Synthesis and structure-activity relationships of novel camphecene analogues as anti-influenza agents

Olga I Yarovaya; Anastasiya S Sokolova; Iliya Ya Mainagashev; Alexandrina S Volobueva; Khristina Lantseva; Sophia S Borisevich; Anna A Shtro; Vladimir V Zarubaev; Nariman F Salakhutdinov

doi:10.1016/j.bmcl.2019.126745

Synthesis and structure-activity relationships of novel camphecene analogues as anti-influenza agents

Bioorg Med Chem Lett. 2019 Dec 1;29(23):126745. doi: 10.1016/j.bmcl.2019.126745. Epub 2019 Oct 19.

Authors

Olga I Yarovaya¹, Anastasiya S Sokolova², Iliya Ya Mainagashev², Alexandrina S Volobueva³, Khristina Lantseva³, Sophia S Borisevich⁴, Anna A Shtro⁵, Vladimir V Zarubaev³, Nariman F Salakhutdinov⁶

Affiliations

¹ N.N. Vorozhtsov Novosibirsk Institute of Organic Chemistry, Siberian Branch, Russian Academy of Sciences, Lavrentjev Avenue 9, 630090 Novosibirsk, Russia; Novosibirsk State University, Pirogova St. 2, 630090 Novosibirsk, Russia. Electronic address: ooo@nioch.nsc.ru.
² N.N. Vorozhtsov Novosibirsk Institute of Organic Chemistry, Siberian Branch, Russian Academy of Sciences, Lavrentjev Avenue 9, 630090 Novosibirsk, Russia.
³ Pasteur Institute of Epidemiology and Microbiology, 14 Mira Str., 197101 St. Petersburg, Russia.
⁴ Laboratory of Chemical Physics, Ufa Institute of Chemistry, Ufa Federal Research Center, Russian Academy of Sciences, 71 Octyabrya pr., 450054 Ufa, Russia.
⁵ Department of Chemotherapy, Influenza Research Institute, 15/17 Prof. Popova St., 197376 St. Petersburg, Russia.
⁶ N.N. Vorozhtsov Novosibirsk Institute of Organic Chemistry, Siberian Branch, Russian Academy of Sciences, Lavrentjev Avenue 9, 630090 Novosibirsk, Russia; Novosibirsk State University, Pirogova St. 2, 630090 Novosibirsk, Russia.

PMID: 31668423
DOI: 10.1016/j.bmcl.2019.126745

Abstract

A chemical library was constructed based on the scaffold of camphecene (2-(E)-((1R,4R)-1,7,7-trimethylbicyclo[2.2.1]heptan-2-ylidene-aminoethanol). The modifications included introduction of mono-and bicyclic heterocyclic moieties in place of the terminal hydroxyl group of camphecene. All compounds were tested for cytotoxicity and anti-viral activity against influenza virus A/Puerto Rico/8/34 (H1N1) in MDCK cells. Among 15 tested compounds 11 demonstrated a selectivity index (SI) higher than 10 and IC₅₀ values in the micromolar range. The antiviral activity and toxicity were shown to strongly depend on the nature of the heterocyclic substituent. Compounds 2 and 14 demonstrated the highest virus-inhibiting activity with SIs of 106 and 183, and bearing pyrrolidine and piperidine moieties, correspondingly. Compound 14 was shown to interfere with viral reproduction at early stages of the viral life cycle (0-2 h post-infection). Taken together, our data suggest potential of camphecene derivatives in particular and camphor-based imine derivatives in general as effective anti-influenza compounds.

Keywords: Antivirals; Camphecene; Camphor; Imine derivatives; Influenza.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Camphor / analogs & derivatives*
Camphor / chemical synthesis
Camphor / chemistry
Ethanolamines / chemical synthesis*
Ethanolamines / chemistry
Humans
Influenza, Human / drug therapy*
Structure-Activity Relationship

Substances

Ethanolamines
camphecene
Camphor