Design, synthesis and antiviral evaluation of novel conjugates of the 1,7,7‐trimethylbicyclo[2.2.1]heptane scaffold and saturated N‐heterocycles via 1,2,3‐triazole linker

Author:

Sokolova Anastasiya S.1,Yarovaya Olga I.1ORCID,Artyushin Oleg I.2,Sharova Elena V.2,Baev Dmitriy S.13,Mordvinova Ekaterina D.4,Shcherbakov Dmitriy N.4,Shnaider Tatiana A.5,Nikitina Tatiana V.6ORCID,Esaulkova Iana L.7,Ilyina Polina A.7,Zarubaev Vladimir V.7ORCID,Brel Valery K.2,Tolstikova Tatyana G.1,Salakhutdinov Nariman F.1

Affiliation:

1. N.N. Vorozhtsov Novosibirsk Institute of Organic Chemistry Siberian Branch of Russian Academy of Sciences Novosibirsk Russian Federation

2. A.N. Nesmeyanov Institute of Organoelement Compounds Russian Academy of Sciences Moscow Russian Federation

3. Synchrotron Radiation Facility SKIF G.K. Boreskov Institute of Catalysis SB RAS Koltsovo Russian Federation

4. State Research Center of Virology and Biotechnology VECTOR, Rospotrebnadzor, Koltsovo Novosibirsk Region Russian Federation

5. Institute of Cytology and Genetics Siberian Branch of Russian Academy of Sciences Novosibirsk Russian Federation

6. Research Institute of Medical Genetics Tomsk National Research Medical Center of the Russian Academy of Sciences Tomsk Russian Federation

7. Pasteur Institute of Epidemiology and Microbiology St. Petersburg Russian Federation

Abstract

AbstractA new series of heterocyclic derivatives with a 1,7,7‐trimethylbicyclo[2.2.1]heptane fragment was designed, synthesised and biologically evaluated. Synthesis of the target compounds was performed using the Cu(I) catalysed cycloaddition reaction. The key starting substances in the click reaction were an alkyne containing a 1,7,7‐trimethylbicyclo[2.2.1]heptane fragment and a series of azides with saturated nitrogen‐containing heterocycles. Some of the derivatives were found to exhibit strong antiviral activity against Marburg and Ebola pseudotype viruses. Lysosomal trapping assays revealed the derivatives to possess lysosomotropic properties. The molecular modelling study demonstrated the binding affinity between the compounds investigated and the possible active site to be mainly due to hydrophobic interactions. Thus, combining a natural hydrophobic structural fragment and a lysosome‐targetable heterocycle may be an effective strategy for designing antiviral agents.

Publisher

Wiley

Subject

Drug Discovery,Pharmaceutical Science

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