Antiviral Activity of Natural Phloroglucinols and Their Analogues

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There are many reports concerning antimicrobial constituents in higher plants. Schonbeck investigated the antibiotic properties of individual parts of a plant separately and found that the flowers of many plants showed especially high antibiotic activities, followed by leaves, roots and lastly branches (Schonbeck, 1967). So far as we know, there are few reports on biologically active compounds from flowers (Mitchell {ntet al., 1970). In the course of our chemical investigation on the self-defensive substances of plants, we examined antibacterial (Escherichia coli and Bacillus subtilis) and antiviral activities (vesicular stomatitis virus [VSV] and herpes simplex virus [HSV]) of methanol extracts from various plants (especially flowers), and found that almost all plant extracts showed anti-Bacillus activities and antiviral activities against both, or either, of VSV and/or HSV (Tada et al., unpublished data). Various constituents of plants, including phenols (Sakagami et al., 1989; Van Hoof et al., 1989), lignoid (MacRae et al., 1989), flavones (Nagai et al., 1990; Gonzalez et al., 1990), coumarins (Reusser et al., 1989), quinones (Konoshima et al., 1989), phloroglucinols (Chan et al, 1989; Tada et al, 1990), sesquiterpenes (De Tommasi et al., 1990), diterpenes (Koehn et al., 1991), and tannins (Nonaka et al., 1990) have been reported with respect to antiviral activity. The flowers of Hypericum chinense L. (Guttiferae) (Japanese name: byouyanagi) exhibited extremely strong antibacterial activity. The plants belonging to the Guttiferae family are well known folk medicines for external wounds with anodyne, stanching and antiphlogistic properties, in Japan. So far we have isolated antimicrobial compounds, Chinesin I and II from flowers of Hypericum chinense L (Nagai and Tada, 1987), otogirin and otogirone from Hypericum erectum (Tada et al., 1991). The structures of these constituents attracted our attention as their partial structure is similar to the 1,3-dioxo-2-carboxamide structure of tetracycline (Boothe et al., 1953). Several antimicrobial acylphloroglucinols were isolated from higher plants, e.g. aspidin from Proiobteris austricaca (Riedl and Mitteldorf, 1956), uliginosin A from Hypericum uliginocum (Parker and Johnson, 1968), humulon (De Keukeleire and Verzele, 1970) and lupulon from Humulus lupulus (Ashurst, 1967). Antimicrobial activities of caespitin and its analogues from the indigenous South African plant, Helichrysum caespititium have been reported (Van der Schye et al., 1986). Acylphloroglucinols, grandinol and its analogues, are also known as plant growth regulators which inhibit photosynthetic electron transfer in plants (Boite et al., 1984; Yoshida et al., 1988; Yoneyama et al., 1989). These fragments of information prompted our research into the structure activity relationships of 2,4-diacylphloroglucinols, 2-acylcyclohexane-1,3-diones and 2-carboxamidocyclohexane-1,3-dione. Various phloroglucinol derivatives and the related compounds were synthesized to examine the antimicrobial and antiviral activities. This structure-activity relationship is discussed. The correlation between the inhibition of virus replication and the alkyl chain length of the substitutents on the phloroglucinol ring was observed. A prestudy of the mode of phloroglucinols suggested that a certain derivative inhibits the synthesis of RNA and proteins of VSV.