The Novel Chiral 2(5 H)-Furanone Sulfones Possessing Terpene Moiety: Synthesis and Biological Activity

Alsu M Khabibrakhmanova; Roza G Faizova; Olga A Lodochnikova; Regina R Zamalieva; Liliya Z Latypova; Elena Y Trizna; Andrey G Porfiryev; Katsunori Tanaka; Oskar A Sachenkov; Airat R Kayumov; Almira R Kurbangalieva

doi:10.3390/molecules28062543

The Novel Chiral 2(5 H)-Furanone Sulfones Possessing Terpene Moiety: Synthesis and Biological Activity

Molecules. 2023 Mar 10;28(6):2543. doi: 10.3390/molecules28062543.

Affiliations

¹ Biofunctional Chemistry Laboratory, A. Butlerov Institute of Chemistry, Kazan Federal University, 18 Kremlyovskaya Street, 420008 Kazan, Russia.
² Arbuzov Institute of Organic and Physical Chemistry, FRC Kazan Scientific Center of RAS, 8 Arbuzov Street, 420088 Kazan, Russia.
³ Institute of Fundamental Medicine and Biology, Kazan Federal University, 18 Kremlyovskaya Street, 420008 Kazan, Russia.
⁴ Biofunctional Synthetic Chemistry Laboratory, RIKEN Cluster for Pioneering Research, 2-1 Hirosawa, Wako-shi 351-0198, Japan.
⁵ Department of Chemical Science and Engineering, School of Materials and Chemical Technology, Tokyo Institute of Technology, 2-12-1 O-okayama, Meguro-ku, Tokyo 152-8552, Japan.
⁶ N.I. Lobachevsky Institute of Mathematics and Mechanics, Kazan Federal University, 18 Kremlyovskaya Street, 420008 Kazan, Russia.

Abstract

Over the past decades, 2(5H)-furanone derivatives have been extensively studied because of their promising ability to prevent the biofilm formation by various pathogenic bacteria. Here, we report the synthesis of a series of optically active sulfur-containing 2(5H)-furanone derivatives and characterize their biological activity. Novel thioethers were obtained by an interaction of stereochemically pure 5-(l)-menthyloxy- or 5-(l)-bornyloxy-2(5H)-furanones with aromatic thiols under basic conditions. Subsequent thioethers oxidation by an excess of hydrogen peroxide in acetic acid resulted in the formation of the corresponding chiral 2(5H)-furanone sulfones. The structure of synthesized compounds was confirmed by IR and NMR spectroscopy, HRMS, and single crystal X-ray diffraction. The leading compound, 26, possessing the sulfonyl group and l-borneol moiety, exhibited the prominent activity against Staphylococcus aureus and Bacillus subtilis with MICs of 8 μg/mL. Furthermore, at concentrations of 0.4-0.5 μg/mL, the sulfone 26 increased two-fold the efficacy of aminoglycosides gentamicin and amikacin against S. aureus. The treatment of the model-infected skin wound in the rat with a combination of gentamicin and sulfone 26 speeded up the bacterial decontamination and improved the healing of the wound. The presented results provide valuable new insights into the chemistry of 2(5H)-furanone derivatives and associated biological activities.

Keywords: 2(5H)-furanone; X-ray diffraction analysis; antimicrobial activity; lactone; stereoisomer; sulfone; synergism with antimicrobials; wound healing.

MeSH terms

Amikacin
Animals
Anti-Bacterial Agents / chemistry
Anti-Bacterial Agents / pharmacology
Bacteria*
Furans / chemistry
Gentamicins
Rats
Staphylococcus aureus*

Substances

Anti-Bacterial Agents
Amikacin
Gentamicins
Furans

Grants and funding

The synthetic part of this work was funded by the subsidy allocated to Kazan Federal University for the state assignment in the sphere of scientific activities (no. FZSM-2023-0018), with the support of the Kazan Federal University Strategic Academic Leadership Program (‘Priority–2030’) (to Almira R. Kurbangalieva). The biological study reported here was funded by RFBR according to the research project No. 20-04-00247 (to Airat R. Kayumov). XRD data were obtained in the Collective Spectro-Analytical Center for the study of the structure, properties, and composition of substances and materials of FRC Kazan Scientifc Center of RAS by support of the State Assignment of the Federal Research Center “Kazan Scientific Center”, Russian Academy of Sciences (to Olga A. Lodochnikova).