2. Academic Validation
  3. Novel slow-binding reversible acetylcholinesterase inhibitors based on uracil moieties for possible treatment of myasthenia gravis and protection from organophosphate poisoning

Novel slow-binding reversible acetylcholinesterase inhibitors based on uracil moieties for possible treatment of myasthenia gravis and protection from organophosphate poisoning

  • Eur J Med Chem. 2022 Nov 24;246:114949. doi: 10.1016/j.ejmech.2022.114949.
Liliya F Saifina 1,  Mohnad Abdalla 2,  Liliya M Gubaidullina 1,  Irina V Zueva 1,  Wafa Ali Eltayb 3,  Amr Ahmed El-Arabey 4,  Alexandra D Kharlamova 1,  Oksana A Lenina 1,  Vyacheslav E Semenov 5,  Konstantin A Petrov 6
Affiliations

Affiliations

  • 1 Arbuzov Institute of Organic and Physical Chemistry, FRC Kazan Scientific Center of RAS, Arbuzov str., 8, Kazan, 420088, Russia.
  • 2 Pediatric Research Institute, Children's Hospital Affiliated to Shandong University, Jinan, 250022, China.
  • 3 Biotechnology Department, Faculty of Science and Technology, Shendi University, Shendi, 11111, Sudan.
  • 4 Department of Pharmacology and Toxicology, Faculty of Pharmacy, Al-Azhar University, Cairo, 11751, Egypt.
  • 5 Arbuzov Institute of Organic and Physical Chemistry, FRC Kazan Scientific Center of RAS, Arbuzov str., 8, Kazan, 420088, Russia. Electronic address: sve@iopc.ru.
  • 6 Arbuzov Institute of Organic and Physical Chemistry, FRC Kazan Scientific Center of RAS, Arbuzov str., 8, Kazan, 420088, Russia; Kazan Federal University, 18 Kremlyovskaya str, Kazan, 420008, Russia.
PMID: 36462442 DOI: 10.1016/j.ejmech.2022.114949
Abstract

A series of new compounds in which uracil and 3,6-dimethyluracil moieties are bridged with different spacers were prepared and evaluated in vitro for the acetyl- and butyrylcholinesterase (AChE and BChE) inhibitory activities. These bisuracils are shown to be very effective inhibitors of AChE, inhibiting the Enzyme at nano- and lower molar concentrations with extremely high selectivity for AChE vs. BChE. Kinetic analysis showed that the lead compound 2h acts as a slow-binding inhibitor of AChE and possess a long drug-target residence time (τ = 1/koff = 18.6 ± 7.5 min). Moreover, compound 2h ameliorated muscle weakness in myasthenia gravis rat model with a lower effective dose and longer lasting effect than pyridostigmine bromide. Besides, it was shown that compound 2h has an effect of increasing efficiency of antidotal therapy as a pretreatment for poisoning by organophosphates.

Keywords

6-methyluracil derivatives; Acetylcholinesterase; Butyrylcholinesterase; Organophosphate poisoning; myasthenia gravis.

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