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Evaluation of Anticholinesterase Activity of the Fungicides Mefentrifluconazole and Pyraclostrobin.
- Source :
-
International journal of molecular sciences [Int J Mol Sci] 2024 Jun 07; Vol. 25 (12). Date of Electronic Publication: 2024 Jun 07. - Publication Year :
- 2024
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Abstract
- Triazoles are compounds with various biological activities, including fungicidal action. They became popular through cholinesterase studies after the successful synthesis of the dual binding femtomolar triazole inhibitor of acetylcholinesterase (AChE, EC 3.1.1.7) by Sharpless et al. via in situ click chemistry. Here, we evaluate the anticholinesterase effect of the first isopropanol triazole fungicide mefentrifluconazole (Ravystar <superscript>®</superscript> ), developed to overcome fungus resistance in plant disease management. Mefentrifluconazole is commercially available individually or in a binary fungicidal mixture, i.e., with pyraclostrobin (Ravycare <superscript>®</superscript> ). Pyraclostrobin is a carbamate that contains a pyrazole ring. Carbamates are known inhibitors of cholinesterases and the carbamate rivastigmine is already in use for the treatment of Alzheimer's disease. We tested the type and potency of anticholinesterase activity of mefentrifluconazole and pyraclostrobin. Mefentrifluconazole reversibly inhibited human AChE and BChE with a seven-fold higher potency toward AChE ( K <subscript>i</subscript> = 101 ± 19 μM). Pyraclostrobin (50 μM) inhibited AChE and BChE progressively with rate constants of (t <subscript>1/2</subscript> = 2.1 min; k <subscript>i</subscript> = 6.6 × 10 <superscript>3</superscript> M <superscript>-1</superscript> min <superscript>-1</superscript> ) and (t <subscript>1/2</subscript> = 1.5 min; k <subscript>i</subscript> = 9.2 × 10 <superscript>3</superscript> M <superscript>-1</superscript> min <superscript>-1</superscript> ), respectively. A molecular docking study indicated key interactions between the tested fungicides and residues of the lipophilic active site of AChE and BChE. Additionally, the physicochemical properties of the tested fungicides were compared to values for CNS-active drugs to estimate the blood-brain barrier permeability. Our results can be applied in the design of new molecules with a lesser impact on humans and the environment.
- Subjects :
- Humans
Butyrylcholinesterase metabolism
Butyrylcholinesterase chemistry
Pyrazoles pharmacology
Pyrazoles chemistry
Strobilurins pharmacology
Strobilurins chemistry
Cholinesterase Inhibitors pharmacology
Cholinesterase Inhibitors chemistry
Acetylcholinesterase metabolism
Acetylcholinesterase chemistry
Fungicides, Industrial pharmacology
Fungicides, Industrial chemistry
Triazoles pharmacology
Triazoles chemistry
Molecular Docking Simulation
Subjects
Details
- Language :
- English
- ISSN :
- 1422-0067
- Volume :
- 25
- Issue :
- 12
- Database :
- MEDLINE
- Journal :
- International journal of molecular sciences
- Publication Type :
- Academic Journal
- Accession number :
- 38928014
- Full Text :
- https://doi.org/10.3390/ijms25126310