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Antibacterial Cannabinoids from Cannabis sativa: A Structure−Activity Study

Giovanni Appendino*^†^‡, Simon Gibbons*, Anna Giana^†^‡, Alberto Pagani^†^‡, Gianpaolo Grassi^§, Michael Stavri, Eileen Smith and M. Mukhlesur Rahman

Dipartimento di Scienze Chimiche, Alimentari, Farmaceutiche e Farmacologiche, Universit

del Piemonte Orientale, Via Bovio 6, 28100 Novara, Italy, Consorzio per lo Studio dei Metaboliti Secondari (CSMS), Viale S. Ignazio 13, 09123 Cagliari, Italy, Centre for Pharmacognosy and Phytotherapy, The School of Pharmacy, University of London, 29-39 Brunswick Square, London WC1N 1AX, U.K., and CRA-CIN Centro di Ricerca per le Colture Industriali, Sede distaccata di Rovigo, Via Amendola 82, 45100 Rovigo, Italy

J. Nat. Prod., 2008, 71 (8), pp 1427–1430

DOI: 10.1021/np8002673

Publication Date (Web): August 6, 2008

* To whom correspondence should be addressed. Tel: +39 0321 373744

(G.A.); +44 207 753 5913

(S.G.). Fax: +39 0321 375621 (G.A.); +44 207 753 5909 (S.G.). E-mail: appendino@pharm.unipmn.it (G.A.); simon.gibbons@pharmacy.ac.uk (S.G.).

†

Universit del Piemonte Orientale.

‡

Consorzio per lo Studio dei Metaboliti Secondari.

University of London.

Centro Ricerca Colture Industriali.

Abstract

Marijuana (Cannabis sativa) has long been known to contain antibacterial cannabinoids, whose potential to address antibiotic resistance has not yet been investigated. All five major cannabinoids (cannabidiol (1b), cannabichromene (2), cannabigerol (3b), Δ⁹-tetrahydrocannabinol (4b), and cannabinol (5)) showed potent activity against a variety of methicillin-resistant Staphylococcus aureus (MRSA) strains of current clinical relevance. Activity was remarkably tolerant to the nature of the prenyl moiety, to its relative position compared to the n-pentyl moiety (abnormal cannabinoids), and to carboxylation of the resorcinyl moiety (pre-cannabinoids). Conversely, methylation and acetylation of the phenolic hydroxyls, esterification of the carboxylic group of pre-cannabinoids, and introduction of a second prenyl moiety were all detrimental for antibacterial activity. Taken together, these observations suggest that the prenyl moiety of cannabinoids serves mainly as a modulator of lipid affinity for the olivetol core, a per se poorly active antibacterial pharmacophore, while their high potency definitely suggests a specific, but yet elusive, mechanism of activity.

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