(-)-Cannabidiol (CBD) and (-)-cannabigerol (CBG) are two major non-psychotropic phytocannabinoids that have many beneficial biological properties. However, due to their low water solubility and prominent first-pass metabolism, their oral bioavailability is moderate, which is unfavorable for medicinal use. Therefore, there is a great need for appropriate chemical modifications to improve their physicochemical and biological properties. In this study, Mannich-type reaction was used for the synthetic modification of CBD and CBG for the first time, and thus fifteen new cannabinoid derivatives containing one or two tertiary amino groups were prepared. Thereafter the antiviral, antiproliferative and antibacterial properties of the derivatives and their effects on certain skin cells were investigated. Some modified CBD derivatives showed remarkable antiviral activity against SARS-CoV-2 without cytotoxic effect, while synthetic modifications on CBG resulted in a significant increase in antiproliferative activity in some cases compared to the parent compound.

Department of Applied Chemistry University of Debrecen Debrecen 4032 Hungary

Department of Medical Microbiology Semmelweis University Budapest 1089 Hungary

Department of Pharmaceutical Chemistry University of Debrecen Debrecen 4032 Hungary

Department of Pharmaceutical Technology University of Debrecen Debrecen 4032 Hungary

Department of Physiology Faculty of Medicine University of Debrecen Debrecen 4032 Hungary

Departments of Dermatology Venereology Allergology and Immunology Staedtisches Klinikum Dessau Brandenburg Medical School Theodor Fontane and Faculty of Health Sciences Brandenburg 06847 Dessau Germany

Doctoral School of Molecular Medicine University of Debrecen Debrecen 4032 Hungary

Doctoral School of Pharmaceutical Sciences University of Debrecen Debrecen 4032 Hungary

HUN REN UD Molecular Recognition and Interaction Research Group University of Debrecen Debrecen 4032 Hungary

HUN REN UD Pharmamodul Research Group University of Debrecen Debrecen 4032 Hungary

Institute of Organic Chemistry and Biochemistry of the Czech Academy of Science Prague 166 10 Czech Republic

Institute of Pharmacodynamics and Biopharmacy University of Szeged Szeged 6720 Hungary

National Laboratory of Virology Szentágothai Research Centre Pécs 7624 Hungary

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