Antimicrobial and Antiinsectan Phenolic Metabolites of Dalea searlsiae

Continued interest in the chemistry of Dalea spp. led to investigation of Dalea searlsiae, a plant native to areas of the western United States. Methanol extractions of D. searlsiae roots and subsequent chromatographic fractionation afforded the new prenylated and geranylated flavanones malheurans A–D (1–4) and known flavanones (5 and 6). Known rotenoids (7 and 8) and isoflavones (9 and 10) were isolated from aerial portions. Structure determination of pure compounds was accomplished primarily by extensive 1D- and 2D-NMR spectroscopy. The absolute configurations of compounds 1–5, 7, and 8 were assigned using electronic circular dichroism spectroscopy. Antimicrobial bioassays revealed significant activity concentrated in the plant roots. Compounds 1–6 exhibited MICs of 2–8 μg/mL against Streptococcus mutans, Bacillus cereus, and oxacillin-sensitive and -resistant Staphylococcus aureus. Aerial metabolites 7–10 were inactive against these organisms, but the presence of 7 and 8 prompted investigation of the antiinsectan activity of D. searlsiae metabolites toward the major crop pest Spodoptera frugiperda (fall armyworm). While compounds 1–10 all caused significant reductions in larval growth rates, associated mortality (33–66%) was highest with flavanone 4 and rotenoids 7 and 8. These findings suggest a differential allocation of antimicrobial and antiinsectan plant resources to root and aerial portions of the plant, respectively

Antimicrobial Isoflavans and Other Metabolites of Dalea jamesii

The phytochemical investigation of extracts of Dalea jamesii root and aerial portions led to the isolation of ten phenolic compounds. Six previously undescribed prenylated isoflavans, summarily named ormegans A – F (1 – 6), were characterized, along with two new arylbenzofurans (7, 8), a known flavone (9), and a known chroman (10). The structures of the new compounds were deduced by NMR spectroscopy, supported by HRESI mass spectrometry. The absolute configurations of 1 – 6 were determined by circular dichroism spectroscopy. Compounds 1 – 9 exhibited in vitro antimicrobial activities, causing 98% or greater growth inhibition at concentrations as low as 2.5 – 5.1 µM against methicillin-resistant Staphylococcus aureus, vancomycin-resistant Enterococcus faecalis, and Cryptococcus neoformans. Interestingly, the most active compound was the dimeric arylbenzofuran 8 (\u3e 90% growth inhibition at 2.5 µM) against both methicillin-resistant S. aureus and vancomycin-resistant E. faecalis, tenfold more active than its corresponding monomer (7)

Investigation of Dalea parryi (Fabaceae) metabolites for anthelmintic activity against the human pathogenic hookworm Ancylostoma ceylanicum

The US Southwest plant Dalea parryi (Fabaceae) was investigated as part of an ongoing study of the potential of plant compounds for anthelmintic activity to the human pathogenic hookworm Ancylostoma ceylanicum. This has resulted in the isolation of three previously undescribed isoflavonoid metabolites, denoted parryans A-C, a chalcone, six pterocarpans, and three known compounds from the roots of D. parryi. Parryans A and B express a rarely-seen O-prenyl substituent. Structures of the previously undescribed compounds were established using 1D and 2D NMR spectroscopy and mass spectrometry. The relative and absolute configurations of the undescribed stereoisomers were assigned using chemical shift and coupling constant data and comparisons of specific rotations to published data. The most active of the isolated compounds only expressed a 17% reduction in survival of A. ceylanicum adult hookworm in an ex vivo assay at 50 μg/mL after 5 days exposure. Toxicity, ranging from 47 to 93% reduction in survival of mammalian splenocytes was expressed by four of the compounds

Fungal ABC Transporter-Associated Activity of Isoflavonoids from the Root Extract of Dalea formosa

New potential treatments for disseminated fungal infections are needed, especially for infections caused by the commonly drug-resistant pathogens Candida albicans and C. glabrata. These pathogens cause systemic candidiasis, a significant cause of mortality in immune-compromised patients. ABC transporters of the pleiotropic drug resistance subfamily, such as Cdr1p of C. albicans, play an important role in antifungal resistance and are potential bioassay targets for antifungal therapies against drug-resistant pathogens. We observed strong antifungal growth inhibitory activity in the methanol extract of Dalea formosa roots. This extract afforded six new isoflavonoids, sedonans A–F (1–6), a new but-2-enolide, 4′-O-methylpuerol A (7), and the new pterocarpan ent-sandwicensin (8). The structures and absolute configurations of these compounds were assigned using spectroscopic and chiroptical techniques. The direct antifungal activity of 1 against C. glabrata (MIC = 20 μM) was higher than that of fluconazole. Sedonans A–F and ent-sandwicensin were also active against Saccharomyces cerevisiae strains that express differing ABC transporter-associated resistance mechanisms but differed in their susceptibility to Cdr1p-mediated detoxification. A sedonan A (1)/ent-sandwicensin (8) combination exhibited synergistic growth inhibition. The results demonstrate that multiple crude extract compounds are differentially affected by efflux-mediated resistance and are collectively responsible for the observed bioactivity

Assessment of the anthelmintic activity and toxicity of metabolites of Dalea pogonathera (Fabaceae)

Dalea pogonathera A. Gray was collected as part of a project to determine if metabolites of the genus Dalea have potential for the treatment of human hookworm disease, based on earlier findings of very active materials in D. ornata. We report here the isolation, characterization, and results of ex vivo bioassays of a new chalcone pogonatheridin A (1), and three new prenylated flavanones (3, 6, and 12). The isolated known compounds, a chalcone (2), flavanones (4,5,7-11,13,14), and a flavan-3-ol (15), were also examined. Pogonatheridin A (1) reduced the survival of the adults of Ancylostoma ceylanicum hookworm by 12.5 % (50 μg/mL), while all other compounds showed very weak or no activity. The compounds were tested (50 μg/mL) for toxicity to healthy mammalian cells. Seven of them (2-8) showed \u3e 98 % reduction in survival of splenocytes, while 1 was somewhat less toxic at 74.3 % reduction in survival. While metabolites of D. pogonathera did not show promise as potential anthelmintics for hookworm disease, the toxicity information is of interest, and the rich diversity of metabolites of Dalea spp. remains apparent

Fungal ABC Transporter-Associated Activity of Isoflavonoids from the Root Extract of <i>Dalea formosa</i>

New potential treatments for disseminated fungal infections are needed, especially for infections caused by the commonly drug-resistant pathogens <i>Candida albicans</i> and <i>C. glabrata</i>. These pathogens cause systemic candidiasis, a significant cause of mortality in immune-compromised patients. ABC transporters of the pleiotropic drug resistance subfamily, such as Cdr1p of <i>C. albicans</i>, play an important role in antifungal resistance and are potential bioassay targets for antifungal therapies against drug-resistant pathogens. We observed strong antifungal growth inhibitory activity in the methanol extract of <i>Dalea formosa</i> roots. This extract afforded six new isoflavonoids, sedonans A–F (<b>1</b>–<b>6</b>), a new but-2-enolide, 4′-<i>O</i>-methylpuerol A (<b>7</b>), and the new pterocarpan <i>ent</i>-sandwicensin (<b>8</b>). The structures and absolute configurations of these compounds were assigned using spectroscopic and chiroptical techniques. The direct antifungal activity of <b>1</b> against <i>C. glabrata</i> (MIC = 20 μM) was higher than that of fluconazole. Sedonans A–F and <i>ent</i>-sandwicensin were also active against <i>Saccharomyces cerevisiae</i> strains that express differing ABC transporter-associated resistance mechanisms but differed in their susceptibility to Cdr1p-mediated detoxification. A sedonan A (<b>1</b>)/<i>ent</i>-sandwicensin (<b>8</b>) combination exhibited synergistic growth inhibition. The results demonstrate that multiple crude extract compounds are differentially affected by efflux-mediated resistance and are collectively responsible for the observed bioactivity

Phenolic Metabolites of Dalea ornata Affect Both Survival and Motility of the Human Pathogenic Hookworm Ancylostoma ceylanicum

Hookworms are ubiquitous human parasites, infecting nearly one billion people worldwide, and are the leading cause of anemia and malnutrition in resource-limited countries. Current drug treatments rely on the benzimidazole derivatives albendazole and mebendazole, but there is emerging resistance to these drugs. As part of a larger screening effort, using a hamster-based ex vivo assay, anthelmintic activity toward Ancylostoma ceylanicum was observed in the crude extract of aerial parts of Dalea ornata. These studies have led to the isolation and characterization of phenolic metabolites 1–10. The structures were determined by 1D and 2D NMR spectroscopy, and the absolute configuration of 1 was assigned using electronic circular dichroism data. The new compound, (2S)-8-(3-methylbut-2-en-1-yl)-6,7,4′-trihydroxyflavanone, was weakly active at 7.3 μM, with 17% reduction in survival of the hookworms after 5 days. The rotenoids deguelin and tephrosin, predictably perhaps, were the most active, with complete worm mortality observed by day 4 (or earlier) at 6.3 and 6.0 μM, respectively. The effects of 1–10 on hookworm motility and on toxicity to hamster splenocytes were also explored as important measures of treatment potential