Synthesis and Evaluation of Antimicrobial and Cytotoxic Activity of Oxathiine-Fused Quinone-Thioglucoside Conjugates of Substituted 1,4-Naphthoquinones.

Yuri E Sabutski,Valery V Mikhailov,Sergey G Polonik,Roman S Popov,Ludmila S Shevchenko,Vladimir A Denisenko,Dmitry L Aminin,Ekaterina A Chingizova,Ekaterina S Menchinskaya,Artur R Chingizov

doi:10.3390/molecules25163577

Abstract

A series of new tetracyclic oxathiine-fused quinone-thioglycoside conjugates based on biologically active 1,4-naphthoquinones and 1-mercapto derivatives of per-O-acetyl d-glucose, d-galactose, d-xylose, and l-arabinose have been synthesized, characterized, and evaluated for their cytotoxic and antimicrobial activities. Six tetracyclic conjugates bearing a hydroxyl group in naphthoquinone core showed high cytotoxic activity with EC50 values in the range of 0.3 to 0.9 μM for various types of cancer and normal cells and no hemolytic activity up to 25 μM. The antimicrobial activity of conjugates was screened against Gram-positive bacteria (Staphylococcus aureus, Bacillus cereus), Gram-negative bacteria (Pseudomonas aeruginosa and Escherichia coli), and fungus Candida albicans by the agar diffusion method. The most effective juglone conjugates with d-xylose or l-arabinose moiety and hydroxyl group at C-7 position of naphthoquinone core at concentration 10 µg/well showed antimicrobial activity comparable with antibiotics vancomicin and gentamicin against Gram-positive bacteria strains. In liquid media, juglone-arabinosidic tetracycles showed highest activity with MIC 6.25 µM. Thus, a positive effect of heterocyclization with mercaptosugars on cytotoxic and antimicrobial activity for group of 1,4-naphthoquinones was shown.

Highlights

Naphthoquinones represent one of the largest families of natural products and are widespread in nature
In the course of our drug research project we developed an ring connecting the carbohydrate moiety to naphthoquinone)
A series of new tetracyclic oxathiine-fused quinone-thioglycoside conjugates based on biologically active 1,4-naphthoquinones have been synthesized, characterized, and evaluated for their cytotoxic and antimicrobial activities

Summary

Introduction

Naphthoquinones represent one of the largest families of natural products and are widespread in nature. They were isolated from plants, marine invertebrates, fungi, and bacteria [1]. The quinone ring contains a system of double bonds conjugated with carbonyl groups: it is susceptible to reduction, oxidation, and addition of O-, N-, and S-nucleophiles [10,11]. The high reactivity of naphthoquinones and the wellof its chemical modification make this group of compounds the profound development developed methods of its chemical modification make thisattractive group offor compounds attractive for the of new types of substances with high biological activity [12]

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