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)

Protozoan Parasite Growth Inhibitors Discovered by Cross-Screening Yield Potent Scaffolds for Lead Discovery

Tropical protozoal infections are a significant cause of morbidity and mortality worldwide; four in particular (human African trypanosomiasis (HAT), Chagas disease, cutaneous leishmaniasis, and malaria) have an estimated combined burden of over 87 million disability-adjusted life years. New drugs are needed for each of these diseases. Building on the previous identification of NEU-617 (<b>1</b>) as a potent and nontoxic inhibitor of proliferation for the HAT pathogen (<i>Trypanosoma brucei</i>), we have now tested this class of analogs against other protozoal species: <i>T. cruzi</i> (Chagas disease), <i>Leishmania major</i> (cutaneous leishmaniasis), and <i>Plasmodium falciparum</i> (malaria). Based on hits identified in this screening campaign, we describe the preparation of several replacements for the quinazoline scaffold and report these inhibitors’ biological activities against these parasites. In doing this, we have identified several potent proliferation inhibitors for each pathogen, such as 4-((3-chloro-4-((3-fluorobenzyl)­oxy)­phenyl)­amino)-6-(4-((4-methyl-1,4-diazepan-1-yl)­sulfonyl)­phenyl)­quinoline-3-carbonitrile (NEU-924, <b>83</b>) for <i>T. cruzi</i> and <i>N</i>-(3-chloro-4-((3-fluorobenzyl)­oxy)­phenyl)-7-(4-((4-methyl-1,4-diazepan-1-yl)­sulfonyl)­phenyl)­cinnolin-4-amine (NEU-1017, <b>68</b>) for <i>L. major</i> and <i>P. falciparum</i>

Abl Tyrosine Kinase Phosphorylates Nonmuscle Myosin Light Chain Kinase to Regulate Endothelial Barrier Function

This study identified multiple novel c-Abl–mediated nmMLCK phosphorylation sites by mass spectroscopy and examined their influence on nmMLCK function and human lung endothelial barrier regulation. The data indicate an essential role for Abl kinase in vascular barrier regulation via phosphorylation of nmMLCK and the actin-binding protein cortactin