Modifications of Isoalantolactone Leading to Effective Anti-bacterial and Anti-viral Compounds

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Author(s): Sergey S. Patrushev, Lyubov G. Burova, Anna A. Shtro, Tatyana V. Rybalova, Dmitry S. Baev, Il’ya V. Shirokikh, Alexander N. Evstropov, Elvira E. Shults*

Journal Name: Letters in Drug Design & Discovery

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Background: Natural sesquiterpene lactones are an important class of heterocyclic compounds in drug discovery since they are possessed a wide range of biological properties including antibacterial activity.

Objective: The objective of this study was to synthesize of isoalantolactone derivatives with a furo[2,3-d]pyrimidin-2-оne moiety and to evaluate their antibacterial and antiviral activity.

Methods: The Sonogashira cross-coupling and subsequent Ag-catalyzed cyclization reactions were the main routes of synthesis. The antibacterial activity and the ability to inhibit biofilms formation on E. coli, S. aureus, A. viscosus, P. aeruginosa and E. faecalis bacterial strains were evaluated. A study of the molecular interactions of new compounds with the multiple virulence factor regulators was performed using docking simulations. The antiviral activity against influenza A virus and human orthopneumovirus H-2А was also studied.

Results: The in vitro antibacterial activity for 4 (MIC = 58.33±4.41 μg/mL) concerning E. coli and 5 (MIC = 96.5±3.25 μg/mL) against A. viscosus and the inhibition of biofilm formation for compounds 2, 4, and 5 on E. coli, S. aureus, P. aeruginosa and E. faecalis bacterial strains has been of interest for the search of improved antimicrobial agents. Compound 3 was endowed with antiviral activity to human orthopneumovirus H-2А with SI >33. The activity of the new type of hybrid compounds is depended on the substituent in the 6th position of furo[2,3-d]pyrimidin-2-one fragment.

Conclusion: The decoration of isoalantolactone with a furo[2,3-d]pyrimidin-2-one fragment led to perspective antiviral and antimicrobial agents. Due to antimicrobial activity, pyridine-4-yl substituted isoalantolactone-furopyrimidinone hybrid is considered as a candidate compound to participate in further research.

Keywords: Natural products, sesquiterpene lactone, pyrimidine, cross-coupling reaction, cyclization, antibacterial activity, antiviral activity

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(E-pub Ahead of Print)
DOI: 10.2174/1570180817999201211193151
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