| Autor: |
Kumar N; Laboratory of Organic and Medicinal Chemistry, Department of Chemistry, Central University of Punjab, Bathinda, Punjab 151401, India., Jangid K; Laboratory of Organic and Medicinal Chemistry, Department of Chemistry, Central University of Punjab, Bathinda, Punjab 151401, India.; Department of Pharmaceutical Sciences and Natural Products, Central University of Punjab, Bathinda, Punjab 151401, India., Kumar V; Department of Pharmacology, Central University of Punjab, Bathinda, Punjab 151401, India., Yadav RP; Gastrointestinal Disease Lab, Department of Microbiology, Central University of Punjab, Bathinda, Punjab 151401, India., Mishra J; Laboratory of Translational Medicine and Nanotherapeutics, Department of Human Genetics and Molecular Medicine, Central University of Punjab, Bathinda, Punjab 151401, India., Upadhayay S; Department of Pharmacology, Central University of Punjab, Bathinda, Punjab 151401, India., Kumar V; Laboratory of Organic and Medicinal Chemistry, Department of Chemistry, Central University of Punjab, Bathinda, Punjab 151401, India., Devi B; Laboratory of Organic and Medicinal Chemistry, Department of Chemistry, Central University of Punjab, Bathinda, Punjab 151401, India., Kumar V; Laboratory of Organic and Medicinal Chemistry, Department of Chemistry, Central University of Punjab, Bathinda, Punjab 151401, India., Dwivedi AR; Department of Pharmaceutical Sciences and Natural Products, Central University of Punjab, Bathinda, Punjab 151401, India.; Gitam School of Pharmacy, Hyderabad, Telangana 502329, India., Kumar P; Department of Pharmacology, Central University of Punjab, Bathinda, Punjab 151401, India., Baranwal S; Gastrointestinal Disease Lab, Department of Microbiology, Central University of Punjab, Bathinda, Punjab 151401, India., Bhatti JS; Laboratory of Translational Medicine and Nanotherapeutics, Department of Human Genetics and Molecular Medicine, Central University of Punjab, Bathinda, Punjab 151401, India., Kumar V; Laboratory of Organic and Medicinal Chemistry, Department of Chemistry, Central University of Punjab, Bathinda, Punjab 151401, India. |
| Abstrakt: |
Alzheimer's disease is a complex neurological disorder linked with multiple pathological hallmarks. The interrelation of therapeutic targets assists in the enhancement of cognitive decline through interference with overall neuronal transmission. We have synthesized and screened various chromone derivatives as potential multitarget-directed ligands for the effective treatment of Alzheimer's disease. The synthesized compounds exhibited multipotent activity against AChE, BuChE, MAO-B, and amyloid β aggregation. Three potent compounds, i.e., VN-3 , VN-14 , and VN-19 were identified that displayed remarkable activities against different targets. These compounds displayed IC 50 values of 80 nM, 2.52 μM, and 140 nM against the AChE enzyme, respectively, and IC 50 values of 2.07 μM, 70 nM, and 450 nM against the MAO-B isoform, respectively. VN-3 displayed potent activity against self-induced Aβ 1-42 aggregation with inhibition of 58.3%. In the ROS inhibition studies, the most potent compounds reduced the intracellular ROS levels up to 80% in SH-SY5Y cells at 25 μM concentration. The compounds were found to be neuroprotective and noncytotoxic even at a concentration of 25 μM against SH-SY5Y cells. In silico studies showed that the compounds were nicely accommodated in the active sites of the receptors along with thermodynamically stable orientations. Compound VN-19 exhibited a balanced multitargeting profile against AChE, BuChE, MAO-B, and Aβ 1-42 enzymes and was further evaluated for in vivo activities on the scopolamine-induced zebrafish model. VN-19 was found to ameliorate the cognitive decline in zebrafish brains by protecting them against scopolamine-induced neurodegeneration. Thus, VN-3 , VN-14 , and VN-19 were identified as potent multitarget-directed ligands with a balanced activity profile against different targets and can be developed as therapeutics for AD. |
