Identification of a potent benzoxaborole drug candidate for treating cryptosporidiosis.

Cryptosporidiosis is a leading cause of life-threatening diarrhea in young children and causes chronic diarrhea in AIDS patients, but the only approved treatment is ineffective in malnourished children and immunocompromised people. We here use a drug repositioning strategy and identify a promising anticryptosporidial drug candidate. Screening a library of benzoxaboroles comprised of analogs to four antiprotozoal chemical scaffolds under pre-clinical development for neglected tropical diseases for Cryptosporidium growth inhibitors identifies the 6-carboxamide benzoxaborole AN7973. AN7973 blocks intracellular parasite development, appears to be parasiticidal, and potently inhibits the two Cryptosporidium species most relevant to human health, C. parvum and C. hominis. It is efficacious in murine models of both acute and established infection, and in a neonatal dairy calf model of cryptosporidiosis. AN7973 also possesses favorable safety, stability, and PK parameters, and therefore, is an exciting drug candidate for treating cryptosporidiosis.

Surface water retention systems for cattail production as a biofuel.

Surface water retention systems act to reduce nutrient pollution by collecting excess nutrients within a watershed via runoff. Harvesting aquatic biomass, such as the invasive cattail, from retention systems removes nutrients absorbed by the plant from the ecosystem permanently. Harvested biomass can be used as a renewable energy source in place of fossil fuels, offsetting carbon emissions. The purpose of this research was to simulate cattail harvest from surface water retention systems to determine their ability to provide suitable growing conditions with annual fluctuations in water availability. The economic and environmental benefits associated with nutrient removal and carbon offsets were also calculated and monetized. A proposed upstream and existing downstream water retention system in southern Manitoba were modelled using a system dynamics model with streamflow inputs provided by a physical hydrologic model, Modélisation Environmentale Communautaire - Surface and Hydrology (MESH). Harvesting cattail and other unconventional feedstocks, such as reeds, sedges, and grasses, from retention systems provided a viable revenue stream for landowners over a ten-year period. This practice generates income for landowners via biomass and carbon credit production on otherwise underutilized marginal cropland invaded with cattail. The economic benefits promote wetland habitat restoration while managing cattail growth to maintain biodiversity. Excess nitrogen and phosphorus are also removed from the ecosystem, reducing downstream nutrient loading. Utilizing surface water retention systems for cattail harvest is a best management strategy for nutrient retention on the landscape and improving agricultural resilience.

Synthesis, SAR and evaluation of [1,4']-bipiperidinyl-4-yl-imidazolidin-2-one derivatives as novel CCR5 antagonists.

Elaboration of our previously disclosed spiropiperidine template led to the development of a series of novel CCR5 antagonists. Results of SAR exploration and preliminary lead characterization are described.