Synthesis and biological evaluation of novel salicylidene uracils: Cytotoxic activity on human cancer cell lines and inhibitory action on enzymatic activity

A series of salicylidene uracil (1–18) derived from 5‐aminouracil and substituted salicylaldehydes were analyzed for cytotoxic activity and enzyme inhibitory potency. Nine out of eighteen derivatives (6–8, 10, 12–15, 18) are novel molecules synthesized for the first time in this work, and other deri...

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Published in:Archiv der Pharmazie (Weinheim) 2024-01, Vol.357 (1), p.e2300374-n/a
Main Authors: Poslu, Ayşe Halıç, Aslan, Şafak Esra, Koz, Gamze, Senturk, Esra, Koz, Ömer, Senturk, Murat, Nalbantsoy, Ayşe, Öztekin, Aykut, Ekinci, Deniz
Format: Article
Language:English
Subjects:
Acetylcholinesterase - metabolism
Adenocarcinoma
Alzheimer's disease
Antineoplastic Agents - pharmacology
Butyrylcholinesterase - metabolism
Cancer
carbonic anhydrase
Carbonic Anhydrase Inhibitors
Cholinesterase Inhibitors - chemistry
cholinesterases
Cytotoxicity
Fourier transforms
glutathione reductase
HEK293 Cells
Humans
Molecular Docking Simulation
Molecular Structure
NMR
Nuclear magnetic resonance
Prostate
salicylidene uracil
Structure-Activity Relationship
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Summary:A series of salicylidene uracil (1–18) derived from 5‐aminouracil and substituted salicylaldehydes were analyzed for cytotoxic activity and enzyme inhibitory potency. Nine out of eighteen derivatives (6–8, 10, 12–15, 18) are novel molecules synthesized for the first time in this work, and other derivatives were previously synthesized by our group. The compounds were characterized by Proton nuclear magnetic resonance, carbon nuclear magnetic resonance, fourier transform infrared spectroscopy, and elemental analysis. All compounds were tested for their in vitro cytotoxicity against PC‐3 (human prostate adenocarcinoma), A549 (human alveolar adenocarcinoma), and SHSY‐5Y (human neuroblastoma) cancer cell lines and the nontumorigenic HEK293 (human embryonic kidney cells) cell line. The 3,5‐di‐tert‐butylsalicylaldehyde derived compound (8) was toxic to PC‐3 human prostate adenocarcinoma cells, showing a promising IC50 value at 7.05 ± 0.76 μM. The present study also aimed to evaluate the inhibitory effects of the compounds against several key enzymes, namely carbonic anhydrase I and II (CA I and CA II), acetylcholinesterase (AChE), butyrylcholinesterase (BChE), and glutathione reductase (GR), which are implicated in various global disorders, such as Alzheimer's disease, epilepsy, cancer, malaria, diabetes, and glaucoma. The inhibitory profiles of the tested compounds were assessed by determining their Ki values, which ranged from 2.96 to 9.24 nM for AChE, 3.78 to 12.57 nM for BChE, 8.42 to 25.74 nM for CA I, 7.24 to 19.74 nM for CA II, and 0.541 to 1.124 μM for GR. Molecular docking studies were also performed for all compounds. Most derivatives exhibited much more effective inhibitory action compared with clinically used standards. Thus, our findings indicate that the salicylidene derivatives presented in this study are promising drug candidates that need further evaluation. A series of salicylidene uracil (1–18) derived from 5‐aminouracil and substituted salicylaldehydes were analyzed for cytotoxic activity and enzyme inhibitory potency. Most derivatives exhibited much more effective inhibitory action compared with clinically used standards.
ISSN:0365-6233
1521-4184
DOI:10.1002/ardp.202300374