1,364 research outputs found
Repurposing of antiparasitic drugs: the hydroxy-naphthoquinone buparvaquone inhibits vertical transmission in the pregnant neosporosis mouse model.
No full textThe three anti-malarial drugs artemiside, artemisone, and mefloquine, and the naphthoquinone buparvaquone known to be active against theileriosis in cattle and Leishmania infections in rodents, were assessed for activity against Neospora caninum infection. All four compounds inhibited the proliferation of N. caninum tachyzoites in vitro with IC50 in the sub-micromolar range, but artemisone and buparvaquone were most effective (IC50 = 3 and 4.9 nM, respectively). However, in a neosporosis mouse model for cerebral infection comprising Balb/c mice experimentally infected with the virulent isolate Nc-Spain7, the three anti-malarial compounds failed to exhibit any activity, since treatment did not reduce the parasite burden in brains and lungs compared to untreated controls. Thus, these compounds were not further evaluated in pregnant mice. On the other hand, buparvaquone, shown earlier to be effective in reducing the parasite load in the lungs in an acute neosporosis disease model, was further assessed in the pregnant mouse model. Buparvaquone efficiently inhibited vertical transmission in Balb/c mice experimentally infected at day 7 of pregnancy, reduced clinical signs in the pups, but had no effect on cerebral infection in the dams. This demonstrates proof-of-concept that drug repurposing may lead to the discovery of an effective compound against neosporosis that can protect offspring from vertical transmission and disease
Roy Haynes: the early years
No full textIn four parts, this thesis covers the early years of the life, development, and career of Roy Haynes beginning with his ancestry and family history in Boston, to the early 1950's in New York, by which time he had become an established fixture on the scene of New York’s new evolution of African American music called bebop. The purpose of this study is to magnify the genesis of one of America’s treasured artists – taking a glimpse into the dawning of his influences and musical exposure, and later highlighting his gift in expressive versatility which carried him throughout his career, displaying the gradual making of an internationally renowned artist.
Part one is comprised of four chapters, and includes an introduction and biographical information. Chapter one covers his genealogy, taking a step back to identify the sources of his African and Caribbean roots that help to inform who he is personally and musically.
Chapter two sheds light upon his social and familial development in the historical context around and between World War I and The Great Depression. It touches upon the social, cultural, and economic existence of the immigrants who found themselves in and around the communities of Lower Roxbury. This section shows when and how Haynes’s talent emerged, and how through his gift he was able to build a sound reputation as a solid musician around New England.
From that reputation, which traveled all the way to New York, chapter three continues with Haynes’s professional career in Boston, then leaps to New York City via a one-way train ticket to join the famed Luis Russell Orchestra.
In chapter four, the author explains plans for additional research, and the continued synthesis and distillation thereof toward the eventual publication of biographical literature for both adults and children.
Continuing with part two of this work, chapter five includes musical analyses highlighting Haynes’s contributions on three particular recordings between 1945 and 1949.
In part three, chapters six through fourteen feature interview transcripts from nine individuals who provide an overview of expert insight spanning several generations on a variety of cultural, musical, and stylistic influences and contributions of Haynes’s artistry.
Finally, in part four, there are several appendices which represent visual images on topics approached throughout, and in support of the narrative.M.A.Includes bibliographical referencesby Leslie K. Hayne
Reply to comments on "highly antimalaria-active artemisinin derivatives: Biological activity does not correlate with chemical reactivity"
No full textIn light of the discussion on C10-substituted derivatives of the antimalarial agent artemisinin in the preceding correspondence article which relates to his earlier work, R. K. Haynes reiterates here that there is no correlation between the ability of artemisinins to react with heme- or non-heme-FeII and their antimalarial activity.</p
Mechanistic Investigations into the Palladium-Catalyzed Decarboxylative Allylic Alkylation of Ketone Enolates Using the PHOX Ligand Architecture
No full textPalladium-catalyzed asymmetric allylic alkylation has become a large and important field for chemical synthesis. Many methodologies in this field offer mild conditions under which challenging and important molecular features can be reliably synthesized, including chiral all-carbon quaternary stereocenters. As a result, palladium- catalyzed asymmetric allylic alkylation has found significant use in total synthesis, and growing use in industry. While the general process of palladium-catalyzed asymmetric allylic alkylation has been studied for decades, there have been a number of recent modifications and developments, such as asymmetric versions of decarboxylative allylic alkylation procedures that are not yet well understood. The development of future implementations and improvements to palladium-catalyzed asymmetric allylic alkylation and related methodologies is expected to be facilitated by a better understanding of these more recent developments, and thus further mechanistic investigation is warranted.
Reported herein is a set of investigations into the palladium-catalyzed decarboxylative asymmetric allylic alkylation of ketone enolates using the PHOX ligand architecture. By monitoring the reaction via 31P NMR, a series of previously unidentified key intermediates is discovered. Two representatives of these key intermediates are isolated and characterized. The solution behavior of these species under reaction-like conditions is studied along with a few novel and related complexes. The role of these intermediates and their impact on the behavior of the reaction and product formation is discussed. Previously confounding experimentally observed behavior for this methodology is rationalized via the properties elucidated for these discovered intermediates.</p
11-Azaartemisinin cocrystals with preserved lactam : acid heterosynthons
No full textThe R22(8) lactam : acid hetero-synthon, found in several new 1 : 1 and 2 : 1 cocrystals between the anti-malarial 11-azaartemisinin and organic acids.</p
Artemisone demonstrates synergistic antiviral activity in combination with approved and experimental drugs active against human cytomegalovirus
No full textWe have recently shown that the artemisinin derivative artemisone, which was screened against malaria in human clinical studies, is a potent inhibitor of human cytomegalovirus (HCMV). Here we evaluated the antiviral effect of artemisone when employed in 2-drug combinations with approved and experimental anti-HCMV agents. Using the Chou-Talalay method, we found that in-vitro combination of artemisone with cidofovir, brincidofovir, or with the HCMV UL97 inhibitor maribavir resulted in antiviral synergism and the combination of artemisone with ganciclovir or with the viral terminase inhibitors letermovir and BDCRB resulted in moderate synergism. Importantly, the combination of artemisone with maribavir demonstrated synergistic antiviral activity ex-vivo, in a clinically-relevant multicellular model of human placental tissues maintained in organ culture. Our findings provide the basis for the use of artemisone in synergistically acting drug combinations, to enhance viral control and reduce antiviral drug toxicitie
In vitro activity of artemisone and artemisinin derivatives against extracellular and intracellular Helicobacter pylori. Corrigendum
No full textThe authors regret that there was an error in the Table 1: The Metronidazole MIC value for the strain E17 should be 2 microg/ml. This is now corrected online.
The authors would like to apologise for any inconvenience caused
Methylene homologues of artemisone: an unexpected structure-activity relationship and a possible implication for the design of C10-substituted artemisinins
No full textWe sought to establish if methylene homologues of artemisone are biologically more active and more stable than artemisone. The analogy is drawn with the conversion of natural O- and N-glycosides into more stable C-glycosides that may possess enhanced biological activities and stabilities. Dihydroartemisinin was converted into 10β-cyano-10-deoxyartemisinin that was hydrolyzed to the α-primary amide. Reduction of the β-cyanide and the α-amide provided the respective methylamine epimers that upon treatment with divinyl sulfone gave the β- and α-methylene homologues, respectively, of artemisone. Surprisingly, the compounds were less active in vitro than artemisone against P. falciparum and displayed no appreciable activity against A549, HCT116, and MCF7 tumor cell lines. This loss in activity may be rationalized in terms of one model for the mechanism of action of artemisinins, namely the cofactor model, wherein the presence of a leaving group at C10 assists in driving hydride transfer from reduced flavin cofactors to the peroxide during perturbation of intracellular redox homeostasis by artemisinins. It is noted that the carba analogue of artemether is less active in vitro than the O-glycoside parent toward P. falciparum, although extrapolation of such activity differences to other artemisinins at this stage is not possible. However, literature data coupled with the leaving group rationale suggest that artemisinins bearing an amino group attached directly to C10 are optimal compound
Corrigendum to ‘In vitro activity of artemisone and artemisinin derivatives against extracellular and intracellular Helicobacter pylori’ International journal of antimicrobial agents, 52(4):528. [https://doi.org/10.1016/j.ijantimicag.2018.08.006]
No full textThe in vitro activity of the new artemisinin derivative artemisone as well as other molecules of the same class against Helicobacter pylori and their effects when combined with standard antibiotics were evaluated. Since H. pylori can be internalised into gastric epithelial cells, the effects of artemisinin, dihydroartemisinin and artemisone against intracellular H. pylori were also investigated. Bacteriostatic [minimum inhibitory concentration (MIC)] and bactericidal [minimum bactericidal concentration (MBC)] activities were assessed against 24 clinical strains of H. pylori with different antibiotics susceptibilities. Artemisone showed MIC50 and MIC90 values of 0.25 mg/L and 0.5 mg/L, respectively, and an MBC50 value of 0.5 mg/L. Artemisone was synergistic with amoxicillin in 60% of strains, with clarithromycin in 40% and with metronidazole in 20%. There was no interaction between artemisone and omeprazole or bismuth citrate. Against intracellular H. pylori, only dihydroartemisinin at 2× MIC caused a 1 log10 CFU decrease after 18 h and 24 h of incubation. This is the first demonstration in vitro of the activity of artemisinin derivatives against intracellular H. pylori and indicates that artemisone has the potential to be efficacious for the treatment of H. pylori infection, especially in combination with antibiotic
Immunomodulatory properties of mesenchymal stem cell in experimental arthritis in rat and mouse models: a systematic review
No full textAbstract not availableKim Hynes, Richard Bright, Susanna Proudman, David Haynes, Stan Gronthos, Mark Bartol
- …
