TY - JOUR

T1 - Design, Synthesis, and Biological Evaluation of (+)-Camphor- and (−)-Fenchone-Based Derivatives as Potent Orthopoxvirus Inhibitors

AU - Sokolova, Anastasiya S.

AU - Kovaleva, Kseniya S.

AU - Kuranov, Sergey O.

AU - Bormotov, Nikolay I.

AU - Borisevich, Sophia S.

AU - Zhukovets, Anastasiya A.

AU - Yarovaya, Olga I.

AU - Serova, Olga A.

AU - Nawrozkij, Maxim B.

AU - Vernigora, Andrey A.

AU - Davidenko, Andrey V.

AU - Khamitov, Eduard M.

AU - Peshkov, Roman Y.

AU - Shishkina, Larisa N.

AU - Maksuytov, Rinat A.

AU - Salakhutdinov, Nariman F.

N1 - Funding Information: The authors acknowledge the Multi‐Access Chemical Service Centre SB RAS for spectral and analytical measurements. This work has been supported by a Russian Foundation for Basic Research (RFBR) Grant 20–33‐70067 and the State assignment of State Research Centre of Virology and Biotechnology VECTOR. The study of search for potential binding site were provided by financial support of the Ministry of Education and Science of the Russian Federation (Establishment of the structure, composition and physicochemical properties of organic, bioorganic, polymer molecules and complex compounds by chromatography, mass spectrometry, IR, UV, EPR and NMR spectroscopy award no. 122031400282–9). The authors thank Nina I. Komarova for performing HPLC analysis. Publisher Copyright: © 2022 Wiley-VCH GmbH.

PY - 2022/6/20

Y1 - 2022/6/20

N2 - In this work, a library of (+)-camphor and (−)-fenchone based N-acylhydrazones, amides, and esters, including para-substituted aromatic/hetaromatic/cyclohexane ring was synthesized, with potent orthopoxvirus inhibitors identified among them. Investigations of the structure-activity relationship revealed the significance of the substituent at the para-position of the aromatic ring. Also, the nature of the linker between a hydrophobic moiety and aromatic ring was clarified. Derivatives with p-Cl, p-Br, p-CF3, and p-NO2 substituted aromatic ring and derivatives with cyclohexane ring showed the highest antiviral activity against vaccinia virus, cowpox, and ectromelia virus. The hydrazone and the amide group were more favourable as a linker for antiviral activity than the ester group. Compounds 3 b and 7 e with high antiviral activity were examined using the time-of-addition assay and molecular docking study. The results revealed the tested compounds to inhibit the late processes of the orthopoxvirus replication cycle and the p37 viral protein to be a possible biological target.

AB - In this work, a library of (+)-camphor and (−)-fenchone based N-acylhydrazones, amides, and esters, including para-substituted aromatic/hetaromatic/cyclohexane ring was synthesized, with potent orthopoxvirus inhibitors identified among them. Investigations of the structure-activity relationship revealed the significance of the substituent at the para-position of the aromatic ring. Also, the nature of the linker between a hydrophobic moiety and aromatic ring was clarified. Derivatives with p-Cl, p-Br, p-CF3, and p-NO2 substituted aromatic ring and derivatives with cyclohexane ring showed the highest antiviral activity against vaccinia virus, cowpox, and ectromelia virus. The hydrazone and the amide group were more favourable as a linker for antiviral activity than the ester group. Compounds 3 b and 7 e with high antiviral activity were examined using the time-of-addition assay and molecular docking study. The results revealed the tested compounds to inhibit the late processes of the orthopoxvirus replication cycle and the p37 viral protein to be a possible biological target.

KW - (+)-camphor

KW - (−)-fenchone

KW - orthopoxviruses inhibitors

KW - p37 envelope protein

KW - structure-activity relationship

UR - http://www.scopus.com/inward/record.url?scp=85128558751&partnerID=8YFLogxK

U2 - 10.1002/cmdc.202100771

DO - 10.1002/cmdc.202100771

M3 - Article

C2 - 35388614

AN - SCOPUS:85128558751

VL - 17

SP - e202100771

JO - ChemMedChem

JF - ChemMedChem

SN - 1860-7179

IS - 12

M1 - e202100771

ER -