Sixteen novel coumarin-based compounds are reported as potent acetylcholinesterase (AChE) inhibitors. The most active compound in this series, 5a (IC 50 0.04 ± 0.01 µM), noncompetitively inhibited AChE with a higher potency than tacrine and galantamine.Compounds 5d, 5j, and 5 m showed a moderate antilipid peroxidation activity. The compounds showed cytotoxicity in the same range as the standard drugs in HEK-293 cells. Molecular docking demonstrated that 5a acted as a dual binding site inhibitor. The coumarin moiety occupied the peripheral anionic site and showed π-π interaction with Trp278. The tertiary amino group displayed significant cation-π interaction with Phe329.The aromatic group showed π-π interaction with Trp83 at the catalytic anionic site. The long chain of methylene lay along the gorge interacting with Phe330 via hydrophobic interaction. Molecular docking was applied to postulate the selectivity toward AChE of 5a in comparison with donepezil and tacrine. Structural insights into the selectivity of the coumarin derivatives toward huAChE were explored by molecular docking and 3D QSAR and molecular dynamics simulation for 20 ns. ADMET analysis suggested that the 2-(2oxo-2H-chromen-4-yl)acetamides showed a good pharmacokinetic profile and no hepatotoxicity. These coumarin derivatives showed high potential for further development as anti-Alzheimer agents. K E Y W O R D S 3D QSAR, acetylcholinesterase inhibitor, coumarin, lipid peroxidation, molecular docking 1 | INTRODUCTION Alzheimerʼs disease (AD) is the most common form of dementia. The symptoms start with difficulty in remembering new information and recent events, followed by apathy, depression, subsequent impaired judgment, confusion, and behavior change. Etiology of AD is complicated and still unclear. β-Amyloid aggregation and neurofibrillary tangles are major abnormalities found in the brain of patients with AD, which eventually lead to neuronal damage. This results in the decrease of acetylcholine (ACh), the neurotransmitter responsible for memory and learning. Acetylcholinesterase inhibitors (AChEIs), such as tacrine, donepezil, galantamine, and rivastigmine, Additional supporting information may be found online in the Supporting Information section at the end of the article. How to cite this article: Kara J, Suwanhom P, Wattanapiromsakul C, et al. Synthesis of 2-(2-oxo-2Hchromen-4-yl)acetamides as potent acetylcholinesterase inhibitors and molecular insights into binding interactions.

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This study investigated the potential anticaries properties of synthetic 1,4-naphthoquinone derivatives. Synthetic 1,4-naphthoquinone derivatives (2-4) were designed and synthesized by employing lawsone methyl ether (LME, 1), a plant-derived 1,4-naphthoquinone, as a lead compound. The synthetic compounds were characterized by infrared spectroscopy, 1H-nuclear magnetic spectroscopy, 13C- nuclear magnetic spectroscopy, and high-resolution mass spectrometry. Minimum inhibitory concentration (MIC), minimum bactericidal concentration (MBC), and growth curves were determined to assess their antibacterial effects against Streptococcus mutans, Lacticaseibacillus casei, and Actinomyces naeslundii. The pH drop assay was also performed on these three bacterial species. The effect on S. mutans biofilm formation was evaluated by crystal violet assay. From the microdilution assay, 2-(prop-2-ynyloxy) naphthalene-1,4-dione (compound 2) showed potent antimicrobial activity against S. mutansand A. naeslundii(MIC of 1.56 and 3.125 µg/mL, respectively) in the same range as chlorhexidine (MIC of 1.95 and 1.95 µg/mL, respectively). The 1,4-naphthoquinone derivatives showed low antibacterial activity against L. casei. LME (compound 1) and 2-(prop-2-ynyloxy) naphthalene-1,4-dione (compound 2) inhibited pH reduction from S. mutans. The compounds at sub-MIC concentrations showed a potent inhibitory effect against S. mutans biofilm formation in a dose- and time-dependent manner. These results suggested that the synthetic 1,4-naphthoquinone derivatives are promising compounds that could be developed as a novel alternative or adjunctive anticaries therapies.

Objective: Presently, one of the most common oral diseases is dental caries, which is a biofilm-mediated disease. Lawsone methyl ether (LME) has shown promising antibacterial activity due to its 1,4-napthoquinone structure. Recently, a 1,2,3-triazole scaffold has been used in the structural modification of potential antimicrobial agents. To develop novel anticaries agents, the structure modification of 1,4-napthoquinone with N-substituted 1,2,3-triazole, therefore, may be a candidate. Material and Methods: LME was used as a lead compound, and three new lawsone derivatives were prepared by two-step reactions. Their antimicrobial effects against three dental caries pathogens; including S. mutans, L. casei, and A. naeslundii were investigated, using the microdilution technique (0.78-100 μg/mL). A growth curve assay was performed to assess the effects of compounds on the growth kinetics of bacteria. Moreover, the effect of synthetic lawsone derivatives on the biofilm formation of S. mutans was also evaluated by crystal violet assay. Results: Overall, S. mutans was most sensitive to lawsone derivatives (minimum inhibitory concentration (MIC)=1.56- 50 μg/mL), followed by A. naeslundii and L. casei: corresponding to their growth curves. Lawsone derivatives, at the concentration of 1/2 MIC and 1/4 MIC, inhibited 12-hour S. mutans biofilm formation by 86.0-98.0%. The inhibitory effect decreased with decreasing concentrations and increasing incubation times. Conclusion: Synthetic lawsone derivatives have an inhibitory effect on the growth of three tested cariogenic bacteria, and the biofilm formation of S. mutans. The compounds exhibited anti-cariogenic bacterial strains and satisfying antibiofilm formation effects on S. mutans.