculated risk ratios (RR) and their 95% confidence intervals (CI) on an intention-to-treat (ITT) basis based on a random-effects model. For continuous data, we calculated mean differences (MD), again based on a random-effects model.Main resultsThe acetylcholinesterase inhibitor plus antipsychotic showed benefit over antipsychotic and placebo in the following outcomes.1. Mental state - PANSS negative symptoms average end point score (2 RCTs, n = 31, MD -1.69 95% CI -2.80 to -0.57), PANSS General Psychopathology average end point score (2 RCTs, n = 31, MD -3.86 95% CI -5.40 to -2.32), and improvement in depressive symptoms showed at least by one short-term study as measured by CDSS scale (data skewed).2. Cognitive domains - attention, (1 RCT, n = 73, MD 1.20 95% CI 0.14 to 2.26), visual memory (2 RCTs, n = 48 , MD 1.90 95% CI 0.52 to 3.28), verbal memory and language (3 RCTs, n = 42, MD 3.46 95% CI 0.67 to 6.26) and executive functioning (1 RCT, n = 24, MD 17.10 95% CI 0.70 to 33.50).3. Tolerability - EPSE: AIMS, (1 RCT, n = 35, MD 1.50 95% CI 1.04 to 1.96).No difference was noted between the two arms in other outcomes. The overall rate of participants leaving studies early was low (13.6 %) and showed no clear difference between the two groups.Authors' conclusionsThe results seem to favour the use of acetylcholinesterase inhibitors in combination with antipsychotics on a few domains of mental state and cognition, but because of the various limitations in the studies as mentioned in the main text, the evidence is weak. This review highlights the need for large, independent, well designed, conducted and reported pragmatic randomised studies.

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Structure-Activity Relationships Reveal Beneficial Selectivity Profiles of Inhibitors Targeting Acetylcholinesterase of Disease-Transmitting Mosquitoes.

Publications

Structure-Activity Relationships Reveal Beneficial Selectivity Profiles of Inhibitors Targeting Acetylcholinesterase of Disease-Transmitting Mosquitoes.

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