Naslov
Evaluation of hydrazone-based compounds as potential drugs for treatment of Alzheimer’s disease

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

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

Izvornik
Proceedings of PhD student poster session of European School of Medicinal Chemistry- 41st Advanced Course of Medicinal Chemistry and “E. Duranti” Seminar for PhD Students / - Urbino, 2022, 17-18

Skup
41st European School of Medicinal Chemistry (ESMEC 2022)

Mjesto i datum
Urbino, Italija, 03.07.2022. - 07.07.2022

Vrsta sudjelovanja
Poster

Vrsta recenzije
Međunarodna recenzija

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

Sažetak
For hydrazones has been reported to possess antimicrobial, anticonvulsant, analgesic, anti- inflammatory, antiplatelet, antitubercular and antitumoral properties. Some compounds with hydrazone moiety have been reported to successfully cross blood-brain barrier (BBB) and inhibit acetylcholinesterase (AChE), butyrylcholinesterase (BChE) and amyloid fibril formation in brain.2 Those activities suggest a possibility for using this class of compounds for treatment of neurodegenerative diseases such as Alzheimer’s (AD) and some hydrazone-based compounds have recently been investigated in that direction. Aim of our study was to evaluate potential of newly-synthetized hydrazone derivatives to be used as multitarget directed ligands (MTDLs) in treatment of Alzheimer’s disease targeting cholinergic system by inhibiting the activity of acetylcholine hydrolyzing enzymes (AChE, BChE), inhibiting the accumulation of β- amiloid plaques and maintaining the biometal balance by chelating certain biometals in the brain. The ability of compounds to cross the blood-brain barrier was also evaluated as the key request for comopunds to be effective in central nervous system. We tested the inhibitory potential of seven new hydrazone derivatives of pyridoxal and pyridine-4- carbaldehyde against human AChE and BChE using Ellman’s method. Inhibitory potential of said hydrazones against β-secretase was measured using β -Secretase (BACE1) Activity Detection Kit. Chelating ability of compounds was determined spectrophotometrically for biometals (Zn(II), Cu(II) and Fe(III)). Hydrazones’ potential for crossing the blood-brain barrier by passive transport was evaluated based on their calculated physicochemical properties and comparison to the recommended physicochemical properties of central nervous system (CNS) drugs. Our results showed that all of the tested compounds reversibly inhibited AChE and BChE with dissociation constants of the enzyme-hydrazone complex (Ki) in micromolar 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. The most potent BChE inhibitor was a pyridoxal- based derivative with non-substituted benzene (1), 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 with exceptions being compound 1 that was BChE selective and compound 11 that was slightly AChE selective. Concentrations of hydrazones used in β- secretase activity assay were 10 and 50 μM. Inhibition results showed that all of our compounds have some ability to lower activity of β-secretase ; 10 μM hydrazones inhibited β- secretase activity in 20 – 50% range, while inhibition by 50 μM hydrazones was in 20 – 75% range. Compound 2 proved to be the most potent β- secretase inhibitor resulting in 45% decrease in β-secretase activity for 10 μM hydrazone, and 75% decrease in activity for 50 μM hydrazone. Metal chelation study showed that four out of seven of our tested compounds (hydrazones 1, 2, 11, 12) have ability to chelate biometals and thus have potential to reduce biometal imbalance in AD brains. For six compounds was determined to possess the ability to penetrate the BBB by passive transport, while hydrazone 2 would probably have a limited ability to pass the BBB due to its higher PSA than recommended. In conclusion, hydrazones represent a good structural base for development of MTDL drugs considering their ability to inhibit activity of AChE, BACE1 and to chelate biometals in CNS. A pyridoxal based hydrazones 1 and 2 can be pointed out as most promising structure cores that have potential for further evaluation and structural refinement that could lead to their possible applicability in treatment of Alzheimer’s disease.

Izvorni jezik
Engleski

Znanstvena područja
Kemija, Farmacija

POVEZANOST RADA