Cholinesterase Inhibitory and Anti-Inflammatory Activity of the Naphtho- and Thienobenzo-Triazole Photoproducts: Experimental and Computational Study

Mlakić, Milena; Faraho, Ivan; Odak, Ilijana; Kovačević, Borislav; Raspudić, Anamarija; Šagud, Ivana; Bosnar, Martina; Škorić, Irena; Barić, Danijela

doi:10.3390/ijms241914676

Cited by 2 publications

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References 32 publications

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“…BChE serves as a co-regulator of cholinergic neurotransmission and is able to catalyze the hydrolysis of acetylcholine, and high levels of BChE are associated with the neuropathological hallmarks of AD [26]. Several compounds from previous studies emerged as being particularly promising [27,28], and some displayed selectivity toward BChE. Based on these results, and taking into account the potential of 1,2,3-triazolium salts, a new series of naphthotriazoles (Figure 1, structure C) was synthesized in this work to examine the influence of the halogen as a substituent on the inhibitory potential towards cholinesterases.…”

Section: Introductionmentioning

confidence: 99%

New Charged Cholinesterase Inhibitors: Design, Synthesis, and Characterization

Mlakić,

Barić,

Ratković

et al. 2024

Molecules

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Triazoles and triazolium salts are very common subunits in the structures of various drugs. Medicaments with a characteristic 1,2,3-triazole core are also being developed to treat neurodegenerative disorders associated with cholinesterase enzyme activity. Several naphtho- and thienobenzo-triazoles from our previous research emerged as being particularly promising in that sense. For this reason, in this research, new naphtho- and thienobenzo-triazoles 23–34, as well as 1,2,3-triazolium salts 44–51, were synthesized and tested. Triazolium salts 44–46 showed excellent activity while salts 47 and 49 showed very good inhibition toward both butyrylcholinesterase (BChE) and acetylcholinesterase (AChE) enzymes. In contrast, neutral photoproducts were shown to be selective towards BChE but with very good inhibition potential as molecules 24–27. The representative of newly prepared compounds, 45 and 50, were stable in aqueous solution and revealed intriguing fluorimetric properties, characterized by a strong Stokes shift of >160 nm. Despite their condensed polycyclic structure shaped similarly to well-known DNA-intercalator ethidium bromide, the studied compounds did not show any interaction with ds-DNA, likely due to the unfavorable steric hindrance of substituents. However, the studied dyes bind proteins, particularly showing very diverse inhibition properties toward AChE and BChE. In contrast, neutral photoproducts were shown to be selective towards a certain enzyme but with moderate inhibition potential. The molecular docking of the best-performing candidates to cholinesterases’ active sites identified cation–π interactions as the most responsible for the stability of the enzyme–ligand complexes. As genotoxicity studies are crucial when developing new active substances and finished drug forms, in silico studies for all the compounds synthesized have been performed.

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Section: Introductionmentioning

confidence: 99%

New Charged Cholinesterase Inhibitors: Design, Synthesis, and Characterization

Mlakić,

Barić,

Ratković

et al. 2024

Molecules

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Cholinesterase Inhibition and Antioxidative Capacity of New Heteroaromatic Resveratrol Analogs: Synthesis and Physico—Chemical Properties

Mlakić,

Talić,

Odak

et al. 2024

IJMS

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The targeted compounds in this research, resveratrol analogs 1–14, were synthesized as mixtures of isomers by the Wittig reaction using heterocyclic triphenylphosphonium salts and various benzaldehydes. The planned compounds were those possessing the trans-configuration as the biologically active trans-resveratrol. The pure isomers were obtained by repeated column chromatography in various isolated yields depending on the heteroaromatic ring. It was found that butyrylcholinesterase (BChE) was more sensitive to the heteroaromatic resveratrol analogs than acetylcholinesterase (AChE), except for 6, the methylated thiophene derivative with chlorine, which showed equal inhibition toward both enzymes. Compounds 5 and 8 achieved the highest BChE inhibition with IC50 values of 22.9 and 24.8 μM, respectively. The same as with AChE and BChE, methylated thiophene subunits of resveratrol analogs showed better enzyme inhibition than unmethylated ones. Two antioxidant spectrophotometric methods, DPPH and CUPRAC, were applied to determine the antioxidant potential of new heteroaromatic resveratrol analogs. The molecular docking of these compounds was conducted to visualize the ligand-active site complexes’ structure and identify the non-covalent interactions responsible for the complex’s stability, which influence the inhibitory potential. As ADME properties are crucial in developing drug product formulations, they have also been addressed in this work. The potential genotoxicity is evaluated by in silico studies for all compounds synthesized.

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Cholinesterase Inhibitory and Anti-Inflammatory Activity of the Naphtho- and Thienobenzo-Triazole Photoproducts: Experimental and Computational Study

Cited by 2 publications

References 32 publications

New Charged Cholinesterase Inhibitors: Design, Synthesis, and Characterization

New Charged Cholinesterase Inhibitors: Design, Synthesis, and Characterization

Cholinesterase Inhibition and Antioxidative Capacity of New Heteroaromatic Resveratrol Analogs: Synthesis and Physico—Chemical Properties

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