Hydrogen Bonding Parameters by Rapid Colorimetric Assessment: Evaluation of Structural Components Found in Biological Ligands and Organocatalysts.

Hydrogen bonding is a key molecular interaction in biological processes, drug delivery, and catalysis. This report describes a high throughput UV-Vis spectroscopic method to measure hydrogen bonding capacity using a pyrazinone sensor. This colormetric sensor reversibly binds to a hydrogen bond donor, resulting in a blue shift as additional equivalents of donor are added. Titration with excess equivalents of donor is used to determine the binding coefficient, ln(Keq ). Over 100 titrations were performed for a variety of biologically relevant compounds. This data enabled development a multiple linear regression model that is capable of predicting 95 % of ln(Keq ) values within 1 unit, allowing for the estimation of hydrogen bonding affinity from a single measurement. To show the effectiveness of the single point measurements, hydrogen bond strengths were obtained for a set of carboxylic acid bioisosteres. The values from the single point measurements were validated with full titrations.

Total Syntheses of Clausenawallines A and E.

The first total syntheses of glycoborinine, clausenawalline A, and clausenawalline E were achieved. The key step employed a vanadium-catalyzed oxidative coupling of two hydroxycarbazole monomers. High-throughput experimentation was used to identify conditions favoring selective heterocoupling of these monomers that possess similar redox potentials. A combination of a vanadium catalyst and 4-acetamido-TEMPO gives rise to greatly enhanced cross selectivity relative to the vanadium catalyst alone. Conditions to selectively form homodimer clausenawalline A or heterodimer clausenawalline E as the major product were found.

Modifications to a Biphenolic Antibacterial Compound: Activity against ESKAPE Pathogens.

Forty-four analogs of honokiol, a compound with known antibacterial activity, especially with respect to oral bacteria, were synthesized to explore the structure-activity relationships against the ESKAPE pathogens. Compounds with high therapeutic indices (hemolysis20 /MIC) were identified. In particular, ester-linked compounds that would be less than environmentally durable than biaryl ether antibacterials such as the broadly used triclosan were found to be active. MRSA mutants could be generated against some, but not all, of the highly active compounds. Based on gene sequencing results, membrane permeability, intracellular sodium, and intracellular pH assays revealed overlapping mechanisms of action.

Modification of Biphenolic Anti-Bacterial to Achieve Broad-Spectrum Activity.

The Gram-positive bacteria, methicillin-resistant Staphylococcus aureus (MRSA) and Gram-negative bacteria, Acinetobacter baumannii, are pathogens responsible for millions of nosocomial infections worldwide. Due to the threat of bacteria evolving resistance to antibiotics, scientists are constantly looking for new classes of compounds to treat infectious diseases. The biphenolic analogs of honokiol that were most potent against oral bacteria had similar bioactivity against MRSA. However, all the compounds proved ineffective against A. baumannii. The inability to inhibit A. baumannii is due to the difficult-to-penetrate lipopolysaccharide-coated outer membrane that makes it challenging for antibiotics to enter Gram-negative bacteria. The C 2 scaffold was optimized from the inhibition of Gram-positive bacteria to broad-spectrum antibacterial compounds that inhibit the dangerous Gram-negative pathogen A. baumannii.

Discovery of an Orally Bioavailable and Central Nervous System (CNS) Penetrant mGlu7 Negative Allosteric Modulator (NAM) in Vivo Tool Compound: N-(2-(1 H-1,2,4-triazol-1-yl)-5-(trifluoromethoxy)phenyl)-4-(cyclopropylmethoxy)-3-methoxybenzamide (VU6012962).

Herein, we report the discovery of a new, orally bioavailable and CNS-penetrant metabotropic glutamate receptor 7 (mGlu7) negative allosteric modulator (NAM) that achieves exposure in cerebral spinal fluid (CSF) 2.5× above the in vitro IC50 at minimum effective doses (MEDs) of 3 mg/kg in preclinical anxiety models.

VU6010608, a Novel mGlu7 NAM from a Series of N-(2-(1H-1,2,4-Triazol-1-yl)-5-(trifluoromethoxy)phenyl)benzamides.

Herein, we report the structure-activity relationships within a series of mGlu7 NAMs based on an N-(2-(1H-1,2,4-triazol-1-yl)-5-(trifluoromethoxy)phenyl)benzamide core with excellent CNS penetration (Kp 1.9-5.8 and Kp,uu 0.4-1.4). Analogues in this series displayed steep SAR. Of these, VU6010608 (11a) emerged with robust efficacy in blocking high frequency stimulated long-term potentiation in electrophysiology studies.