Synthesis and antimicrobial activity of a series of caespitin derivatives

Abstract

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...

Structure-Activity Relationships of Polycyclic Aromatic Amines with Calcium Channel Blocking Activity

“…8-Benzylamino-8,11-oxapentacyclo[5.4.0.0 2,6 .0 3,10 .0 5,9 ]undecane (NGP 1-01, 1) [7,8] (Figure 1) is structurally unrelated to any of the known calcium antagonists but was found to inhibit the calcium current in L-type calcium channels [9,10] . This finding provided a new tool for the study of drug action on ion channels.…”

“…By substituting the 8,11-oxapentacyclo-[5.4.0.0 2,6 .0 3,10 .0 5,9 ]undecane skeleton with 3-hydroxyhexacyclo-[6.5.0.0. 3,7 .0 4,12 .0 5,10 .0 9,13 ]tridecane (12), 8,13-dioxapentacyclo[6.5.0.0 2,6 .0 5,10 .0 3,11 ]tridecane-9-one (13), and pentacyclo-[5.4.0.0 2,6 .0 3,10 .0 5,9 ]undecane (14), the effect of the polycyclic skeleton could also be investigated. Increased inhibition of calcium current was observed with aromatic substitution (especially ortho and meta substitution) in the pentacycloundecane series.…”

Electron-Induced (EI) Mass Fragmentation is Directed by Intra- molecular H-Bonding in Two Isomeric Benzodipyran Systems

“…The resulting solution was stripped to dryness under vacuum. The residue was chromatographed using 9:1 benzene/ethyl acetate, to yield chroman 1 in 70% yield as the compound (of two) with the longest column retention time (mp 102-104 °C; C, H analysis: calc for C 15 H 20 O 4 : 68.16, 7.63%; found: 67.97, 7.74%; M, 264, M + , 264; 1 H-NMR data as previously reported [2]. The isomeric 5,7-dihydroxy-2,2-dimethyl-8-butyryl chroman − the product with the shorter retention time − was not isolated due to very poor yield.…”

“…Due to earlier work [2] with the 2,2-dimethylchroman (5,7-dihydroxy-2,2-dimethyl-8-butyryl chroman) 1 and benzodipyran derivatives 2 and 3 (Figure 1), the mass spectrometry of related compounds was of particular interest to us. We proceeded to study these compounds with simple EIMS and low resolution NMR.…”

“…Early investigations into the potentially useful pharmacological properties of chroman and benzodipyran derivatives focused primarily on their antiallergic [1] and antimicrobial [2] activities. A resurgence of interest in these compounds since the early 1990s explored their utility across a broad spectrum of activities such as anticancer agents with low toxicity [4], anti-inflammatory agents [5], potassium channel openers with possible cardioprotective properties [6,7], and agonists at serotonergic 5-HT 1A receptors [8].…”