The rise of multidrug-resistant (MDR) Gram-negative bacteria is a major global health problem necessitating the discovery of new classes of antibiotics. Novel bacterial topoisomerase inhibitors (NBTIs) target the clinically validated bacterial type II topoisomerases with a distinct binding site and mechanism of action to fluoroquinolone antibiotics, thus avoiding cross-resistance to this drug class. Here we report the discovery of a series of NBTIs incorporating a novel indane DNA binding moiety. X-ray cocrystal structures of compounds 2 and 17a bound to Staphylococcus aureus DNA gyrase–DNA were determined, revealing specific interactions with the enzyme binding pocket at the GyrA dimer interface and a long-range electrostatic interaction between the basic amine in the linker and the carboxylate of Asp83. Exploration of the structure–activity relationship within the series led to the identification of lead compound 18c, which showed potent broad-spectrum activity against a panel of MDR Gram-negative bacteria.

The AAA+ ATPase p97 (valosin-containing protein, VCP) is a master regulator of protein homeostasis and therefore represents a novel target for cancer therapy. Starting from a known allosteric inhibitor, NMS-873, we systematically optimized this scaffold, in particular, by applying a benzene-to-acetylene isosteric replacement strategy, specific incorporation of F, and eutomer/distomer identification, which led to compounds that exhibited nanomolar biochemical and cell-based potency. In cellular pharmacodynamic assays, robust effects on biomarkers of p97 inhibition and apoptosis, including increased levels of ubiquitinated proteins, CHOP and cleaved caspase 3, were observed. Compound (R)-29 (UPCDC-30766) represents the most potent allosteric inhibitor of p97 reported to date.

Provided herein are novel lactams as Cbl-b inhibitors, pharmaceutical compositions, use of such compounds in treating cancer, and processes for preparing such compounds.

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We present a novel concept for the design of supersoft topical drugs. Enzymatic cleavage of the carbonate ester of the potent pan Janus kinase (JAK) inhibitor 2 releases hydroxypyridine 3. Due to hydroxypyridine-pyridone tautomerism, 3 undergoes a rapid conformational change preventing the compound to assume the bioactive conformation required for binding to JAK kinases. We demonstrate that the hydrolysis in human blood and the subsequent shape change lead to the deactivation of 2.

Provided herein are cyclopentathiophene carboxamide derivatives as platelet activating factor receptor (PAFR) antagonists, pharmaceutical compositions, use of such compounds in treating ocular diseases, allergies, and inflammation-related disorders, and processes for preparing such compounds.

The role of peroxisome proliferator-activated receptor alpha (PPARα) in retinal biology is clarifying, and evidence demonstrates that novel PPARα agonists hold promising therapeutic utility for diseases like diabetic retinopathy and age-related macular degeneration. Herein, we disclose the design and initial structure–activity relationships for a new biaryl aniline PPARα agonistic chemotype. Notably, this series exhibits subtype selectivity for PPARα over other isoforms, a phenomenon postulated to be due to the unique benzoic acid headgroup. This biphenyl aniline series is sensitive to B-ring functionalization but allows isosteric replacement, and provides an opportunity for C-ring extension. From this series, 3g, 6j, and 6d were identified as leads with <90 nM potency in a cell-based luciferase assay cell and exhibited efficacy in various disease-relevant cell contexts, thereby setting the stage for further characterization in more advanced in vitro and in vivo models.

A novel photocaged PI3K inhibitor 2 was designed and synthesized by introducing a cascade photocaging group to block its key interaction with the kinase. Upon UV light irradiation, the photocaged compound released a highly potent PI3K inhibitor to recover its anticancer properties and a fluorescent dye for real-time reporting of drug release, providing a new approach for studying the PI3K signaling transduction pathway as well as developing precisely controlled cancer therapeutics.

Glutamate plays a key role in cognition and mood, and it has been shown that inhibiting ionotropic glutamate receptors disrupts cognition, while enhancing ionotropic receptor activity is pro-cognitive. One approach to elevating glutamatergic tone has been to antagonize presynaptic metabotropic glutamate receptor 2 (mGluR2). A desire for selectivity over the largely homologous mGluR3 motivated a strategy to achieve selectivity through the identification of mGluR2 negative allosteric modulators (NAMs). Extensive screening and optimization efforts led to the identification of a novel series of 4-arylquinoline-2-carboxamides. This series was optimized for mGluR2 NAM potency, clean off-target activity, and desirable physical properties, which resulted in the identification of improved C4 and C7 substituents. The initial lead compound from this series was Ames-positive in a single strain with metabolic activation, indicating that a reactive metabolite was likely responsible for the genetic toxicity. Metabolic profiling and Ames assessment across multiple analogs identified key structure–activity relationships associated with Ames positivity. Further optimization led to the Ames-negative mGluR2 negative allosteric modulator MK-8768.

A targeted bibliographic search exposed the deficiencies within existing PROTAC preclinical pipelines, including missing, poor-quality data and technical limitations in the experimental assays. Several recommendations are proposed to improve the efficiency of preclinical platforms for PROTACs.

The activation of PINK1 by small molecules has emerged as a promising strategy in treating Parkinson’s disease (PD). Recent progress in this area has raised excitement around PINK1 activators as PD treatments, and herein we offer insight into these developments and their potential to deliver much needed novel PD treatments.

Parkinson’s Disease (PD) is a neurodegenerative movement disorder characterized by symptoms like resting tremor, rigidity, bradykinesia, and postural instability, mainly due to dopamine depletion and degeneration of dopaminergic neurons. Mitochondrial dysfunction plays a critical role in the disease’s progression, while amyotrophic Lateral Sclerosis (ALS), or Lou Gehrig’s disease, is a fatal progressive neurodegenerative disease characterized by significant motor neuron loss in the primary motor cortex, brainstem, and spinal cord. This loss results in impaired movements such as breathing, leading to death within 2–5 years of diagnosis. Patients experience muscle weakness in the hands, arms, legs, and swallowing muscles and may require breathing aids. This Patent Highlight describes blends, such as microbiome compositions, that can be used to treat various diseases or conditions, particularly those affecting the nervous system, like neurodegenerative diseases (PD and ALS).

Provided herein are novel nitrogen-containing 2,3-dihydroquinazolinone compounds as Nav1.8 inhibitors, pharmaceutical compositions, use of such compounds in treating pain and cardiovascular diseases, and processes for preparing such compounds.

Platinum–acridine anticancer agents (PAs) containing acyclic (1 and 3) and heterocyclic (R)-3-aminopiperidine (2) and 2-iminopyrrolidine (4) based linker moieties were studied. Similar to 1, rigidified 2 shows a strong positive correlation between potency and SLC47A1 (multidrug and toxin extrusion protein 1, MATE1) gene expression levels across the NCI-60 panel of cancer cell lines. All derivatives show nanomolar activity in HepG2 (liver), NCI-H460 (lung), and MDA-MB-436 (breast), which express high levels of SLC47A1 (Cancer Cell Line Encyclopedia, CCLE). The PAs are up to 350-fold more potent than cisplatin. In a MATE1 inhibition assay, a significant reduction in activity is observed in the three cancer cell lines (4000-fold lower for HepG2). Molecular docking experiments provide insight into the compatibility of the structurally diverse set of PAs with MATE1-mediated transport. MATE1 is a predictive marker and actionable target that sensitizes cancer cells regardless of the tissue of origin to PAs.

4′-Phosphopantetheinyl transferase (PptT) is an essential enzyme for Mycobacterium tuberculosis (Mtb) survival and virulence and therefore an attractive target for a tuberculosis therapeutic. In this work, two modeling-informed approaches toward the isosteric replacement of the amidinourea moiety present in the previously reported PptT inhibitor AU 8918 are reported. Although a designed 3,5-diamino imidazole unexpectedly adopted an undesired tautomeric form and was inactive, replacement of the amidinourea moiety afforded a series of active PptT inhibitors containing 2,6-diaminopyridine scaffolds.

Depression is a widespread issue in the United States and the leading cause of disability globally, impacting people of all ages. Although selective serotonin reuptake inhibitors (SSRIs) are commonly used for treatment, they have limited effectiveness and may take weeks to show results. There is a pressing need for fast and effective solutions for various types of depression, including chronic, clinical, situational, and undiagnosed cases. Alternative interventions are necessary not only for diagnosed depression but also for enhancing creativity, mindfulness, sexual desire, and overall well-being in individuals without a medical diagnosis of depression. This Patent Highlight discloses compositions designed to reduce inflammation and improve or maintain mental and physical health. These compositions target issues like depression, pain, mood disorders, anxiety, PTSD, digestive problems, relaxation, focus, creativity, and aim to decrease reliance on pharmaceutical and illicit drugs. The compositions involve combinations of at least one 5-HT2A serotonin receptor agonist and one TRP receptor agonist, possibly including a TRP receptor antagonist.

Dicobalt hexacarbonyl 5-alkynyl furopyrimidine nucleoside analogs, with 4-methylphenyl (p-tolyl) and 4-pentylphenyl substituents attached at the C-6 base position, designed in the form of ribose acetyl esters, were synthesized (42–96%). Attached at the C-5 position were propargyl alcohol, its methyl ether and acetate derivatives, butynol, and the 4-methylphenyl- (p-tolyl) and 4-pentylphenyl-substituted alkynyl groups, which were coordinated to a dicobalt hexacarbonyl unit. The structure of 5-(3-acetoxyprop-1-yn-1-yl)-6-p-tolyl-2′-deoxyribofuranosyl-furo[2,3-d]pyrimidin-2-one was determined by X-ray crystallography. Density functional theory calculations performed on the corresponding derivative yielded geometric parameters for the dicobalt hexacarbonyl adduct of this ligand. The cytotoxic activity of each of dicobalt modified nucleosides on cancer cells of different phenotypes was determined in vitro. The investigated compounds showed antiproliferative effects with median inhibitory concentration (IC50) values in the ranges of 14–90 and 9–50 μM for HeLa and K562 cells, respectively. The formation of reactive oxygen species in the presence of modified nucleosides was determined in K562 cells. The results indicate that the mechanism of action for the studied compounds may be related to the induction of oxidative stress.

Provided herein are novel pyrazoloquinoline compounds as KRAS inhibitors, their pharmaceutical compositions, the use of such compounds in treating cancer, and processes for preparing such compounds.

Pyrimidine is a ubiquitous component in natural products and approved drugs, providing an ideal modular scaffold for generating libraries with drug-like properties. DNA-encoded library technology introduces a novel library modality where each small molecule is covalently linked to a unique oligo tag. This technology offers the advantages of rapidly generating and interrogating large-scale libraries containing billions of members, substantially reducing the entry barrier to their use in both academia and the pharmaceutical industry. In this Letter, we describe the synthesis of three DNA-encoded libraries based on different functionalized pyrimidine cores featuring diversified chemoselectivity and regioselectivity. Preliminary screening of these DNA-encoded libraries against BRD4 identified compounds with nanomolar inhibition activities.

This viewpoint outlines the case for developing new chemical entities (NCEs) as racemates in infectious diseases and where both enantiomers and racemate retain similar on- and off-target activities as well as similar PK profiles. There are not major regulatory impediments for the development of a racemic drug, and minimizing the manufacturing costs becomes a particularly important objective when bringing an anti-infective therapeutic to the marketplace in the endemic settings of infectious diseases.