Evaluation of pyrrolidine and pyrazolone derivatives as inhibitors of trypanosomal phosphodiesterase B1 (TbrPDEB1)

Author Posting. © The Author(s), 2015. This is the author's version of the work. It is posted here by permission of Elsevier for personal use, not for redistribution. The definitive version was published in Tetrahedron Letters 56 (2015): 2832-2835, doi:10.1016/j.tetlet.2015.04.061.Human African trypanosomiasis (HAT) is a parasitic disease, caused by the protozoan pathogen Trypanosoma brucei, which affects thousands every year and which is in need of new therapeutics. Herein we report the synthesis and assessment of a series of pyrrolidine and pyrazolone derivatives of human phosphodiesterase 4 (hPDE4) inhibitors for the assessment of their activity against the trypanosomal phosphodiesterase TbrPDEB1. The synthesized compounds showed weak potency against TbrPDEB1.We acknowledge funding from the National Institutes of Health (R01AI082577)

Synthesis and assessment of catechol diether compounds as inhibitors of trypanosomal phosphodiesterase B1 (TbrPDEB1)

Author Posting. © The Author(s), 2013. This is the author's version of the work. It is posted here by permission of Elsevier B.V. for personal use, not for redistribution. The definitive version was published in Bioorganic & Medicinal Chemistry Letters 23 (2013): 5971-5974, doi:10.1016/j.bmcl.2013.08.057.Human African trypanosomiasis (HAT) is a parasitic neglected tropical disease that affects 10,000 patients each year. Current treatments are sub-optimal, and the disease is fatal if not treated. Herein, we report our continuing efforts to repurpose the human phosphodiesterase 4 (hPDE4) inhibitor piclamilast to target trypanosomal phosphodiesterase TbrPDEB1. We prepared a range of substituted heterocyclic replacements for the 4-amino-3,5-dichloro-pyridine head group of piclamilast, and found that these compounds exhibited weak inhibitory activity of TbrPDEB1.We acknowledge funding from the National Institutes of Health (R01AI082577)

Bioinformatic analysis of the neprilysin (M13) family of peptidases reveals complex evolutionary and functional relationships

<p>Abstract</p> <p>Background</p> <p>The neprilysin (M13) family of endopeptidases are zinc-metalloenzymes, the majority of which are type II integral membrane proteins. The best characterised of this family is neprilysin, which has important roles in inactivating signalling peptides involved in modulating neuronal activity, blood pressure and the immune system. Other family members include the endothelin converting enzymes (ECE-1 and ECE-2), which are responsible for the final step in the synthesis of potent vasoconstrictor endothelins. The ECEs, as well as neprilysin, are considered valuable therapeutic targets for treating cardiovascular disease. Other members of the M13 family have not been functionally characterised, but are also likely to have biological roles regulating peptide signalling. The recent sequencing of animal genomes has greatly increased the number of M13 family members in protein databases, information which can be used to reveal evolutionary relationships and to gain insight into conserved biological roles.</p> <p>Results</p> <p>The phylogenetic analysis successfully resolved vertebrate M13 peptidases into seven classes, one of which appears to be specific to mammals, and insect genes into five functional classes and a series of expansions, which may include inactive peptidases. Nematode genes primarily resolved into groups containing no other taxa, bar the two nematode genes associated with <it>Drosophila </it>DmeNEP1 and DmeNEP4. This analysis reconstructed only one relationship between chordate and invertebrate clusters, that of the ECE sub-group and the DmeNEP3 related genes. Analysis of amino acid utilisation in the active site of M13 peptidases reveals a basis for their biochemical properties. A relatively invariant S1' subsite gives the majority of M13 peptidases their strong preference for hydrophobic residues in P1' position. The greater variation in the S2' subsite may be instrumental in determining the specificity of M13 peptidases for their substrates and thus allows M13 peptidases to fulfil a broad range of physiological roles.</p> <p>Conclusion</p> <p>The M13 family of peptidases have diversified extensively in all species examined, indicating wide ranging roles in numerous physiological processes. It is predicted that differences in the S2' subsite are fundamental to determining the substrate specificities that facilitate this functional diversity.</p

Synthesis and evaluation of human phosphodiesterases (PDE) 5 inhibitor analogs as trypanosomal PDE inhibitors. 2. Tadalafil analogs

Author Posting. © The Author(s), 2012. This is the author's version of the work. It is posted here by permission of Elsevier B.V. for personal use, not for redistribution. The definitive version was published in Bioorganic & Medicinal Chemistry Letters 22 (2012): 2582-2584, doi:10.1016/j.bmcl.2012.01.118.In this report we describe our ongoing target repurposing efforts focused on discovery of inhibitors of the essential trypanosomal phosphodiesterase TbrPDEB1. This enzyme has been implicated in virulence of Trypanosoma brucei, the causative agent of human African trypanosomiasis (HAT). We outline the synthesis and biological evaluation of analogs of tadalafil, a human PDE5 inhibitor currently utilized for treatment of erectile dysfunction, and report that these analogs are weak inhibitors of TbrPDEB1.This work was supported by the National Institutes of Health (R01AI082577), Boston University and Northeastern University

Synthesis and evaluation of human phosphodiesterases (PDE) 5 inhibitor analogs as trypanosomal PDE inhibitors. 1. Sildenafil analogs

Author Posting. © The Author(s), 2012. This is the author's version of the work. It is posted here by permission of Elsevier B.V. for personal use, not for redistribution. The definitive version was published in Bioorganic & Medicinal Chemistry Letters 22 (2012): 2579-2581, doi:10.1016/j.bmcl.2012.01.119.Parasitic diseases, such as African sleeping sickness, have a significant impact on the health and well-being in the poorest regions of the world. Pragmatic drug discovery efforts are needed to find new therapeutic agents. In this report we describe target repurposing efforts focused on trypanosomal phosphodiesterases. We outline the synthesis and biological evaluation of analogs of sildenafil (1), a human PDE5 inhibitor, for activities against trypanosomal PDEB1 (TbrPDEB1). We find that, while low potency analogs can be prepared, this chemical class is a sub-optimal starting point for further development of TbrPDE inhibitors.This work was supported by the National Institutes of Health (R01AI082577), Boston University and Northeastern University

A Pair of Compact Red Galaxies at Redshift 2.38, Immersed in a 100 kpc Scale Ly-alpha Nebula

We present Hubble Space Telescope (HST) and ground-based observations of a pair of galaxies at redshift 2.38, which are collectively known as 2142-4420 B1 (Francis et al. 1996). The two galaxies are both luminous extremely red objects (EROs), separated by 0.8 arcsec. They are embedded within a 100 kpc scale diffuse Ly-alpha nebula (or blob) of luminosity ~10^44 erg/s. The radial profiles and colors of both red objects are most naturally explained if they are young elliptical galaxies: the most distant yet found. It is not, however, possible to rule out a model in which they are abnormally compact, extremely dusty starbursting disk galaxies. If they are elliptical galaxies, their stellar populations have inferred masses of ~10^11 solar masses and ages of ~7x10^8 years. Both galaxies have color gradients: their centers are significantly bluer than their outer regions. The surface brightness of both galaxies is roughly an order of magnitude greater than would be predicted by the Kormendy relation. A chain of diffuse star formation extending 1 arcsec from the galaxies may be evidence that they are interacting or merging. The Ly-alpha nebula surrounding the galaxies shows apparent velocity substructure of amplitude ~ 700 km/s. We propose that the Ly-alpha emission from this nebula may be produced by fast shocks, powered either by a galactic superwind or by the release of gravitational potential energy.Comment: 33 pages, 9 figures, ApJ in press (to appear in Jun 10 issue

The SAMI pilot survey: The kinematic morphology-density relation in Abell 85, Abell 168 and Abell 2399

We examine the kinematic morphology of early-type galaxies (ETGs) in three galaxy clusters Abell 85, 168 and 2399. Using data from the Sydney-AAOMulti-object Integral field spectrograph we measure spatially resolved kinematics for 79 ETGs in these clusters. We calculate λR, a proxy for the projected specific stellar angular momentum, for each galaxy and classify the 79 ETGs in our samples as fast or slow rotators. We calculate the fraction of slow rotators in the ETG populations (fSR) of the clusters to be 0.21 ± 0.08, 0.08 ± 0.08 and 0.12 ± 0.06 for Abell 85, 168 and 2399, respectively, with an overall fraction of 0.15 ± 0.04. These numbers are broadly consistent with the values found in the literature, confirming recent work asserting that the fraction of slow rotators in the ETG population is constant across many orders of magnitude in global environment. We examine the distribution of kinematic classes in each cluster as a function of environment using the projected density of galaxies: the kinematic morphology-density relation.We find that in Abell 85 fSR increases in higher density regions but in Abell 168 and 2399 this trend is not seen. We examine the differences between the individual clusters to explain this. In addition, we find slow rotators on the outskirts of two of the clusters studied, Abell 85 and 2399. These galaxies reside in intermediate to low density regions and have clearly not formed at the centre of a cluster environment. We hypothesize that they formed at the centres of groups and are falling into the clusters for the first time

Rubble pile asteroids are forever

Rubble piles asteroids consist of reassembled fragments from shattered monolithic asteroids and are much more abundant than previously thought in the solar system. Although monolithic asteroids that are a kilometer in diameter have been predicted to have a lifespan of few 100 million years, it is currently not known how durable rubble pile asteroids are. Here, we show that rubble pile asteroids can survive ambient solar system bombardment processes for extremely long periods and potentially 10 times longer than their monolith counterparts. We studied three regolith dust particles recovered by the Hayabusa space probe from the rubble pile asteroid 25143 Itokawa using electron backscatter diffraction, time-of-flight secondary ion mass spectrometry, atom probe tomography, and 40Ar/39Ar dating techniques. Our results show that the particles have only been affected by shock pressure of ca. 5 to 15 GPa. Two particles have 40Ar/39Ar ages of 4,219 ± 35 and 4,149 ± 41 My and when combined with thermal and diffusion models; these results constrain the formation age of the rubble pile structure to ≥4.2 billion years ago. Such a long survival time for an asteroid is attributed to the shock-absorbent nature of rubble pile material and suggests that rubble piles are hard to destroy once they are created. Our results suggest that rubble piles are probably more abundant in the asteroid belt than previously thought and provide constrain to help develop mitigation strategies to prevent asteroid collisions with Earth

Assessing the Quality of Care for Pneumonia in Integrated Community Case Management: A Cross-Sectional Mixed Methods Study

Background Pneumonia is the leading infectious cause of mortality in children under five worldwide. Community-level interventions, such as integrated community case management, have great potential to reduce the burden of pneumonia, as well as other diseases, especially in remote populations. However, there are still questions as to whether community health workers (CHW) are able to accurately assess symptoms of pneumonia and prescribe appropriate treatment. This research addresses limitations of previous studies using innovative methodology to assess the accuracy of respiratory rate measurement by CHWs and provides new evidence on the quality of care given for children with symptoms of pneumonia. It is one of few that assesses CHW performance in their usual setting, with independent re-examination by experts, following a considerable period of time post-training of CHWs. Methods In this cross-sectional mixed methods study, 1,497 CHW consultations, conducted by 90 CHWs in two districts of Luapula province, Zambia, were directly observed, with measurement of respiratory rate for children with suspected pneumonia recorded by video. Using the video footage, a retrospective reference standard assessment of respiratory rate was conducted by experts. Counts taken by CHWs were compared against the reference standard and appropriateness of the treatment prescribed by CHWs was assessed. To supplement observational findings, three focus group discussions and nine in depth interviews with CHWs were conducted. Results and Conclusion The findings support existing literature that CHWs are capable of measuring respiratory rates and providing appropriate treatment, with 81% and 78% agreement, respectively, between CHWs and experts. Accuracy in diagnosis could be strengthened through further training and the development of improved diagnostic tools appropriate for resource-poor settings