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Malaria is one of the most challenging human infectious diseases and both prevention and control have been hindered by the development of Plasmodium falciparum resistance to existing therapies. Several new compounds with novel mechanisms are in clinical development for the treatment of malaria including DSM265, an inhibitor of Plasmodium dihydroorotate dehydrogenase. In order to explore the mechanisms by which resistance might develop to DSM265 in the field, we selected for DSM265-resistant P. falciparum parasites in vitro. Any of five different amino acid changes led to reduced efficacy on the parasite and to decreased DSM265 binding to P. falciparum DHODH. The DSM265-resistant parasites retained full sensitivity to atovaquone. All but one of the observed mutations were in the DSM265 binding site, and the remaining C276F was in the adjacent flavin cofactor site. The C276F mutation was previously identified in a recrudescent parasite during a Phase IIa clinical study. We confirmed that this mutation (and the related C276Y) accounted for the full level of observed DSM265 resistance by re-generating the mutation using CRISPR/Cas9 genome editing. X-ray structure analysis of the C276F mutant enzyme showed that conformational changes of nearby residues were required to accommodate the larger F276 residue, which in turn led to a restriction in the size of the DSM265 binding pocket. These findings underscore the importance of developing DSM265 as part of a combination therapy with other agents for successful use against malaria.

As a follow-up on a study of a family of boron-oxygen-nitrogen compounds composed of two datively bonded B-O-N backbones, we investigate a similar series of compounds that have similar fragments but are covalently bonded. B3LYP/6-31G(d,p) quantum mechanical calculations have been performed to determine the minimum-energy geometries, vibrational frequencies, and thermochemical properties of the parent compound and a series of nitro-substituted derivatives. Our results indicate that some of the derivatives have at least appropriate thermodynamics for possible high-energy materials, in some cases being favorable over similar dimeric compounds with coordinate covalent B-N bonds.

Although they were first reported in 1963, molecules with a boron-oxygen-nitrogen dimeric backbone do not seem to have been investigated seriously in terms of thermodynamic properties. Here we report on the calculated structures and properties, including thermodynamics, of several so-called "BON-BON" molecules. With the popularity of nitrogen-containing substituents on new high-energy materials, nitro-substituted BON-BONs were a focus of our investigation. A total of 42 BON-BON molecules were evaluated, and thermochemical analysis shows a decrease in the specific enthalpy of combustion or decomposition with increasing NO(2) content, consistent with other systems.

As part of a continuing study of new potential high energy materials, here we present results of calculations on cyclopropane molecules with three or more nitro groups. DFT calculations suggest that all molecules can exist as minimum-energy stationary states. Energy calculations indicate that some nitrocyclopropanes have a specific enthalpy of decomposition in excess of 8 kJ g −1 , suggesting that they be explored as new potential high energy materials.