A series of novel quinoline-based tetracyclic ring-systems were synthesized and evaluated in vitro for their antiplasmodial, antiproliferative and antimicrobial activities. The novel hydroiodide salts 10 and 21 showed the most promising antiplasmodial inhibition, with compound 10 displaying higher selectivity than the employed standards. The antiproliferative assay revealed novel pyridophenanthridine 4b to be significantly more active against human prostate cancer (IC50 = 24 nM) than Puromycin (IC50 = 270 nM) and Doxorubicin (IC50 = 830 nM), which are used for clinical treatment. Pyridocarbazoles 9 was also moderately effective against all the employed cancer cell lines and moreover showed excellent biofilm inhibition (9a: MBIC = 100 µM; 9b: MBIC = 100 µM).

An extract from the bryozoan Amathia lamourouxi with antiplasmodial activity was identified through high-throughput screening of an Australian marine invertebrate extract library against Plasmodium falciparum. Chemical investigation of A. lamourouxi resulted in the isolation of six new brominated alkaloids, convolutamines K and L (1 and 2), volutamides F−H (3−5), and 2,5-dibromo-1-methyl-1H-indole-3-carbaldehyde (6). Three of the compounds (2−4) displayed moderate to potent antiplasmodial activity against both the chloroquine-sensitive (3D7) and chloroquine-resistant (Dd2) parasite strains of Plasmodium falciparum with an IC 50 range of 0.57−1.7 μM and a high selectivity index against a human cell line (HEK293).

Chagas disease is caused by infection with the protozoan parasite, Trypanosoma cruzi. The disease causes ~12,000 deaths annually and is one of the world’s 20 neglected tropical diseases, as defined by the World Health Organisation. The drug discovery pipeline for Chagas disease currently has few new clinical candidates, with high attrition rates an ongoing issue. To determine if the Trypanosoma cruzi strain utilised to assess in vitro compound activity impacts activity, a comparison of laboratory-adapted T. cruzi strains from differing geographical locations was undertaken for a selection of compounds with anti-T. cruzi activity. To minimise the possible effect of differences in experimental methodology, the same host cell and multiplicity of infection were utilised. To determine whether the compound exposure time influenced results, activity was determined following exposure for 48 and 72 h of incubation. To ascertain whether replication rates affected outcomes, comparative rates of replication of the T. cruzi strains were investigated, using the nucleoside analogue, 5-ethynyl-2′-deoxyuridine. Minimal differences in the in vitro activity of compounds between strains were observed following 48 h incubation, whereas significant differences were observed following 72 h incubation, in particular for the cytochrome P450 inhibitors tested and the cell cycle inhibitor, camptothecin. Thus, the use of panels of laboratory adapted strains in vitro may be dependent on the speed of action that is prioritised. For the identification of fast-acting compounds, an initial shorter duration assay using a single strain may be used. A longer incubation to identify compound activity may alternatively require profiling of compounds against multiple T. cruzi strains.

Chagas disease caused by the protozoan Trypanosoma cruzi is endemic to 21 countries in the Americas, effects approximately 6 million people and on average results in 12,000 deaths annually. Human African Trypanosomiasis (HAT) is caused by the Trypanosoma brucei sub-species, endemic to 36 countries within sub-Saharan Africa. Treatment regimens for these parasitic diseases are complicated and not effective against all disease stages; thus, there is a need to find improved treatments. To identify new molecules for the drug discovery pipelines for these diseases, we have utilised in vitro assays to identify compounds with selective activity against both T. cruzi and T.b. brucei from the Medicines for Malaria Venture (MMV) Pathogen Box compound collection. To prioritise these molecules for further investigation, temporal and wash off assays were utilised to identify the speed of action and cidality of compounds. For translational relevance, compounds were tested against clinically relevant T.b. brucei subspecies. Compounds with activity against T. cruzi cytochrome P450 (TcCYP51) have not previously been successful in clinical trials for chronic Chagas disease; thus, to deprioritise compounds with this activity, they were tested against recombinant TcCYP51. Compounds with biological profiles warranting progression offer important tools for drug and target development against kinetoplastids.

Oral fructose decreases fat oxidation and increases carbohydrate (CHO) oxidation in obese subjects, but the metabolic response to fructose in lean individuals is less well understood. The purpose of this study was to assess the effects of a single fructose-rich mixed meal on substrate oxidation in young healthy non-obese males. We hypothesized that a decrease in fat oxidation and an increase in carbohydrate oxidation would be observed following a fructose-rich mixed meal compared to a glucose-rich mixed meal. Twelve healthy males, normal to overweight and age 23–31 years old, participated in a double-blind, cross-over study. Each participant completed two study visits, eating a mixed meal containing 30% of the calories from either fructose or glucose. Blood samples for glucose, insulin, triglycerides, and leptin as well as gas exchange by indirect calorimetry were measured intermittently for 7 hours. Serum insulin was higher after a fructose mixed meal but plasma glucose, plasma leptin and serum triglycerides were not different. Mean postprandial respiratory quotient and estimated fat oxidation did not differ between the fructose and glucose meals. The change in fat oxidation between the fructose and glucose rich meals negatively correlated with BMI (r=−0.59, P=0.04 and r=−0.59, P=0.04 at the 4 and 7 hour time points, respectively). In healthy non-obese males, BMI correlates with altered postprandial fat oxidation after a high-fructose mixed meal. The metabolic response to a high fructose meal may be modulated by BMI.