The D3-trishomocubyl system was prepared from tertiary pentacyclo[5.4.0.0(2,6).0(3,10).0(5,9)]undecan-8-ols 5 in one step by using a modified Ritter reaction yielding only one of the possible two geometrical isomers of 4-amino-3-alkyl (or aryl)-D3-trishomocubane (8). Promising antagonism of reserpine-induced catalepsy was exhibited by these compounds which compared favorable with that of amantadine. Weak to mild anticholinergic properties were observed during the reduction of oxotremorine induced tremor and salivation procedure. Acute toxicities similar to that of amantadine were observed for some of these compounds. D3-Trishomocubyl-4-amines appeared as a promising new class of anti-Parkinson agents.

decomposition ' of the diradical, rather than by radical coupling. The benzyl ether (VI) may be formed from addition of methanol to the ortho-quinone methide intermediate (V), originating from the same diradical. The apparent ease of initial homolysis of the 1,2-(0%) bond could be related to the stability of the phenoxyl and benzylic radical systems (11) formed, presumably after x + 5c* transitions as indicated by the relatively short wavelength (300 nm) employed.Whereas the course of photolytic fragmentation is not

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Chemical modification of the naturally occurring phlorophenone antimicrobial agent caespitin is described. These modifications include variations in the phenone side chain, substitution with prenyl, allyl, and benzyl in the 4-position of the phlorophenone nucleus, and ring cyclizations via etherification to give furan and chroman compounds. Several of these derivatives show enhanced in vitro potency over caespitin. Studies on the development of microbial resistance against these compounds show that no or very little resistance developed after several passes of these compounds in representative microbial strains.Caespitin [C-1; 2-(4-methylpentanoyl)-4-(3-methylbuten-2-yl)phloroglucinol] is a naturally occurring phlorophenone derivative isolated from the indigenous southern African plant Helichrysum caespititium (2). The antimicrobial activity of phlorophenones and related compounds isolated as natural products or synthesized de novo has been reported as early as 1954 (8) and investigated since (6, 7). The in vitro potency of caespitin and the compounds studied previously (6-8) against a variety of bacteria and fungi has not been found comparable to that of most of the antimicrobial agents currently in use. Comprehensive studies done on the antimicrobial and pharmacological action of these compounds, including studies on the development of microbial resistance, are still lacking. Consequently, a research program was initiated to investigate these aspects in an endeavor to optimize the antimicrobial potency and spectrum of phloroglucinol-derived compounds. A synthesis program led to the production of 42 compounds related to caespitin (1), which were tested in vitro against a selection of grampositive and gram-negative bacteria, yeasts, and fungi. MIC determinations. The MIC was determined by a tube dilution method. Standard inocula for the tests on bacteria were prepared by incubating slopes of TSA inoculated with the organisms for 24 h at 37°C, from which suspensions yielding ca. 106 CFU/ml were obtained for use in the experiments. Twofold serial dilutions of each test compound were prepared in brain-heart infusion (BHI; Oxoid CM225) broth down to 1 jig/ml. A growth control of BHI broth was included in each series. To each of the prepared sets of concentrations of each test compound was added 0.1-ml portions of the organism suspensions. The MIC was defined as the lowest concentration of a compound preventing visual growth after 48 h at 37°C. Suspensions of the two yeasts, C. albicans and C. tropicalis, obtained from SDA cultures were diluted in sterile physiological saline to give 106 CFU/ml.Cultures of the molds in Sabouraud liquid medium (SLM; Oxoid CM146) were kept at 4°C until used and then incubated at 37°C for 5 to 14 days. For use, the suspensions were diluted to contain ca. 106 CFU/ml. Concentrations of each of the compounds were prepared in SLM in twofold steps from 100 to 0.1 ,ug/ml. The same procedure for testing against the bacteria was used for the fungi, only with SLM. Growth controls of SLM were in...

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