title: Synthesis and screening of triazolopyrimidine scaffold as multi-functional agents for Alzheimer's disease therapies.
abstract: In present study a series of triazolopyrimidine-quinoline and cyanopyridine-quinoline hybrids were designed, synthesized and evaluated as acetylcholinesterase inhibitors (AChEIs). Molecular docking and scoring was utilized for the design of inhibitors. The molecules were synthesized via an easily accessible, convergent synthetic route. Three triazolopyrimidine based compounds showed nanomolar activity towards acetylcholinesterase. Among them, Ethyl 6-fluoro-4-(4-(5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl)piperazin-1-yl)quinoline-3-carboxylate (10d), strongly inhibited AChE with IC50 value of 42 nM. Furthermore compound 10d was identified as most promising compound with 12 fold selectivity against butyrylcholinesterase (BuChE). This compound displayed a composed multitargeted profile with promising inhibition of self-induced and AChE - induced Aβ aggregation and antioxidant activity.
authors.affiliation: Department of Chemistry, Jamia Millia Islamia (Central University), New Delhi 110025, India.
authors.forename: Jitendra
authors.initials: J
authors.lastname: Kumar
authors.affiliation: Dr. B. R. Ambedkar Centre for Biomedical Research, University of Delhi, New Delhi 110007, India.
authors.forename: Poonam
authors.initials: P
authors.lastname: Meena
authors.affiliation: Department of Chemistry, Jamia Millia Islamia (Central University), New Delhi 110025, India.
authors.forename: Anju
authors.initials: A
authors.lastname: Singh
authors.affiliation: Department of Chemistry, B. R. Ambedkar Bihar University, Muzaffarpur 842001, Bihar, India.
authors.forename: Ehtesham
authors.initials: E
authors.lastname: Jameel
authors.affiliation: Department of Chemistry, Jamia Millia Islamia (Central University), New Delhi 110025, India.
authors.forename: Mudasir
authors.initials: M
authors.lastname: Maqbool
authors.affiliation: Department of Chemistry, Jamia Millia Islamia (Central University), New Delhi 110025, India.
authors.forename: Mohammad
authors.initials: M
authors.lastname: Mobashir
authors.affiliation: Department of Chemistry, Indian Institute of Technology Delhi, Hauz Khas, New Delhi 110016, India.
authors.forename: Ashutosh
authors.initials: A
authors.lastname: Shandilya
authors.affiliation: Dr. B. R. Ambedkar Centre for Biomedical Research, University of Delhi, New Delhi 110007, India. Electronic address: mtiwari07@gmail.com.
authors.forename: Manisha
authors.initials: M
authors.lastname: Tiwari
authors.affiliation: Department of Chemistry, Jamia Millia Islamia (Central University), New Delhi 110025, India. Electronic address: nhoda@jmi.ac.in.
authors.forename: Nasimul
authors.initials: N
authors.lastname: Hoda
authors.affiliation: Department of Chemistry, Indian Institute of Technology Delhi, Hauz Khas, New Delhi 110016, India; Kusuma School of Biological Sciences, IIT Delhi, New Delhi 110016, India; Supercomputing Facility for Bioinformatics & Computational Biology, IIT Delhi, New Delhi 110016, India.
authors.forename: B
authors.initials: B
authors.lastname: Jayaram
mesh_terms: D000110:Acetylcholinesterase / Q000737:chemistry / Q000378:metabolism; D000544:Alzheimer Disease / Q000188:drug therapy*; D016229:Amyloid beta-Peptides / Q000737:chemistry; D000818:Animals; D000975:Antioxidants / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use; D002091:Butyrylcholinesterase / Q000737:chemistry / Q000378:metabolism; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D060326:Chemistry Techniques, Synthetic; D002800:Cholinesterase Inhibitors / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use; D004353:Drug Evaluation, Preclinical; D006801:Humans; D007700:Kinetics; D062105:Molecular Docking Simulation; D010446:Peptide Fragments / Q000737:chemistry; D066329:Protein Aggregates / Q000187:drug effects; D011487:Protein Conformation; D011743:Pyrimidines / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use
chemical_list: D016229:Amyloid beta-Peptides; D000975:Antioxidants; D002800:Cholinesterase Inhibitors; D010446:Peptide Fragments; D066329:Protein Aggregates; D011743:Pyrimidines; C075222:amyloid beta-protein (1-42); D000110:Acetylcholinesterase; D002091:Butyrylcholinesterase
keywords: Acetylcholinesterase; Alzheimer's disease; Butyrylcholinesterase; Molecular docking; Quinoline; Triazolopyrimidine