| Autor: |
Zaib S; Department of Biochemistry, Faculty of Life Sciences, University of Central Punjab, Lahore 54590, Pakistan., Munir R; Department of Chemistry, Kinnaird College for Women, Lahore 54000, Pakistan., Younas MT; Department of Biochemistry, Faculty of Life Sciences, University of Central Punjab, Lahore 54590, Pakistan., Kausar N; Department of Chemistry, University of Gujrat, Gujrat 50700, Pakistan., Ibrar A; Department of Chemistry, Faculty of Natural Sciences, The University of Haripur, Haripur 22620, Pakistan., Aqsa S; Department of Chemistry, Kinnaird College for Women, Lahore 54000, Pakistan., Shahid N; Department of Chemistry, Kinnaird College for Women, Lahore 54000, Pakistan., Asif TT; Department of Chemistry, Kinnaird College for Women, Lahore 54000, Pakistan., Alsaab HO; Department of Pharmaceutics and Pharmaceutical Technology, Taif University, P.O. Box 11099, Taif 21944, Saudi Arabia., Khan I; Department of Chemistry, Manchester Institute of Biotechnology, The University of Manchester, 131 Princess Street, Manchester M1 7DN, UK. |
| Abstrakt: |
Alzheimer's disease (AD) is a progressive neurodegenerative disorder and the leading cause of dementia worldwide. The limited pharmacological approaches based on cholinesterase inhibitors only provide symptomatic relief to AD patients. Moreover, the adverse side effects such as nausea, vomiting, loss of appetite, muscle cramps, and headaches associated with these drugs and numerous clinical trial failures present substantial limitations on the use of medications and call for a detailed insight of disease heterogeneity and development of preventive and multifactorial therapeutic strategies on urgent basis. In this context, we herein report a series of quinoline-thiosemicarbazone hybrid therapeutics as selective and potent inhibitors of cholinesterases. A facile multistep synthetic approach was utilized to generate target structures bearing multiple sites for chemical modifications and establishing drug-receptor interactions. The structures of all the synthesized compounds were fully established using readily available spectroscopic techniques (FTIR, 1 H- and 13 C-NMR). In vitro inhibitory results revealed compound 5b as a promising and lead inhibitor with an IC 50 value of 0.12 ± 0.02 μM, a 5-fold higher potency than standard drug (galantamine; IC 50 = 0.62 ± 0.01 μM). The synergistic effect of electron-rich (methoxy) group and ethylmorpholine moiety in quinoline-thiosemicarbazone conjugates contributes significantly in improving the inhibition level. Molecular docking analysis revealed various vital interactions of potent compounds with amino acid residues and reinforced the in vitro results. Kinetics experiments revealed the competitive mode of inhibition while ADME properties favored the translation of identified inhibitors into safe and promising drug candidates for pre-clinical testing. Collectively, inhibitory activity data and results from key physicochemical properties merit further research to ensure the design and development of safe and high-quality drug candidates for Alzheimer's disease. |
