Discovery of Pyrrolidine-2,3-diones as Novel Inhibitors of P. aeruginosa PBP3.

The alarming threat of the spread of multidrug resistant bacteria currently leaves clinicians with very limited options to combat infections, especially those from Gram-negative bacteria. Hence, innovative strategies to deliver the next generation of antibacterials are urgently needed. Penicillin binding proteins (PBPs) are proven targets inhibited by ß-lactam antibiotics. To discover novel, non-ß-lactam inhibitors against PBP3 of Pseudomonas aeruginosa, we optimised a fluorescence assay based on a well-known thioester artificial substrate and performed a target screening using a focused protease-targeted library of 2455 compounds, which led to the identification of pyrrolidine-2,3-dione as a potential scaffold to inhibit the PBP3 target. Further chemical optimisation using a one-pot three-component reaction protocol delivered compounds with excellent target inhibition, initial antibacterial activities against P. aeruginosa and no apparent cytotoxicity. Our investigation revealed the key structural features; for instance, 3-hydroxyl group (R2) and a heteroaryl group (R1) appended to the N-pyrroldine-2,3-dione via methylene linker required for target inhibition. Overall, the discovery of the pyrrolidine-2,3-dione class of inhibitors of PBP3 brings opportunities to target multidrug-resistant bacterial strains and calls for further optimisation to improve antibacterial activity against P. aeruginosa.

From Pyrazolones to Azaindoles: Evolution of Active-Site SHP2 Inhibitors Based on Scaffold Hopping and Bioisosteric Replacement.

The tyrosine phosphatase SHP2 controls the activity of pivotal signaling pathways, including MAPK, JAK-STAT, and PI3K-Akt. Aberrant SHP2 activity leads to uncontrolled cell proliferation, tumorigenesis, and metastasis. SHP2 signaling was recently linked to drug resistance against cancer medications such as MEK and BRAF inhibitors. In this work, we present the development of a novel class of azaindole SHP2 inhibitors. We applied scaffold hopping and bioisosteric replacement concepts to eliminate unwanted structural motifs and to improve the inhibitor characteristics of the previously reported pyrazolone SHP2 inhibitors. The most potent azaindole 45 inhibits SHP2 with an IC50 = 0.031 µM in an enzymatic assay and with an IC50 = 2.6 µM in human pancreas cells (HPAF-II). Evaluation in a series of cellular assays for metastasis and drug resistance demonstrated efficient SHP2 blockade. Finally, 45 inhibited proliferation of two cancer cell lines that are resistant to cancer drugs and diminished ERK signaling.

A Palladium-Catalyzed Domino Reaction To Access 3-Amino-2H-indazoles from Hydrazines and 2-Halobenzonitriles.

The development of a novel selective synthesis of 3-amino-2H-indazoles from readily available 2-halobenzonitriles is presented. The reaction proceeds through a domino reaction sequence, consisting of a regioselective palladium-catalyzed coupling of monosubstituted hydrazines with 2-halobenzonitriles, followed by an intramolecular hydroamination through a 5-exo-dig cyclization and subsequent isomerization to directly afford a wide variety of substituted 2H-indazole analogues in good to excellent yields.