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Vitamin B3-Based Biologically Active Compounds as Inhibitors of Human Cholinesterases.

ABSTRACT: We evaluated the potential of nine vitamin B3 scaffold-based derivatives as acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibitors, as a starting point for the development of novel drugs for treating disorders with cholinergic neurotransmission-linked pathology. As the results indicate, all compounds reversibly inhibited both enzymes in the micromolar range pointing to the preference of AChE over BChE for binding the tested derivatives. Molecular docking studies revealed the importance of interactions with AChE active site residues Tyr337 and Tyr124, which dictated most of the observed differences. The most potent inhibitor of both enzymes with Ki of 4 ?M for AChE and 8 ?M for BChE was the nicotinamide derivative 1-(4'-phenylphenacyl)-3-carbamoylpyridinium bromide. Such a result places it within the range of several currently studied novel cholinesterase inhibitors. Cytotoxicity profiling did not classify this compound as highly toxic, but the induced effects on cells should not be neglected in any future detailed studies and when considering this scaffold for drug development.

SUBMITTER: Zandona A

PROVIDER: S-EPMC7663184 | biostudies-literature | 2020 Oct

REPOSITORIES: biostudies-literature

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Vitamin B3-Based Biologically Active Compounds as Inhibitors of Human Cholinesterases.

Zandona Antonio A Lihtar Gabriela G Maraković Nikola N Miš Katarina K Bušić Valentina V Gašo-Sokač Dajana D Pirkmajer Sergej S Katalinić Maja M

International journal of molecular sciences 20201029 21

We evaluated the potential of nine vitamin B3 scaffold-based derivatives as acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibitors, as a starting point for the development of novel drugs for treating disorders with cholinergic neurotransmission-linked pathology. As the results indicate, all compounds reversibly inhibited both enzymes in the micromolar range pointing to the preference of AChE over BChE for binding the tested derivatives. Molecular docking studies revealed the imp ...[more]

PMID: 33138280

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Project description:Despite the progress made in immunization and drug development, so far there are no prophylactic vaccines and effective therapies for many viral infections, including infections caused by coronaviruses. In this regard, the search for new antiviral substances continues to be relevant, and the enormous potential of marine resources are a stimulus for the study of marine compounds with antiviral activity in experiments and clinical trials. The highly pathogenic human coronaviruses-severe acute respiratory syndrome-related coronavirus (SARS-CoV), Middle East respiratory syndrome coronavirus (MERS-CoV), severe acute respiratory syndrome-related coronavirus 2 (SARS-CoV-2) remain a serious threat to human health. In this review, the authors hope to bring the attention of researchers to the use of biologically active substances of marine origin as potential broad-spectrum antiviral agents targeting common cellular pathways and various stages of the life cycle of different viruses, including coronaviruses. The review has been compiled using references from major databases such as Web of Science, PubMed, Scopus, Elsevier, Springer and Google Scholar (up to June 2020) and keywords such as 'coronaviruses', 'marine organisms', 'biologically active substances', 'antiviral drugs', 'SARS-CoV', 'MERS-CoV', 'SARS-CoV-2', '3CLpro', 'TMPRSS2', 'ACE2'. After obtaining all reports from the databases, the papers were carefully analysed in order to find data related to the topic of this review (98 references). Biologically active substances of marine origin, such as flavonoids, phlorotannins, alkaloids, terpenoids, peptides, lectins, polysaccharides, lipids and others substances, can affect coronaviruses at the stages of penetration and entry of the viral particle into the cell, replication of the viral nucleic acid and release of the virion from the cell; they also can act on the host's cellular targets. These natural compounds could be a vital resource in the fight against coronaviruses.

Dataset Information

Vitamin B3-Based Biologically Active Compounds as Inhibitors of Human Cholinesterases.

Publications

Vitamin B3-Based Biologically Active Compounds as Inhibitors of Human Cholinesterases.

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