New Approach in Development of Acetylcholinesterase Inhibitors for the Treatment of Alzheimer’s Disease

Acetylcholinesterase inhibitors (AChEIs) portray the main group ofdrugs currently used for the treatment of Alzheimer’s disease (AD).In this article we present new approaches for the development ofAChEIs including the design and synthesis of dual binding siteinhibitors and multi-target-directed ligands (MTDLs). Dual binding siteinhibitors can be designed as donepezil derivatives or as homo- orheterodimeric CAS ligands. MTDLs reveal AChEI moleculeinteracting with other targets relevant for the pathophysiology of ADor other symptoms commonly found in the AD patients. MTDLs canbe designed by linking AChEI molecules with pharmacophoricgroups of other active drug and by creating a hybrid molecule.These strategies lead to the development of new AChEIs withincreased potency, therapeutic efficacy for the treatment ofsymptoms and attenuating the pathogenesis of AD.Keywords: acetylcholinesterase inhibitor, Alzheimer’s disease, dualbinding site inhibitor, multi target-directed ligand

In Vitro antimicrobial, antiglycolytic, and antibiofilm activities of synthetic 1,4-naphthoquinone derivatives against cariogenic bacteria

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. mutans and 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

Acetylcholinesterase Inhibitory Activity of Standardized Cannabinoids-rich Fractions

Background: Since cannabis has been legally allowed for medicinal purposes in many countries, it has become the most interesting issue, particularly in neurologic disorders, such as Alzheimer’s disease (AD). Inhibition of acetylcholinesterase (AChE) is one of the mechanisms for the treatment of AD. Objectives: The present study aimed to establish a method for the preparation of cannabinoid-rich extracts and determine their AChE inhibitory activity. Methods: The cannabinoid-rich extracts were prepared through a green extraction process using microwave-assisted extraction (MAE) followed by hydrophobic column separation. The contents of cannabidiol (CBD) and Δ-9-tetrahydrocannabinol (THC) were determined using high-performance liquid chromatography (HPLC). In vitro AChE inhibitory activity was determined via the photometric method using AChE from Electrophorus electricus. Results: Three cannabinoids-rich fractions were obtained with different concentrations of CBD and THC, namely Fractions I (CBD of 8.1% w/w; THC of 52.2% w/w), II (CBD of 9.2% w/w; THC of 8.0% w/w), and III (CBD 1.3% w/w, THC 33.5% w/w). These cannabinoid-rich extracts exhibited AChE inhibitory activity, with IC50 values of 52.3, 59.8, and 71.2 µg/mL, respectively.  Conclusion: This finding suggests that CBD, but not THC, might be an active compound contributing to AChE inhibitory effect

In vitro efficacy of synthetic lawsone derivative disinfectant solution on removing dual-species biofilms and effect on acrylic denture surface properties

Abstract Candida albicans (C. albicans) and Streptococcus mutans (S. mutans) biofilms involve in denture stomatitis. This study compared compound 1 to 2% chlorhexidine gluconate (CHX), Polident, and distilled water (DW) in biofilms reduction and effect on polymethylmethacrylate acrylic (PMMA) properties. The structure of lawsone (naphthoquinone derivative) was modified by the addition of an alkylnyloxy group to yield compound 1. Dual-species biofilms of C. albicans and S. mutans were developed on PMMA discs. The colony-forming unit count measured the number of residual biofilm cells after exposure to the test agents. PMMA discs were examined for color stability, surface roughness, hardness, and chemical structure after 28 days. At 3 min, compound 1 was less effective than CHX in reducing C. albicans (p = 0.004) and S. mutans (p = 0.034) but more effective than Polident in reducing C. albicans (p = 0.001). At 15 min, no viable cells were detectable for compound 1 and its effectiveness was comparable to CHX (p = 0.365). SEM showed fungal cell surface damages in CHX, compound 1 and Polident groups. Only color change was affected by time (p < 0.001) and type of test agent (p = 0.008), and only CHX reached a clinical perception level. Compound 1 is a promising agent for removing biofilm from the PMMA surface without substantially degrading surface properties

Synthesis and evaluation of coumarin derivatives on antioxidative, tyrosinase inhibitory activities, melanogenesis, and in silico investigations

Abstract New coumarin derivatives were designed using a 2-(2-oxo-2H-chromen-4-yl)acetic acid scaffold conjugated with amino acid esters or tyramine. The anti-tyrosinase and anti-lipid peroxidation activities of the synthesized compounds were investigated. Coumarin derivatives 7,9, 11–13, 15–18 showed strong anti-lipid peroxidation activity. Compound 13 exhibited uncompetitive tyrosinase inhibitory activity with an IC50 value of 68.86 µM. Compound 14 (% activity = 123.41) showed stronger tyrosinase activating activity than 8-methoxypsolaren (8-MOP, % activity = 109.46). In silico studies revealed different poses between the inhibitors and activators near the tyrosinase catalytic site. Compounds 13 (25–50 μM) and 14 (25–100 μM) did not show cytotoxicity against B16F10 cells. In contrast to the tyrosinase inhibition assay, compound 13 (50 μM) suppressed melanogenesis in B16F10 cells with two times higher potency than KA (100 μM). Compound 14 at 100 μM showed melanogenesis enhancement in B16F10 cells in a dose-dependent manner, however, inferior to the 8-MOP. Based on the findings, compound 13 and 14 offer potential for development as skin-lightening agents and vitiligo therapy agents, respectively

Synthesis of 2‐(2‐oxo‐2 H ‐chromen‐4‐yl)acetamides as potent acetylcholinesterase inhibitors and molecular insights into binding interactions

Sixteen novel coumarin-based compounds are reported as potent acetylcholinesterase (AChE) inhibitors. The most active compound in this series, 5a (IC50 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-(2-oxo-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. © 2019 Deutsche Pharmazeutische Gesellschaf