ORIGINAL RESEARCH 4-Oxobenzo[d]1,2,3-triazin-pyridinium-phenylacetamide derivatives as new anti-Alzheimer agents: design, synthesis, in vitro evaluation, molecular modeling, and molecular dynamic study Fahimeh Hosseini 1 & Maryam Mohammadi-Khanaposhtani 2 & Homa Azizian 3 & Ali Ramazani 1 & Maliheh Barazandeh Tehrani 4 & Hamid Nadri 5 & Bagher Larijani 6 & Mahmoud Biglar 6 & Hossein Adibi 6 & Mohammad Mahdavi 6 Received: 6 October 2019 /Accepted: 3 December 2019 # Springer Science+Business Media, LLC, part of Springer Nature 2020 Abstract A new series of 4-oxobenzo[d]1,2,3-triazin-pyridinium-phenylacetamide hybrids 8a–p was designed, synthesized, and screened as the potential cholinesterase inhibitors against acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE). Obtained anti- cholinesterase activities demonstrated that all the title compounds exhibited excellent inhibition against BuChE and moderate inhibitory activity toward AChE in comparison to standard cholinesterase inhibitor donepezil. For example, compound 8e exhibited about 49-fold higher inhibitory activity than donepezil (IC 50 = 3.2 ± 0.3 μM) against BuChE. This compound inhibited BuChE via a mixed-type inhibition mode. This finding demonstrated that compound 8e in addition to catalytic anionic site (CAS) can also interact with the peripheral anionic site (PAS) of BuChE. Molecular modeling and molecular dynamic studies were also performed on synthesized compounds. Keywords Anti-Alzheimer . 4-Oxobenzo[d]1,2,3-triazin . Phenylacetamide . Molecular dynamic . Molecular modeling Introduction Alzheimer ’ s disease (AD) is a neurodegenerative disorder with main clinical manifestations such as progressive memory loss, language deterioration, and severe cognitive decline [1]. The most common cause of dementia in the elderly people is AD [2]. The exact pathogenic mechanism of this disease re- mains unclear but researchers suggests that factors such as decrease neurotransmitter acetylcholine (ACh) level in the hippocampal and cortical regions of the brain, the ab- normal deposition of β-amyloid peptides (Aβ), the for- mation of neurofibrillary tangles, oxidative stress, and Fahimeh Hosseini and Maryam Mohammadi-Khanaposhtani contributed equally to this work. Electronic supplementary material The online version of this article (https://doi.org/10.1007/s11224-019-01472-0) contains supplementary material, which is available to authorized users. * Ali Ramazani aliramazani@znu.ac.ir * Mohammad Mahdavi momahdavi@tums.ac.ir 1 Department of Chemistry, University of Zanjan, P.O. Box 45195-313, Zanjan, Iran 2 Cellular and Molecular Biology Research Center, Health Research Institute, Babol University of Medical Sciences, Babol, Iran 3 Department of Medicinal Chemistry, School of Pharmacy-International Campus, Iran University of Medical Sciences, Tehran, Iran 4 Department of Medicinal Chemistry, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran 5 Department of Medicinal Chemistry, Faculty of Pharmacy and Pharmaceutical Sciences Research Center, Shahid Sadoughi University of Medical Sciences, Yazd, Iran 6 Endocrinology and Metabolism Research Center, Endocrinology and Metabolism Clinical Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran Structural Chemistry https://doi.org/10.1007/s11224-019-01472-0