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
  • 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: [email protected].
  • 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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