Synthesis and evaluation of quinazolin-4-ones as hypoxia-inducible factor-1α inhibitors.

Quinazolin-4-one 1 was identified as an inhibitor of the HIF-1α transcriptional factor from a high-throughput screen. HIF-1α up-regulation is common in many cancer cells. In this Letter, we describe an efficient one-pot sequential reaction for the synthesis of quinazolin-4-one 1 analogues. The structure-activity relationship (SAR) study led to the 5-fold more potent analogue, 16.

Synthesis and antibacterial activity of 6-O-arylbutynyl ketolides with improved activity against some key erythromycin-resistant pathogens.

A series of novel 6-O-substituted homopropargyl ketolides was synthesized and evaluated against various erythromycin-resistant pathogens. Promising in vitro antibacterial activity was demonstrated for compounds bearing this structural motif.

Identification of Potent and Selective Diphenylpropanamide RORγ Inhibitors.

Retinoic acid-related orphan receptor RORγt plays a pivotal role in the differentiation of TH17 cells. Antagonizing RORγt transcriptional activity is a potential means to treat TH17-related autoimmune diseases. Herein, we describe the identification of a series of diphenylpropanamides as novel and selective RORγ antagonists. Diphenylpropanamide 4n inhibited transcriptional activity of RORγt, but not RORα, in cells. In addition, it suppressed human TH17 cell differentiation at sub-micromolar concentrations.

The Synthesis and Evaluation of Dihydroquinazolin-4-ones and Quinazolin-4-ones as Thyroid Stimulating Hormone Receptor Agonists.

We herein describe the rapid synthesis of a diverse set of dihydroquinazolin-4-ones and quinazolin-4-ones, their biological evaluation as thyroid stimulating hormone receptor (TSHR) agonists, and SAR analysis. Among the compounds screened, 8b was 60-fold more potent than the hit compound 1a, which was identified from a high throughput screen of over 73,000 compounds.

Novel antibacterial class.

We report the discovery and characterization of a novel ribosome inhibitor (NRI) class that exhibits selective and broad-spectrum antibacterial activity. Compounds in this class inhibit growth of many gram-positive and gram-negative bacteria, including the common respiratory pathogens Streptococcus pneumoniae, Haemophilus influenzae, Staphylococcus aureus, and Moraxella catarrhalis, and are nontoxic to human cell lines. The first NRI was discovered in a high-throughput screen designed to identify inhibitors of cell-free translation in extracts from S. pneumoniae. The chemical structure of the NRI class is related to antibacterial quinolones, but, interestingly, the differences in structure are sufficient to completely alter the biochemical and intracellular mechanisms of action. Expression array studies and analysis of NRI-resistant mutants confirm this difference in intracellular mechanism and provide evidence that the NRIs inhibit bacterial protein synthesis by inhibiting ribosomes. Furthermore, compounds in the NRI series appear to inhibit bacterial ribosomes by a new mechanism, because NRI-resistant strains are not cross-resistant to other ribosome inhibitors, such as macrolides, chloramphenicol, tetracycline, aminoglycosides, or oxazolidinones. The NRIs are a promising new antibacterial class with activity against all major drug-resistant respiratory pathogens.