RESUMEN
New amiridine-thiouracil conjugates with different substituents in the pyrimidine fragment (R = CH3 , CF2 Ð, CF3 , (CF2 )2 H) and different spacer lengths (n = 1-3) were synthesized. The conjugates rather weakly inhibit acetylcholinesterase (AChE) and exhibit high inhibitory activity (IC50 up to 0.752 ± 0.021 µM) 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 ß-amyloid, thereby exerting a disease-modifying effect. According to computer calculations, all synthesized conjugates have an ADME profile acceptable for drugs.
Asunto(s)
Enfermedad de Alzheimer , Aminoquinolinas , Butirilcolinesterasa , Humanos , Butirilcolinesterasa/metabolismo , Acetilcolinesterasa/metabolismo , Simulación del Acoplamiento Molecular , Relación Estructura-Actividad , Inhibidores de la Colinesterasa/farmacología , Inhibidores de la Colinesterasa/química , Péptidos beta-Amiloides/metabolismo , PirimidinasRESUMEN
Chemoselective O-alkylation of 1-aryl-3-polyfluoroalkylpyrazol-5-oles under basic conditions resulted in a series of 5-alkoxypyrazoles (26 derivatives). They showed an acceptable ADME profile (in silico) and can be considered as drug-like. In experiments inâ vivo (CD-1 mice), it was found that the obtained compounds do not have toxic properties at a dose of more than 150â mg/kg (for most compounds at a dose of >300â mg/kg, and for lead compounds - >600â mg/kg). 22 Compounds from this series demonstrated from moderate to high analgesic effects (28-104 % at 1â h and 37-109 % at 2â h after administration) inâ vivo in the hot plate test (SD rats, 15â mg/kg, intraperitoneal (ip)). The lead compound was 4-([1-phenyl-3-(trifluoromethyl)pyrazol-5-yl]oxy)butan-1-ol, which not only increased the latent period in the hot plate test by 103 % at both measurement points but also showed a pronounced analgesic effect under conditions of capsaicin-induced nociception (CD-1 mice, 15â mg/kg, ip). According to molecular modeling, all synthesized compounds can interact with the TRPV1 ion channel. This biological target was confirmed in inâ vitro experiments on Chinese hamster ovary cells expressing rTRPV1. 5-Alkoxypyrazoles were partial agonists of the TRPV1 ion channel in various degree, and the most active was the same pyrazole as in inâ vivo tests.
Asunto(s)
Analgésicos , Canales Catiónicos TRPV , Cricetinae , Ratas , Ratones , Animales , Analgésicos/farmacología , Analgésicos/uso terapéutico , Células CHO , Ratas Sprague-Dawley , CricetulusRESUMEN
A series of 2-arylhydrazinylidene-3-oxo-4,4,4-trifluorobutanoic acids was synthesized via dealkylation of ethyl 2-arylhydrazinylidene-3-oxo-4,4,4-trifluorobutanoates under the action of a Lewis acid. Under the same conditions, ethyl 2-arylhydrazinylidene-3-oxobutanoates were also found to undergo dealkylation rather than the previously described cyclization into cinnolones. Study of the esterase profile of these compounds showed that trifluoromethyl-containing acids, in contrast to non-fluorinated analogs, were effective and selective inhibitors of carboxylesterase (CES), without substantially inhibiting structurally related cholinesterases (acetylcholinesterase and butyrylcholinesterase). Moreover, both 3-oxo-4,4,4-trifluorobutanoic and 3-oxobutanoic acids having methyl or methoxy substituent in the arylhydrazinylidene fragment showed high antioxidant activity in the ABTS test. Thus, 2-arylhydrazinylidene-3-oxo-4,4,4-trifluorobutanoic acids were found to constitute a new class of effective and selective CES inhibitors that also possess high radical-scavenging activity.
Asunto(s)
Antioxidantes/uso terapéutico , Carboxilesterasa/antagonistas & inhibidores , Simulación del Acoplamiento Molecular/métodos , Antioxidantes/farmacología , HumanosRESUMEN
A new one-pot reaction between polyfluoroalkylated 3-oxo esters, methyl ketones and primary or secondary alkyl amines is reported as an efficient approach to 3-alkylamino-5-hydroxy-5-polyfluoroalkylcyclohex-2-en-1-ones. The scope of three-component cyclization and its plausible mechanism are discussed. The described protocol makes it possible to vary the functional substituents in 2, 3 and 5 positions of carbocycles. Anhydrous conditions are necessary for the productive synthesis of aminocyclohexenones, whereas in the presence of water the competitive formation of alkyl ammonium salts of keto hydroxy carboxylates is observed. Dehydration of the aminocyclohexenones was effectively used for the synthesis of 3-alkylamino-5-trifluoromethylphenols, some of which exhibited moderate antifungal activities against eight pathogenic fungal strains.