Novel pyrazolo[3,4-d]pyrimidines as dual Src/Bcr-Abl kinase inhibitors: Synthesis and biological evaluation for chronic myeloid leukemia treatment.

The Bcr-Abl tyrosine kinase (TK) is the molecular hallmark of chronic myeloid leukemia (CML). Src is another TK kinase whose involvement in CML was widely demonstrated. Small molecules active as dual Src/Bcr-Abl inhibitors emerged as effective targeted therapies for CML and a few compounds are currently in clinical use. In this study, we applied a target-oriented approach to identify a family of pyrazolo[3,4-d]pyrimidines as dual Src/Bcr-Abl inhibitors as anti-leukemia agents. Considering the high homology between Src and Bcr-Abl, in-house Src inhibitors 8a-l and new analogue compounds 9a-n were screened as dual Src/Bcr-Abl inhibitors. The antiproliferative activity on K562 CML cells and the ADME profile were determined for the most promising compounds. Molecular modeling studies elucidated the binding mode of the inhibitors into the Bcr-Abl (wt) catalytic pocket. Compounds 8j and 8k showed nanomolar activities in enzymatic and cellular assays, together with favorable ADME properties, emerging as promising candidates for CML therapy. Finally, derivatives 9j and 9k, emerging as valuable inhibitors of the most aggressive Bcr-Abl mutation, T315I, constitute a good starting point in the search for compounds able to treat drug-resistant forms of CML. Overall, this study allowed us to identify more potent compounds than those previously reported by the group, marking a step forward in searching for new antileukemic agents.

The Rise of Bacterial G-Quadruplexes in Current Antimicrobial Discovery.

Antimicrobial resistance (AMR) is a silent critical issue that poses several challenges to health systems. While the discovery of novel antibiotics is currently stalled and prevalently focused on chemical variations of the scaffolds of available drugs, novel targets and innovative strategies are urgently needed to face this global threat. In this context, bacterial G-quadruplexes (G4s) are emerging as timely and profitable targets for the design and development of antimicrobial agents. Indeed, they are expressed in regulatory regions of bacterial genomes, and their modulation has been observed to provide antimicrobial effects with translational perspectives in the context of AMR. In this work, we review the current knowledge of bacterial G4s as well as their modulation by small molecules, including tools and techniques suitable for these investigations. Finally, we critically analyze the needs and future directions in the field, with a focus on the development of small molecules as bacterial G4s modulators endowed with remarkable drug-likeness.