A novel tricyclic ß-lactam exhibiting potent antibacterial activities against carbapenem-resistant Enterobacterales: Synthesis and structure-activity-relationships.

A series of tricyclic ß-lactams were synthesized and evaluated for in vitro antibacterial activities against carbapenem-resistant Enterobacterales (CREs). Starting from a reported tricyclic ß-lactam that combined the cephalosporin skeleton having a γ-lactone ring with a carboxylic acid group, which was reported as a unique partial structure of Lactivicin, we identified the compound which shows potent antibacterial activities against all tested CREs by introducing sulfoxide. In addition, the sulfoxide-introduced tricyclic ß-lactam also shows a strong therapeutic efficacy in the neutropenic mouse lung infection model. These results indicate that the tricyclic ß-lactam skeleton will show sufficient therapeutic performance in clinical use and therefore can serve as a scaffold in the search for new antibacterial agents against CREs.

Synthesis and SAR Study of Carbamoyl Pyridone Bicycle Derivatives as Potent Inhibitors of Influenza Cap-dependent Endonuclease.

The medicinal chemistry and structure-activity relationships (SAR) for a novel series of carbamoyl pyridone bicycle (CAB) compounds as influenza Cap-dependent endonuclease (CEN) inhibitors are disclosed. Substituent effects were evaluated at the C (N)-1, N-3, and C-7 positions of the CAB ring system using a docking study. Submicromolar EC50 values were achieved in the cellular assay with C-7-unsubstituted CAB which possessed a benzhydryl group on either the C-1 or the N-1 position. An N-3 substituent was found to be critical for the plasma protein binding effect in vitro, and the CAB-N analogue 2v exhibited reasonable total clearance (CLtot). More importantly, compound 2v displayed significant efficacy in a mouse model infected with influenza viruses.

Indazole-based potent and cell-active Mps1 kinase inhibitors: rational design from pan-kinase inhibitor anthrapyrazolone (SP600125).

Monopolar spindle 1 (Mps1) is essential for centrosome duplication, the spindle assembly check point, and the maintenance of chromosomal instability. Mps1 is highly expressed in cancer cells, and its expression levels correlate with the histological grades of cancers. Thus, selective Mps1 inhibitors offer an attractive opportunity for the development of novel cancer therapies. To design novel Mps1 inhibitors, we utilized the pan-kinase inhibitor anthrapyrazolone (4, SP600125) and its crystal structure bound to JNK1. Our design efforts led to the identification of indazole-based lead 6 with an Mps1 IC50 value of 498 nM. Optimization of the 3- and 6-positions on the indazole core of 6 resulted in 23c with improved Mps1 activity (IC50 = 3.06 nM). Finally, application of structure-based design using the X-ray structure of 23d bound to Mps1 culminated in the discovery of 32a and 32b with improved potency for cellular Mps1 and A549 lung cancer cells. Moreover, 32a and 32b exhibited reasonable selectivities over 120 and 166 kinases, respectively.

Diaminopyridine-based potent and selective mps1 kinase inhibitors binding to an unusual flipped-Peptide conformation.

Monopolar spindle 1 (Mps1) is an attractive cancer drug target due to the important role that it plays in centrosome duplication, the spindle assembly checkpoint, and the maintenance of chromosomal stability. A design based on JNK inhibitors with an aminopyridine scaffold and subsequent modifications identified diaminopyridine 9 with an IC50 of 37 nM. The X-ray structure of 9 revealed that the Cys604 carbonyl group of the hinge region flips to form a hydrogen bond with the aniline NH group in 9. Further optimization of 9 led to 12 with improved cellular activity, suitable pharmacokinetic profiles, and good in vivo efficacy in the mouse A549 xenograft model. Moreover, 12 displayed excellent selectivity over 95 kinases, indicating the contribution of its unusual flipped-peptide conformation to its selectivity.

Structure-based CoMFA as a predictive model - CYP2C9 inhibitors as a test case.

In this study, we tried to establish a general scheme to create a model that could predict the affinity of small compounds to their target proteins. This scheme consists of a search for ligand-binding sites on a protein, a generation of bound conformations (poses) of ligands in each of the sites by docking, identifications of the correct poses of each ligand by consensus scoring and MM-PBSA analysis, and a construction of a CoMFA model with the obtained poses to predict the affinity of the ligands. By using a crystal structure of CYP 2C9 and the twenty known CYP inhibitors as a test case, we obtained a CoMFA model with a good statistics, which suggested that the classification of the binding sites as well as the predicted bound poses of the ligands should be reasonable enough. The scheme described here would give a method to predict the affinity of small compounds with a reasonable accuracy, which is expected to heighten the value of computational chemistry in the drug design process.