Synthesis and Evaluation of Benzylamine Inhibitors of Neuropathogenic Naegleria fowleri "Brain-Eating" Amoeba.

Current therapy for primary amoebic meningoencephalitis (PAM), a highly lethal brain infection in humans caused by Naegleria fowleri amoeba, is restricted to repurposed drugs with limited efficacy and success. Discovery of an antiamoebic benzylamine scaffold 2 precipitated a medicinal chemistry effort to improve potency, cytotoxicity profile, and drug-like properties. Thirty-four compounds were prepared, leading to compound 28 with significant gains in potency (EC50 = 0.92 µM), solubility, and microsomal stability and a demonstrated absence of cytotoxicity in SH-SY5Y human neuroblastoma cells (CC50 > 20 µM). The compounds demonstrated excellent blood-brain barrier permeability in an in vitro assay, thereby providing a new structural scaffold that inhibits N. fowleri viability and permits the investigation of therapeutic interventions in an understudied neglected disease.

Relationship of actigraphy-assessed sleep efficiency and sleep duration to reactivity to stress.

OBJECTIVE: Sleep duration is an important predictor of cardiovascular health outcomes, but the role of sleep efficiency is less clear. This study investigated actigraphy-assessed sleep efficiency and sleep duration and their relationship with responses to mental and physical challenge tasks. METHODS: To record sleep, actigraph devices were worn on the wrist continuously by 25 participants (age: 33.9±6.9, 60% female) for the duration of a seven-day period. Movement data were used to estimate sleep duration and efficiency. Mental (Stroop test) and physical (cold pressor) challenges were used to assess reactivity to and recovery from stress. During these tasks, heart rate, blood pressure, and emotional states were measured. RESULTS: Significant findings from the mental challenge included a negative correlation between sleep efficiency and reaction time. There were no significant relationships between sleep efficiency and cardiovascular measures during the mental challenge, but sleep duration was related to cardiovascular reactivity. For the physical challenge, sleep efficiency was positively and significantly correlated with blood pressure recovery and sleep duration was not related to any outcome measures. DISCUSSION: Previous literature has focused on sleep duration when assessing sleep and cardiovascular outcomes. However, sleep efficiency may be equally or more important when investigating reactivity to and recovery from stress.

Isolation and characterization of nongeminal cyclic methylphenylphosphazene tetramers.

Heating pure samples of the cyclic phosphazenes, cis- or trans-[Me(Ph)PN](3), yielded mixtures of the cis and trans isomers of the cyclic phosphazene trimers, [Me(Ph)PN](3), and all four geometric isomers of the tetramers, [Me(Ph)PN](4). Varying the temperature and heating times changes the ratio of these components. Following the thermolysis by NMR spectroscopy indicated that only a mixture of the two isomeric trimers occurred initially. Longer heating times produced mixtures of the isomers of the tetramer. Column chromatography and solubility differences were used to separate each of the isomers of the tetramer. Spectroscopic and X-ray crystallographic studies suggest that the four different geometrical isomers of the tetramer can be described as cone, partial cone, 1,2-alternate, and 1,3-alternate by analogy to calix[4]arene.