From the Mediterranean to the Libyan Sahara. Chemical analyses of Garamantian glass.

This paper presents the results of electron microprobe analysis of 124 samples of glass from sites in Libya, most from the Saharan oasis belt of the Wadi al-Ajal. Imported Roman vessel glass; beads; vitreous production waste; and Islamic glass bangles have all been analysed, and provide the first chemical information on glass from this region

Lead Optimization of a Pyrazole Sulfonamide Series of Trypanosoma brucei <i>N</i>‑Myristoyltransferase Inhibitors: Identification and Evaluation of CNS Penetrant Compounds as Potential Treatments for Stage 2 Human African Trypanosomiasis

Trypanosoma brucei <i>N</i>-myristoyltransferase (<i>Tb</i>NMT) is an attractive therapeutic target for the treatment of human African trypanosomiasis (HAT). From previous studies, we identified pyrazole sulfonamide, DDD85646 (<b>1</b>), a potent inhibitor of <i>Tb</i>NMT. Although this compound represents an excellent lead, poor central nervous system (CNS) exposure restricts its use to the hemolymphatic form (stage 1) of the disease. With a clear clinical need for new drug treatments for HAT that address both the hemolymphatic and CNS stages of the disease, a chemistry campaign was initiated to address the shortfalls of this series. This paper describes modifications to the pyrazole sulfonamides which markedly improved blood–brain barrier permeability, achieved by reducing polar surface area and capping the sulfonamide. Moreover, replacing the core aromatic with a flexible linker significantly improved selectivity. This led to the discovery of DDD100097 (<b>40</b>) which demonstrated partial efficacy in a stage 2 (CNS) mouse model of HAT

Neither mycorrhizal inoculation nor atmospheric CO₂ concentration has strong effects on pea root production and root loss

Chagas’ disease, caused by the protozoan parasite Trypanosoma cruzi, is the most common cause of cardiac-related deaths in endemic regions of Latin America. There is an urgent need for new safer treatments because current standard therapeutic options, benznidazole and nifurtimox, have significant side effects and are only effective in the acute phase of the infection with limited efficacy in the chronic phase. Phenotypic high content screening against the intracellular parasite in infected VERO cells was used to identify a novel hit series of 5-amino-1,2,3-triazole-4-carboxamides (ATC). Optimization of the ATC series gave improvements in potency, aqueous solubility, and metabolic stability, which combined to give significant improvements in oral exposure. Mitigation of a potential Ames and hERG liability ultimately led to two promising compounds, one of which demonstrated significant suppression of parasite burden in a mouse model of Chagas’ disease