Development of cyanopyridine–triazine hybrids as lead multitarget anti-Alzheimer agents Mudasir Maqbool a , Apra Manral b , Ehtesham Jameel c , Jitendra Kumar a , Vikas Saini b , Ashutosh Shandilya d , Manisha Tiwari b,⇑ , Nasimul Hoda a,⇑ , B. Jayaram d,e,f a Department of Chemistry, Jamia Millia Islamia (Central University), Jamia Nagar, New Delhi 110025, India b Dr. B. R. Ambedkar Centre for Biomedical Research, University of Delhi, New Delhi 110007, India c Department of Chemistry, B. R. Ambedkar Bihar University, Muzaffarpur 842001, Bihar, India d Department of Chemistry, Indian Institute of Technology Delhi, Hauz Khas, New Delhi 110016, India e Kusuma School of Biological Sciences, IIT Delhi, New Delhi 110016, India f Supercomputing Facility for Bioinformatics & Computational Biology, IIT Delhi, New Delhi 110016, India article info Article history: Received 6 March 2016 Revised 20 April 2016 Accepted 21 April 2016 Available online xxxx Keywords: Alzheimer’s disease Acetylcholinesterase Triazine Molecular docking Butyrylcholinesterase Ab 1–42 disaggregation abstract A series of new cyanopyridine–triazine hybrids were designed, synthesized and screened as multitar- geted 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 com- pounds 4a–4h against cholinesterases, Ab 1–42 disaggregation, oxidative stress, cytotoxicity, and neuro- protection against Ab 1–42 -induced toxicity of the synthesized compounds were evaluated. Compounds 4d and 4h showed promising inhibitory activity on acetylcholinesterase (AChE) with IC 50 values 0.059 and 0.080 lM, respectively, along with good inhibition selectivity against AChE over butyryl- cholinesterase (BuChE). Molecular modelling studies revealed that these compounds interacted simulta- neously 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 deriva- tives can reduce neuronal death induced by H 2 O 2 -mediated oxidative stress and Ab 1–42 induced cytotox- icity. 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–tri- azine hybrids can be considered as a candidate with potential impact for further pharmacological devel- opment in Alzheimer’s therapy. Ó 2016 Elsevier Ltd. All rights reserved. 1. Introduction Alzheimer’s disease (AD) is an age-related neurodegenerative disorder, characterized by progressive cognitive impairment, dementia and neuropsychiatric symptoms. 1,2 It starts with minus- cule changes of hippocampal synaptic adequacy, simultaneous neuronal degeneration, and ultimately death of the patient. It is a chronic disorder that cannot be prevented, cured or slowed hence is the third leading cause of death after cardiovascular diseases and cancer worldwide. The complete etiology of the disease is still not clear. However, the synaptic dysfunction is believed to be caused due to extracel- lular amyloid-b (Ab) aggregation, 3 produced by the proteolytic cleavage of a transmembrane protein amyloid precursor protein (APP) by the b- and c-secretases. Intracellular tangle formation due to hyperphosphorylation of microtubule associated protein tau 4 which in turn is governed by the overexpression of glycogen synthase kinase beta (GSK-3b), 5 also accounts for the synaptic dys- function. These two protein misfoldings are considered to be the main hallmarks of this ailment. Another popular physiological tar- get in AD is cholinergic pathway that tides symptoms of dementia and learning difficulties to the significant decrease of acetylcholine http://dx.doi.org/10.1016/j.bmc.2016.04.041 0968-0896/Ó 2016 Elsevier Ltd. All rights reserved. Abbreviations: ACh, acetylcholine; AChE, acetylcholinesterase; eelAChE, electric eel acetylcholinesterase; BuCh, butyrylcholine; BuChE, butyrylcholinesterase; eqBuChE, equine serum butyrylcholinesterase; ChE, cholinesterase; AD, Alzheimer’s disease; Ab, amyloid beta; AChEI, acetylcholinesterase inhibitor; BChEI, butyryl- cholinesterase inhibitor; PAS, peripheral anionic site; CAS, catalytic active site; TcAChE, Torpedo Californica acetylcholinesterase; ROS, reactive oxygen species; SAR, structure activity relationship; SEM, scanning electron microscope; TEM, transmission electron microscopy; ThT assay, thioflavin T assay; equiv, equivalent. ⇑ Corresponding authors. E-mail addresses: mtiwari07@gmail.com (M. Tiwari), nhoda@jmi.ac.in (N. Hoda). Bioorganic & Medicinal Chemistry xxx (2016) xxx–xxx Contents lists available at ScienceDirect Bioorganic & Medicinal Chemistry journal homepage: www.elsevier.com/locate/bmc Please cite this article in press as: Maqbool, M.; et al. Bioorg. Med. Chem. (2016), http://dx.doi.org/10.1016/j.bmc.2016.04.041