Khudina_2023_Arch.Pharm.(Weinheim)__e2300447

Reference

Title : Conjugates of amiridine and thiouracil derivatives as effective inhibitors of butyrylcholinesterase with the potential to block beta-amyloid aggregation - Khudina_2023_Arch.Pharm.(Weinheim)__e2300447
Author(s) : Khudina OG , Grishchenko MV , Makhaeva GF , Kovaleva NV , Boltneva NP , Rudakova EV , Lushchekina SV , Shchegolkov EV , Borisevich SS , Burgart YV , Saloutin VI , Charushin VN
Ref : Arch Pharm (Weinheim) , :e2300447 , 2023
Abstract :

New amiridine-thiouracil conjugates with different substituents in the pyrimidine fragment (R = CH(3) , CF(2) , CF(3) , (CF(2) )(2) H) and different spacer lengths (n = 1-3) were synthesized. The conjugates rather weakly inhibit acetylcholinesterase (AChE) and exhibit high inhibitory activity (IC(50) up to 0.752 +/- 0.021 microM) and selectivity to butyrylcholinesterase (BChE), which increases with spacer elongation; the lead compounds are 11c, 12c, and 13c. The conjugates are mixed-type reversible inhibitors of both cholinesterases and practically do not inhibit the structurally related off-target enzyme carboxylesterase. The results of molecular docking to AChE and BChE are consistent with the experiment on enzyme inhibition and explain the structure-activity relationships, including the rather low anti-AChE activity and the high anti-BChE activity of long-chain conjugates. The lead compounds displace propidium from the AChE peripheral anion site (PAS) at the level of the reference compound donepezil, which agrees with the mixed-type mechanism of AChE inhibition and the main mode of binding of conjugates in the active site of AChE due to the interaction of the pyrimidine moiety with the PAS. This indicates the ability of the studied conjugates to block AChE-induced aggregation of beta-amyloid, thereby exerting a disease-modifying effect. According to computer calculations, all synthesized conjugates have an ADME profile acceptable for drugs.

PubMedSearch : Khudina_2023_Arch.Pharm.(Weinheim)__e2300447
PubMedID: 38072670

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Citations formats

Khudina OG, Grishchenko MV, Makhaeva GF, Kovaleva NV, Boltneva NP, Rudakova EV, Lushchekina SV, Shchegolkov EV, Borisevich SS, Burgart YV, Saloutin VI, Charushin VN (2023)
Conjugates of amiridine and thiouracil derivatives as effective inhibitors of butyrylcholinesterase with the potential to block beta-amyloid aggregation
Arch Pharm (Weinheim) :e2300447

Khudina OG, Grishchenko MV, Makhaeva GF, Kovaleva NV, Boltneva NP, Rudakova EV, Lushchekina SV, Shchegolkov EV, Borisevich SS, Burgart YV, Saloutin VI, Charushin VN (2023)
Arch Pharm (Weinheim) :e2300447