title: Development of cyanopyridine-triazine hybrids as lead multitarget anti-Alzheimer agents.
abstract: A series of new cyanopyridine-triazine hybrids were designed, synthesized and screened as multitargeted anti-Alzheimer's agents. These molecules were designed while using computational techniques and were synthesized via a feasible concurrent synthetic route. Inhibition potencies of synthetic compounds 4a-4h against cholinesterases, Aβ1-42 disaggregation, oxidative stress, cytotoxicity, and neuroprotection against Aβ1-42-induced toxicity of the synthesized compounds were evaluated. Compounds 4d and 4h showed promising inhibitory activity on acetylcholinesterase (AChE) with IC50 values 0.059 and 0.080μM, respectively, along with good inhibition selectivity against AChE over butyrylcholinesterase (BuChE). Molecular modelling studies revealed that these compounds interacted simultaneously with the catalytic active site (CAS) and the peripheral anionic site (PAS) of AChE. The mixed type inhibition of compound 4d further confirmed their dual binding nature in kinetic studies. Furthermore, the results from neuroprotection studies of most potent compounds 4d and 4h indicate that these derivatives can reduce neuronal death induced by H2O2-mediated oxidative stress and Aβ1-42 induced cytotoxicity. In addition, in silico analysis of absorption, distribution, metabolism and excretion (ADME) profile of best compounds 4d and 4h revealed that they have drug like properties. Overall, these cyanopyridine-triazine hybrids can be considered as a candidate with potential impact for further pharmacological development in Alzheimer's therapy.
authors.affiliation: Department of Chemistry, Jamia Millia Islamia (Central University), Jamia Nagar, New Delhi 110025, India.
authors.forename: Mudasir
authors.initials: M
authors.lastname: Maqbool
authors.affiliation: Dr. B. R. Ambedkar Centre for Biomedical Research, University of Delhi, New Delhi 110007, India.
authors.forename: Apra
authors.initials: A
authors.lastname: Manral
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), Jamia Nagar, 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: Vikas
authors.initials: V
authors.lastname: Saini
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), Jamia Nagar, 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 / Q000378:metabolism; D000544:Alzheimer Disease / Q000188:drug therapy* / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000975:Antioxidants / Q000737:chemistry / Q000494:pharmacology*; D002091:Butyrylcholinesterase / Q000378:metabolism; D002460:Cell Line; D002800:Cholinesterase Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D015195:Drug Design; D006801:Humans; D062105:Molecular Docking Simulation; D058990:Molecular Targeted Therapy; D018696:Neuroprotective Agents / Q000737:chemistry / Q000494:pharmacology*; D018384:Oxidative Stress / Q000187:drug effects; D010446:Peptide Fragments / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011725:Pyridines / Q000737:chemistry / Q000494:pharmacology*; D014227:Triazines / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D016229:Amyloid beta-Peptides; D000975:Antioxidants; D002800:Cholinesterase Inhibitors; D018696:Neuroprotective Agents; D010446:Peptide Fragments; D011725:Pyridines; D014227:Triazines; C075222:amyloid beta-protein (1-42); D000110:Acetylcholinesterase; D002091:Butyrylcholinesterase
keywords: Acetylcholinesterase; Alzheimer’s disease; Aβ(1–42) disaggregation; Butyrylcholinesterase; Molecular docking; Triazine