Browsing by Author "Gul, Halise Inci"

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Aminoalkylated Phenolic Chalcones: Investigation of Biological Effects on Acetylcholinesterase and Carbonic Anhydrase I and Ii as Potential Lead Enzyme Inhibitors
(Bentham Science Publ Ltd, 2020) Yamali, Cem; Gul, Halise Inci; Cakir, Tahir; Demir, Yeliz; Gulcin, Ilhami
Background: Phenolic Mannich bases have been reported as acetylcholinesterase (AChE) inhibitors for the medication of Alzheimer's disease. Carbonic Anhydrases (CAs) are molecular targets for anticonvulsant, diuretic and antiglaucoma drugs in the clinic. Phenolic compounds have also been mentioned as CA inhibitors. The importance of Mannich bases in drug design inspired our research group to design novel phenolic Mannic bases as potent enzyme inhibitors. Objective: In this study, novel Mannich bases, 1-(3,5-bis-aminomethyl-4-hydroxyphenyl)-3-(4-substitutedphenyl)-2-propen-1-ones (1-9), were designed to discover new and potent AChE inhibitors for the treatment of Alzheimer's disease and also to report their carbonic anhydrase inhibitory potency against the most studied hCA I and hCA II isoenzymes with the hope to find out promising enzyme inhibitors. Methods: Mannich bases were synthesized by the Mannich reaction. The structures of the compounds were elucidated by H-1 NMR, C-13 NMR, and HRMS. Enzyme inhibitory potency of the compounds was evaluated spectrophotometrically towards AChE, hCA I and hCA II enzymes. Results and Discussion: The compounds showed inhibition potency in nanomolar concentrations against AChE with Ki values ranging from 20.44 +/- 3.17 nM to 43.25 +/- 6.28 nM. They also showed CAs inhibition potency with Ki values in the range of 11.76 +/- 1.29-31.09 +/- 2.7 nM (hCA I) and 6.08 +/- 1.18-23.12 +/- 4.26 nM (hCA II). Compounds 1 (hCA I), 5 (hCA II), and 4 (AChE) showed significant inhibitory potency against the enzymes targeted. Conclusion: Enzyme assays showed that Mannich derivatives might be considered as lead enzyme inhibitors to design more selective and potent compounds targeting enzyme-based diseases.
Quinazolinone-Based Benzenesulfonamides With Low Toxicity and High Affinity as Monoamine Oxidase-A Inhibitors: Synthesis, Biological Evaluation and Induced-Fit Docking Studies
(Academic Press inc Elsevier Science, 2022) Yamali, Cem; Gul, Halise Inci; Sakarya, Mehtap Tugrak; Saglik, Begum Nurpelin; Ece, Abdulilah; Demirel, Goksun; Oner, Ahmet Cihat
The research in selective monoamine oxidases (MAO-A and MAO-B) inhibitors has been increased due to their therapeutic value for neurodegenerative diseases. In this study, 4-((2-(aryl)-4-oxoquinazolin-3(4H)-yl)amino) benzenesulfonamides were synthesized and their MAOs inhibition potentials were investigated applying in vitro fluorometric technique. The most potent compounds 7 and 8 against MAO-A had IC50 values of 0.058 +/- 0.002 and 0.094 +/- 0.003 mu M, respectively, while the reference moclobemide had an IC50 value of 6.061 mu M. Compounds 7 (> 1724 times) and 8 (> 1063 times) more selective and reversible inhibitors of MAO-A rather than MAO-B. Toxicity studies of 7 (IC50 = 210.23 mu M) and 8 (IC50 = 259.27 mu M) showed that compounds can be considered as non-toxic towards SH-SY5Y cell line at their effective concentrations against MAO-A. In silico docking simulations successfully explained the observed activities and also highlighted structural water molecules to play a key role in the ligand-enzyme interactions. Calculated molecular descriptors are also obeying Lipinski's rule of five and brain/blood partition coefficients, a critical parameter in neurodegenerative diseases. These reversible inhibitors can have considerable advantages compared to irreversible inhibitors which may possess serious pharmacological side effects.