Arch Pharm Chem Life Sci. 2019;e1900177. wileyonlinelibrary.com/journal/ardp © 2019 Deutsche Pharmazeutische Gesellschaft | 1 of 13 https://doi.org/10.1002/ardp.201900177 Received: 20 June 2019 | Revised: 26 July 2019 | Accepted: 1 August 2019 DOI: 10.1002/ardp.201900177 REVIEW ARTICLE Emerging therapeutic potentials of dual‐acting MAO and AChE inhibitors in Alzheimer’s and Parkinson’s diseases Bijo Mathew 1 | Della G. T. Parambi 2 | Githa E. Mathew 3 | Md. Sahab Uddin 4,5 | Sini T. Inasu 1 | Hoon Kim 6 | Akash Marathakam 7 | Mazhuvancherry Kesavan Unnikrishnan 7 | Simone Carradori 8 1 Department of Pharmaceutical Chemistry Research Lab, Division of Drug Design and Medicinal Chemistry, Ahalia School of Pharmacy, Palakkad, India 2 Department of Pharmaceutical Chemistry, Jouf University, Sakaka, Saudi Arabia 3 Department of Pharmacology, Grace College of Pharmacy, Palakkad, India 4 Department of Pharmacy, Southeast University, Dhaka, Bangladesh 5 Pharmakon Neuroscience Research Network, Dhaka, Bangladesh 6 Department of Pharmacy and Research, Institute of Life Pharmaceutical Sciences, Sunchon National University, Suncheon, Republic of Korea 7 Department of Pharmaceutical Chemistry, National College of Pharmacy, Calicut, India 8 Department of Pharmacy, “G. d’Annunzio” University of Chieti‐Pescara, Chieti, Italy Correspondence Bijo Mathew, Division of Drug Design and Medicinal Chemistry Research Lab, Department of Pharmaceutical Chemistry, Ahalia School of Pharmacy, Palakkad, Kerala 678557, India. Email: bijovilaventgu@gmail.com and bijo.mathew@ahalia.ac.in Hoon Kim, Department of Pharmacy and Research Institute of Life Pharmaceutical Sciences, Sunchon National University, Suncheon 57922, Republic of Korea. Email: hoon@sunchon.ac.kr Abstract No drug has been approved to prevent neuronal cell loss in patients suffering from Parkinson’s disease (PD) or Alzheimer’s disease (AD); despite increased comprehen- sion of the underlying molecular causes, therapies target cognitive functional improvement and motor fluctuation control. Drug design strategies that adopt the “one protein, one target” philosophy fail to address the multifactorial aetiologies of neurodegenerative disorders such as AD and PD optimally. On the contrary, restoring neurotransmitter levels by combined combinatorial inhibition of cholinesterases, monoamine oxidases, and adenosine A 2A A receptors, in conjunction with strategies to counter oxidative stress and beta‐amyloid plaque accumulation, would constitute a therapeutically robust, multitarget approach. This extensive review delineates the therapeutic advantages of combining dual‐acting molecules that inhibit monoamine oxidases and cholinesterases and/or adenosine A 2A A receptors, and describes the structure–activity relationships of compound classes that include, but are not limited to, alkaloids, coumarins, chalcones, donepezil–propargylamine conjugates, homoiso- flavonoids, resveratrol analogs, hydrazones, and pyrazolines. In the wake of recent advances in network biology, in silico approaches, and omics, this review emphasizes the need to consider conceptually informed research strategies for drug discovery, in the context of the mounting burden posed by chronic neurodegenerative diseases with complex aetiologies and pathophysiologies involving multiple signalling path- ways and numerous drug targets. KEYWORDS acetylcholinesterase, adenosine antagonist, monoamine oxidase, multitarget 1 | INTRODUCTION Multitarget direct ligand (MTDL) design strategies constitute a new paradigm in neurochemistry for the development of dual‐acting molecules against multiple targets in the neurodegenerative cascade. [1] Conventional drug design approaches that embrace the “one protein, one target” philosophy fail to provide meaningful ways of treating the multifactorial aetiologies of neurodegenerative disorders. [2] The affinity of a single drug for a single target protein is vulnerable to the development of resistance because active target sites are prone to