Design Synthesis and Pharmacological Evaluation of Novel Acridine Derivatives as Multi Target Mao and Cholinesterase Inhibitor

Abstract

Although few single target drugs are approved by FDA for Alzheimers disease, clinical treatments available have only palliative effects. Past few years saw the development of many MTDL s for AD but still a therapeutic agent for AD is unaccomplished. In the present scenario, due to the complexity of the Alzheimers disease and non-availability of a better drug for the treatment of the AD it is important to design a new drug which is a multi-target directed ligand. Present research focussed at developing a multitarget directed ligand for Alzheimer s disease which will be an Acetylcholinesterase, Butyrylcholinesterase and Mono Amine Oxidase B inhibitor. Following MTDL approach we designed more than 300 molecules and did the preliminary insilico studies. Many compounds were omitted due to its toxicity and less acceptable ADME properties. Finally we selected 40 compounds with acceptable physicochemical parameters, BBB penetration and toxicity parameters for docking studies on AChE, BuChE and MAO enzymes. From the 40 compounds the compounds with best dock score, binding interactions and feasibility of synthesis are selected for synthesis. In conclusion the present research study reports the successful synthesis of twenty novel flavone substituted tacrine and acridine derivatives as multitarget cholinesterase and monoamine oxidase inhibitor with antioxidant properties and hepatoprotective activity. Invitro AChE, BuChE, MAO B inhibitory activity and DPPH radical scavenging activity were determined for all the 20 synthesized compounds. Five compounds which showed best activity in invitro enzyme inhibition studies are selected for cell line studies. Invitro neuro toxicity studies and hepatotoxicity studies conducted on SHSY5Y cell line and HepG2 cell line. Most active compounds with less toxicity in invitro studies were chosen for Invivo toxicity studies in Zebra Fish. Finally invivo acute and subacute toxicity studies conducted and antialzheimer s activity studies done in wistar rats. newline