Novel aroyl guanidine anti-trypanosomal compounds that exert opposing effects on parasite energy metabolism.

Human African trypanosomiasis (HAT), or sleeping sickness, is a neglected tropical disease with current treatments marred by severe side effects or delivery issues. To identify novel classes of compounds for the treatment of HAT, high throughput screening (HTS) had previously been conducted on bloodstream forms of T. b. brucei, a model organism closely related to the human pathogens T. b. gambiense and T. b. rhodesiense. This HTS had identified a number of structural classes with potent bioactivity against T. b. brucei (IC50 ≤ 10 µM) with selectivity over mammalian cell-lines (selectivity index of ≥10). One of the confirmed hits was an aroyl guanidine derivative. Deemed to be chemically tractable with attractive physicochemical properties, here we explore this class further to develop the SAR landscape. We also report the influence of the elucidated SAR on parasite metabolism, to gain insight into possible modes of action of this class. Of note, two sub-classes of analogues were identified that generated opposing metabolic responses involving disrupted energy metabolism. This knowledge may guide the future design of more potent inhibitors, while retaining the desirable physicochemical properties and an excellent selectivity profile of the current compound class.

Analgesic Use and Daytime Sleepiness in Residents With and Without Dementia in Residential Aged Care Facilities.

BACKGROUND: Managing pain in residents of residential aged care facilities (RACFs) is challenging, especially for people with dementia. Clinicians must weigh the benefits of analgesic use against the potential for adverse events, particularly daytime sleepiness. OBJECTIVES: The aim was to investigate the association between analgesic use and daytime sleepiness in residents with and without dementia in RACFs. METHODS: This was a cross-sectional study of 383 permanent residents from six low-level and high-level RACFs in South Australia. Main measures included analgesic use in the previous 24 h, analgesic load and self-reported daytime sleepiness. Covariates included relevant comorbidities (insomnia, depression, painful conditions), Charlson's Comorbidity Index, sedative load, self-reported and clinician-observed pain and dementia severity. Logistic regression was used to compute odds ratios (ORs) and confidence intervals (CIs) for the association between analgesic use and daytime sleepiness. RESULTS: Analgesics were used by 288 residents (75.2%) in the previous 24 h. These included paracetamol (n = 264, 68.9%), opioids (n = 110, 28.7%) and oral NSAIDs (n = 14, 3.7%). Overall, 116 (30.3%) residents were categorized as having daytime sleepiness. Of those with dementia, 77 (45.6%) were categorized as having daytime sleepiness. Opioid use in the previous 24 h was not associated with daytime sleepiness in unadjusted or adjusted analyses. Paracetamol use was positively associated with daytime sleepiness (OR 2.31; 95% CI 1.20-4.42). CONCLUSION: Although daytime sleepiness occurred in a large number of residents, especially those with dementia, this sleepiness was not necessarily associated with use of opioids. The risk of opioid-induced sedation may have been managed by strategies including preferential prescribing of paracetamol to residents at risk of sleepiness, opioid discontinuation in residents who experienced sleepiness, and use of low doses of opioids.

Identification of compounds with anti-proliferative activity against Trypanosoma brucei brucei strain 427 by a whole cell viability based HTS campaign.

Human African Trypanosomiasis (HAT) is caused by two trypanosome sub-species, Trypanosoma brucei rhodesiense and Trypanosoma brucei gambiense. Drugs available for the treatment of HAT have significant issues related to difficult administration regimes and limited efficacy across species and disease stages. Hence, there is considerable need to find new alternative and less toxic drugs. An approach to identify starting points for new drug candidates is high throughput screening (HTS) of large compound library collections. We describe the application of an Alamar Blue based, 384-well HTS assay to screen a library of 87,296 compounds against the related trypanosome subspecies, Trypanosoma brucei brucei bloodstream form lister 427. Primary hits identified against T.b. brucei were retested and the IC(50) value compounds were estimated for T.b. brucei and a mammalian cell line HEK293, to determine a selectivity index for each compound. The screening campaign identified 205 compounds with greater than 10 times selectivity against T.b. brucei. Cluster analysis of these compounds, taking into account chemical and structural properties required for drug-like compounds, afforded a panel of eight compounds for further biological analysis. These compounds had IC(50) values ranging from 0.22 µM to 4 µM with associated selectivity indices ranging from 19 to greater than 345. Further testing against T.b. rhodesiense led to the selection of 6 compounds from 5 new chemical classes with activity against the causative species of HAT, which can be considered potential candidates for HAT early drug discovery. Structure activity relationship (SAR) mining revealed components of those hit compound structures that may be important for biological activity. Four of these compounds have undergone further testing to 1) determine whether they are cidal or static in vitro at the minimum inhibitory concentration (MIC), and 2) estimate the time to kill.