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Development of cyanopyridine-triazine hybrids as lead multitarget anti-Alzheimer agents.
Bioorg Med Chem. 2016 06 15; 24(12):2777-88.BM

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+Show Affiliations

Department of Chemistry, Jamia Millia Islamia (Central University), Jamia Nagar, New Delhi 110025, India.Dr. B. R. Ambedkar Centre for Biomedical Research, University of Delhi, New Delhi 110007, India.Department of Chemistry, B. R. Ambedkar Bihar University, Muzaffarpur 842001, Bihar, India.Department of Chemistry, Jamia Millia Islamia (Central University), Jamia Nagar, New Delhi 110025, India.Dr. B. R. Ambedkar Centre for Biomedical Research, University of Delhi, New Delhi 110007, India.Department of Chemistry, Indian Institute of Technology Delhi, Hauz Khas, New Delhi 110016, India.Dr. B. R. Ambedkar Centre for Biomedical Research, University of Delhi, New Delhi 110007, India. Electronic address: mtiwari07@gmail.com.Department of Chemistry, Jamia Millia Islamia (Central University), Jamia Nagar, New Delhi 110025, India. Electronic address: nhoda@jmi.ac.in.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.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

27157006

Citation

Maqbool, Mudasir, et al. "Development of Cyanopyridine-triazine Hybrids as Lead Multitarget anti-Alzheimer Agents." Bioorganic & Medicinal Chemistry, vol. 24, no. 12, 2016, pp. 2777-88.
Maqbool M, Manral A, Jameel E, et al. Development of cyanopyridine-triazine hybrids as lead multitarget anti-Alzheimer agents. Bioorg Med Chem. 2016;24(12):2777-88.
Maqbool, M., Manral, A., Jameel, E., Kumar, J., Saini, V., Shandilya, A., Tiwari, M., Hoda, N., & Jayaram, B. (2016). Development of cyanopyridine-triazine hybrids as lead multitarget anti-Alzheimer agents. Bioorganic & Medicinal Chemistry, 24(12), 2777-88. https://doi.org/10.1016/j.bmc.2016.04.041
Maqbool M, et al. Development of Cyanopyridine-triazine Hybrids as Lead Multitarget anti-Alzheimer Agents. Bioorg Med Chem. 2016 06 15;24(12):2777-88. PubMed PMID: 27157006.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Development of cyanopyridine-triazine hybrids as lead multitarget anti-Alzheimer agents. AU - Maqbool,Mudasir, AU - Manral,Apra, AU - Jameel,Ehtesham, AU - Kumar,Jitendra, AU - Saini,Vikas, AU - Shandilya,Ashutosh, AU - Tiwari,Manisha, AU - Hoda,Nasimul, AU - Jayaram,B, Y1 - 2016/04/22/ PY - 2016/03/06/received PY - 2016/04/20/revised PY - 2016/04/21/accepted PY - 2016/5/10/entrez PY - 2016/5/10/pubmed PY - 2017/7/14/medline KW - Acetylcholinesterase KW - Alzheimer’s disease KW - Aβ(1–42) disaggregation KW - Butyrylcholinesterase KW - Molecular docking KW - Triazine SP - 2777 EP - 88 JF - Bioorganic & medicinal chemistry JO - Bioorg Med Chem VL - 24 IS - 12 N2 - 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. SN - 1464-3391 UR - https://www.unboundmedicine.com/medline/citation/27157006/Development_of_cyanopyridine_triazine_hybrids_as_lead_multitarget_anti_Alzheimer_agents_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0968-0896(16)30284-X DB - PRIME DP - Unbound Medicine ER -