Design, synthesis and in-vitro evaluation of fluorinated triazoles as multi-target directed ligands for Alzheimer disease
| Autor: | Alok Jain, Dattatray Shinde Suchita, Tanay Dalvi, Akshay Srivastava, Bichismita Sahu, Bhaskar Dewangan, Gopal Agarwal |
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| Rok vydání: | 2021 |
| Předmět: |
Halogenation
Clinical Biochemistry Pharmaceutical Science Inflammation Ligands Blood–brain barrier 01 natural sciences Biochemistry Protein Aggregates Structure-Activity Relationship Alzheimer Disease Drug Discovery medicine Humans Moiety Chelation Molecular Biology IC50 chemistry.chemical_classification Reactive oxygen species Amyloid beta-Peptides Dose-Response Relationship Drug Molecular Structure 010405 organic chemistry Organic Chemistry Triazoles medicine.disease In vitro 0104 chemical sciences 010404 medicinal & biomolecular chemistry medicine.anatomical_structure chemistry Blood-Brain Barrier Drug Design Molecular Medicine medicine.symptom Alzheimer's disease Reactive Oxygen Species |
| Zdroj: | Bioorganic & Medicinal Chemistry Letters. 42:127999 |
| ISSN: | 0960-894X |
| DOI: | 10.1016/j.bmcl.2021.127999 |
| Popis: | Alzheimer disease is multi-factorial and inflammation plays a major role in the disease progression and severity. Metals and reactive oxygen species (ROS) are the key mediators for inflammatory conditions associated with Alzheimer’s. Along multi-factorial nature, major challenge for developing new drug is the ability of the molecule to cross blood brain barrier (BBB). We have designed and synthesized multi-target directed hexafluorocarbinol containing triazoles to inhibit Amyloid β aggregation and simultaneously chelate the excess metals present in the extracellular space and scavenge the ROS thus reduce the inflammatory condition. From the screened compound library, compound 1c found to be potent and safe. It has demonstrated inhibition of Amyloid β aggregation (IC50 of 4.6 μM) through selective binding with Amyloid β at the nucleation site (evidenced from the molecular docking). It also chelate metals (Cu+2, Zn+2 and Fe+3) and scavenges ROS significantly. Due to the presence of hexafluorocarbinol moiety in the molecule it may assist to permeate BBB and improve the pharmacokinetic properties. The in-vitro results of compound 1c indicate the promiscuity for the development of hexafluorocarbinol containing triazoles amide scaffold as multi-target directed therapy against Alzheimer disease. |
| Databáze: | OpenAIRE |
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