Naslov
Hydrazone-based compounds evaluated as inhibitors of human cholinesterases

Autori
Bartolić, Marija ; Matošević, Ana ; Bušić, Valentina ; Gašo-Sokač, Dajana ; Bosak, Anita

Vrsta, podvrsta i kategorija rada
Sažeci sa skupova, sažetak, znanstveni

Izvornik
17th International Symposium on Cholinergic Mechanisms (ISCM2022) - Programme and Abstracts / Kovarik, Zrinka ; Primožič, Ines - Zagreb : Institut za medicinska istraživanja i medicinu rada, 2022, 56-56

ISBN
978-953-96817-8-2

Skup
17th International Symposium on Cholinergic Mechanisms, ISCM2022

Mjesto i datum
Dubrovnik, Hrvatska, 08.05.2022. - 12.05.2022

Vrsta sudjelovanja
Poster

Vrsta recenzije
Međunarodna recenzija

Ključne riječi
hydrazones ; Alzheimer`s disease ; acetylcholinesterase ; butyrylcholinesterase

Sažetak
Hydrazones are a class of organic compounds with an RR’C=NNH2 structure. This class of compounds has been reported to possess antimicrobial, anticonvulsant, analgesic, anti-inflammatory, antiplatelet, antitubercular, antitumoral properties. Recently, hydrazone-based compounds were also investigated as a class of compounds with the potential to be used in treating neurodegenerative diseases such as Alzheimer’s (AD). Some hydrazone -based compounds have been reported to successfully cross the blood -brain barrier and inhibit the activity of acetylcholinesterase (AChE), butyrylcholinesterase (BChE) and amyloid fibril formation in the brain. In this pilot-study, we tested the inhibitory potential of seven new hydrazone derivatives of pyridoxal and pyridine-4- carbaldehyde against human AChE and BChE. Our results showed that all of the tested compounds reversibly inhibited AChE and BChE with dissociation constants of the enzyme -hydrazone complex (Ki) in 9.9 – 301 μM range. The most potent AChE inhibitor was compound 2, a pyridoxal derivative with two nitro groups on benzene ring with Ki = 16 μM, while the lowest inhibitory potential was that of 4 - pyridinecarboxaldehyde based hydrazone (9) with non -substituted benzene. Generally, pyridoxal - based derivatives were more potent inhibitors of AChE than 4 -pyridinecarboxaldehyde based. The most potent BChE inhibitor was compound 1, a pyridoxal -based derivative with non-substituted benzene, while the lowest inhibition potency was detected for compound 11, a 4- pyridinecarboxaldehyde based hydrazone with fluorine on benzene ring. It was noticed that pyridoxal-based derivatives were generally low selective to AChE, while 4 - pyridinecarboxaldehyde based were BChE selective. The exceptions were compound 1 that was BChE selective, and 11 that was slightly AChE selective. As target enzymes are located in neurons, we evaluated hydrazones’ potential for crossing the blood-brain barrier by passive transport based on their calculated physicochemical properties and comparison to the recommended physicochemical properties of central nervous system drugs. Six hydrazones were determined to possess the ability to penetrate the blood-brain barrier by passive transport, while compound 2 has one violation of Lipinski’s rule of five and should be able to passively penetrate the blood -brain barrier. In conclusion, a pyridoxal- based hydrazone 1 can be pointed out as compound that has potential for further evaluation and structural refinement as molecule with possible applicability in treatment of Alzheimer’s disease symptoms.

Izvorni jezik
Engleski

Znanstvena područja
Kemija, Farmacija

POVEZANOST RADA