A Novel Oral GyrB/ParE Dual Binding Inhibitor Effective against Multidrug-Resistant and Other High-Threat Pathogens.

Drug-resistant Neisseria gonorrhoeae is a serious global health concern. New drugs are needed that can overcome existing drug resistance and limit the development of new resistances. Here, we describe the small molecule tricyclic pyrimidoindole JSF-2414 [8-(6-fluoro-8-(methylamino)-2-((2-methylpyrimidin-5-yl)oxy)-9H-pyrimido[4,5-b]indol-4-yl)-2-oxa-8-azaspiro[4.

Aglow: A Fluorescence Assay and Machine Learning Model to Identify Inhibitors of Intracellular Infection.

is a genus of Gram-negative bacteria that has for centuries caused large-scale morbidity and mortality. In recent years, the resurgence of rickettsial diseases as a major cause of pyrexias of unknown origin, bioterrorism concerns, vector movement, and concerns over drug resistance is driving a need to identify novel treatments for these obligate intracellular bacteria. Utilizing an uvGFP plasmid reporter, we developed a screen for identifying anti-rickettsial small molecule inhibitors using as a model organism.

Antitubercular Triazines: Optimization and Intrabacterial Metabolism.

The triazine antitubercular JSF-2019 was of interest due to its in vitro efficacy and the nitro group shared with the clinically relevant delamanid and pretomanid. JSF-2019 undergoes activation requiring FH and one or more nitroreductases in addition to Ddn. An intrabacterial drug metabolism (IBDM) platform was leveraged to demonstrate the system kinetics, evidencing formation of NO and a des-nitro metabolite.

Chiral bisoxazoline ligands designed to stabilize bimetallic complexes.

Chiral bisoxazoline ligands containing naphthyridine, pyridazine, pyrazole, and phenol bridging units were prepared and shown to form bimetallic complexes with various metal salts. X-ray crystal structures of bis-nickel naphthyridine-bridged, bis-zinc pyridazine-bridged, and bis-nickel as well as bis-palladium pyrazole-bridged complexes were obtained.

A Novel Small-Molecule Inhibitor of the Demethylmenaquinone Methyltransferase MenG Is Bactericidal to Both Growing and Nutritionally Deprived Persister Cells.

Active tuberculosis (TB) and latent infection both require lengthy treatments to achieve durable cures. This problem has partly been attributable to the existence of nonreplicating "persisters" that are difficult to kill using conventional anti-TB treatments. Compounds that target the respiratory pathway have the potential to kill both replicating and persistent and shorten TB treatment, as this pathway is essential in both metabolic states.

Combining Metabolite-Based Pharmacophores with Bayesian Machine Learning Models for Mycobacterium tuberculosis Drug Discovery.

Integrated computational approaches for Mycobacterium tuberculosis (Mtb) are useful to identify new molecules that could lead to future tuberculosis (TB) drugs. Our approach uses information derived from the TBCyc pathway and genome database, the Collaborative Drug Discovery TB database combined with 3D pharmacophores and dual event Bayesian models of whole-cell activity and lack of cytotoxicity. We have prioritized a large number of molecules that may act as mimics of substrates and metabolites in the TB metabolome.

A Dual-Catalysis Anion-Binding Approach to the Kinetic Resolution of Amines: Insights into the Mechanism via a Combined Experimental and Computational Study.

Racemic benzylic amines undergo kinetic resolution via benzoylation with benzoic anhydride in the presence of a dual catalyst system consisting of a readily available amide-thiourea catalyst and 4-dimethylaminopyridine (DMAP). An evaluation of various experimental parameters was performed in order to derive a more detailed understanding of what renders this process selective. The catalyst's aggregation behavior and anion-binding ability were evaluated in regard to their relevance for the catalytic process.

Conjugate-base-stabilized Brønsted acids: catalytic enantioselective Pictet-Spengler reactions with unmodified tryptamine.

A conjugate-base-stabilized Brønsted acid facilitates catalytic enantioselective Pictet-Spengler reactions with unmodified tryptamine. The chiral carboxylic acid catalyst is readily assembled in just two steps and enables the formation of β-carbolines with up to 92% ee. Achiral acid additives or in situ Boc-protection facilitate catalyst turnover.

A dual-catalysis approach to the kinetic resolution of 1,2-diaryl-1,2-diaminoethanes.

The kinetic resolution of racemic C(2)-symmetric 1,2-diaryl-1,2-diaminoethanes was accomplished for the first time through application of a dual-catalysis approach.

Kinetic resolution of amines via dual catalysis: remarkable dependence of selectivity on the achiral cocatalyst.

A dual-catalysis/anion-binding approach with a chiral hydrogen bonding (HB) catalyst and an achiral nucleophilic cocatalyst was applied to the kinetic resolution of amines. Out of a structurally diverse collection of 22 nucleophilic species, 4-di-n-propylaminopyridine emerged as the most efficient cocatalyst, allowing for the kinetic resolution of benzylic amines with s-factors of up to 67.

A dual-catalysis approach to the asymmetric Steglich rearrangement and catalytic enantioselective addition of O-acylated azlactones to isoquinolines.

A dual-catalysis approach, namely the combination of an achiral nucleophilic catalyst and a chiral anion-binding catalyst, was applied to the Steglich rearrangement to provide α,α-disubstituted amino acid derivatives in a highly enantioselective fashion. Replacement of the nucleophilic co-catalyst for isoquinoline resulted in a divergent reaction pathway and an unprecedented transformation of O-acylated azlactones. This strategy provided highly substituted α,β-diamino acid derivatives with excellent levels of stereocontrol.

A dual-catalysis/anion-binding approach to the kinetic resolution of allylic amines.

A dual-catalysis approach enables the small-molecule catalyzed kinetic resolution of allylic amines by acylation. By employing 2 mol % of each 4-(pyrrolidino)pyridine (PPY) and a readily available chiral hydrogen-bonding cocatalyst, the first nonenzymatic kinetic resolution of allylic amines was accomplished with s factors of up to 20.

Facile synthesis of a chiral urea bridged bisoxazoline ligand and structural characterization of its bis-copper(II)-chloride complex.

A facile synthesis of a new bisoxazoline ligand is described. This ligand contains a urea bridging unit and is capable of stabilizing bimetallic complexes. An X-ray crystal structure of a bis-copper complex is reported.