Development of cyanopyridine-triazine hybrids as lead multitarget anti-Alzheimer agents

作者：Maqbool Mudasir; Manral Apra; Jameel Ehtesham; Kumar Jitendra; Saini Vikas; Shandilya Ashutosh; Tiwari Manisha^*; Hoda Nasimul^*; Jayaram B

来源：Bioorganic & Medicinal Chemistry, 2016, 24(12): 2777-2788.

DOI：10.1016/j.bmc.2016.04.041

• Alzheimer's disease
• Acetylcholinesterase
• Triazine
• Molecular docking
• Butyrylcholinesterase
• A beta(1-42) disaggregation

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, A beta(1-42) disaggregation, oxidative stress, cytotoxicity, and neuroprotection against A beta(1-42)-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 0.080 mu M, 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 A beta(1-42) 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.

• 出版日期2016-6-15