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

Liliya F Saifina; Mohnad Abdalla; Liliya M Gubaidullina; Irina V Zueva; Wafa Ali Eltayb; Amr Ahmed El-Arabey; Alexandra D Kharlamova; Oksana A Lenina; Vyacheslav E Semenov; Konstantin A Petrov

doi:10.1016/j.ejmech.2022.114949

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. 2023 Jan 15:246:114949. doi: 10.1016/j.ejmech.2022.114949. Epub 2022 Nov 24.

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/k_off = 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.

MeSH terms

Acetylcholinesterase / metabolism
Animals
Butyrylcholinesterase / metabolism
Cholinesterase Inhibitors / chemistry
Cholinesterase Inhibitors / pharmacology
Cholinesterase Inhibitors / therapeutic use
Kinetics
Myasthenia Gravis* / chemically induced
Myasthenia Gravis* / drug therapy
Organophosphate Poisoning* / drug therapy
Rats
Uracil / pharmacology
Uracil / therapeutic use

Substances

Cholinesterase Inhibitors
Butyrylcholinesterase
Acetylcholinesterase
Uracil