Highly Nitrated Cyclopropanes as New High Energy Materials: DFT Calculations on the Properties of C\u3csub\u3e3\u3c/sub\u3eH\u3csub\u3e6\u3c/sub\u3e−n(NO\u3csub\u3e2\u3c/sub\u3e)n (n=3–6)

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 8kJg−1, suggesting that they be explored as new potential high energy materials

Introducing NOB-NOBs: nitrogen-oxygen-boron cycles with potential high-energy properties

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 bond

BON-BONs: Cyclic Molecules with a Boron-Oxygen-Nitrogen Backbone. Computational Studies of Their Thermodynamic Properties

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 NO2 content, consistent with other systems

BON-BONs: Cyclic Molecules with a Boron-Oxygen-Nitrogen Backbone. Computational Studies of Their Thermodynamic Properties

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 NO2 content, consistent with other systems

Discovery, Biological Profiling and Mechanistic Studies of Three Novel Antimalarials

Emerging resistance of the malaria causing Plasmodium parasite to current first-line therapies underscores the need for new antimalarial agents with broad ranging activity against multiple stages of the parasite. No new chemical class of antimalarials has been introduced into clinical practice since 1996. Overcoming emerging drug resistance requires new drugs with novel modes of action. With the aim of identifying new classes of antimalarials, I completed a phenotypic high throughput screen of two synthetic chemistry libraries against erythrocytic stage P. falciparum and compiled a portfolio of chemically novel validated antiplasmodials (ALCHM1 - 18). Herein I describe the discovery and characterization of three prioritized scaffolds: a tetrazole-based ALCHM3 series, an azetidine amide ALCHM17 series and a piperidine carboxamide ALCHM18 series. I report here on the biological profiling, mechanistic characterization and potential as next-generation anti-malarial agents of these three previously unreported scaffolds. ALCHM3 is a novel chemical series, with fast kill kinetics that targets the historically druggable heme polymerization pathway. The fast kill azetidine amide ALCHM17 series, is a novel scaffold with inhibitory activity in the pre-erythrocytic and erythrocytic stages, and the first azetidine scaffold with Pfcarl associated resistance. The piperidine carboxamide ALCHM18 is a proteasome β5 subunit-selective inhibitor, with a moderate rate of kill, species selectivity, strong starting in vitro and in vivo ADME properties, and potential to become the first proteasome inhibiting preclinical candidate for malaria treatment

Introducing NOB-NOBs: nitrogen-oxygen-boron cycles with potential high-energy properties

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 bond

Highly Nitrated Cyclopropanes as New High Energy Materials: DFT Calculations on the Properties of C\u3csub\u3e3\u3c/sub\u3eH\u3csub\u3e6\u3c/sub\u3e−n(NO\u3csub\u3e2\u3c/sub\u3e)n (n=3–6)

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 8kJg−1, suggesting that they be explored as new potential high energy materials

Fast-Killing Tyrosine Amide ((S)-SW228703) with Blood- and Liver-Stage Antimalarial Activity Associated with the Cyclic Amine Resistance Locus (PfCARL).

Current malaria treatments are threatened by drug resistance, and new drugs are urgently needed. In a phenotypic screen for new antimalarials, we identified (S)-SW228703 ((S)-SW703), a tyrosine amide with asexual blood and liver stage activity and a fast-killing profile. Resistance to (S)-SW703 is associated with mutations in the Plasmodium falciparum cyclic amine resistance locus (PfCARL) and P. falciparum acetyl CoA transporter (PfACT), similarly to several other compounds that share features such as fast activity and liver-stage activity. Compounds with these resistance mechanisms are thought to act in the ER, though their targets are unknown. The tyramine of (S)-SW703 is shared with some reported PfCARL-associated compounds; however, we observed that strict S-stereochemistry was required for the activity of (S)-SW703, suggesting differences in the mechanism of action or binding mode. (S)-SW703 provides a new chemical series with broad activity for multiple life-cycle stages and a fast-killing mechanism of action, available for lead optimization to generate new treatments for malaria

Potent Antimalarials with Development Potential Identified by Structure-Guided Computational Optimization of a Pyrrole-Based Dihydroorotate Dehydrogenase Inhibitor Series.

Dihydroorotate dehydrogenase (DHODH) has been clinically validated as a target for the development of new antimalarials. Experience with clinical candidate triazolopyrimidine DSM265 (1) suggested that DHODH inhibitors have great potential for use in prophylaxis, which represents an unmet need in the malaria drug discovery portfolio for endemic countries, particularly in areas of high transmission in Africa. We describe a structure-based computationally driven lead optimization program of a pyrrole-based series of DHODH inhibitors, leading to the discovery of two candidates for potential advancement to preclinical development. These compounds have improved physicochemical properties over prior series frontrunners and they show no time-dependent CYP inhibition, characteristic of earlier compounds. Frontrunners have potent antimalarial activity in vitro against blood and liver schizont stages and show good efficacy in Plasmodium falciparum SCID mouse models. They are equally active against P. falciparum and Plasmodium vivax field isolates and are selective for Plasmodium DHODHs versus mammalian enzymes