Synthesis, biological evaluation and molecular docking studies of novel 1,2,3-triazole-quinazolines as antiproliferative agents displaying ERK inhibitory activity.

ERK1/2 inhibitors have attracted special attention concerning the ability of circumventing cases of innate or log-term acquired resistance to RAF and MEK kinase inhibitors. Based on the 4-aminoquinazoline pharmacophore of kinases, herein we describe the synthesis of 4-aminoquinazoline derivatives bearing a 1,2,3-triazole stable core to bridge different aromatic and heterocyclic rings using copper-catalysed azide-alkyne cycloaddition reaction (CuAAC) as a Click Chemistry strategy. The initial screening of twelve derivatives in tumoral cells (CAL-27, HN13, HGC-27, and BT-20) revealed that the most active in BT-20 cells (25a, IC50 24.6 µM and a SI of 3.25) contains a more polar side chain (sulfone). Furthermore, compound 25a promoted a significant release of lactate dehydrogenase (LDH), suggesting the induction of cell death by necrosis. In addition, this compound induced G0/G1 stalling in BT-20 cells, which was accompanied by a decrease in the S phase. Western blot analysis of the levels of p-STAT3, p-ERK, PARP, p53 and cleaved caspase-3 revealed p-ERK1/2 and p-STA3 were drastically decreased in BT-20 cells under 25a incubation, suggesting the involvement of these two kinases in the mechanisms underlying 25a-induced cell cycle arrest, besides loss of proliferation and viability of the breast cancer cell. Molecular docking simulations using the ERK-ulixertinib crystallographic complex showed compound 25a could potentially compete with ATP for binding to ERK in a slightly higher affinity than the reference ERK1/2 inhibitor. Further in silico analyses showed comparable toxicity and pharmacokinetic profiles for compound 25a in relation to ulixertinib.

A Scoping Review of Pharmacists' and Pharmacy Students' Knowledge, Skills, and Attitudes in Medical Emergencies.

OBJECTIVES: Competence can be defined as a set of knowledge, skills, and attitudes. In a medical emergency scenario, competent pharmacists are increasingly required, mainly as a result of the expansion of professional functions in this context. Therefore, the objective of this study was to map the scientific evidence that shows the development of knowledge and/or skills, and/or attitudes in the training of pharmacists and pharmacy students to work in emergency care. FINDINGS: The scoping review was conducted in the PubMed, Embase, Latin American and Caribbean Health Sciences Literature, Scopus, Web of Science, and Cumulative Index to Nursing and Allied Health Literature databases in January 2021, as recommended by the Joanna Briggs Institute. Our study retrieved 6276 files, and 31 articles met the inclusion criteria. It was observed that the studies were developed mainly in the United States of America and addressed the development and/or assessment of knowledge and skills, and training in cardiac emergencies. The most used teaching strategy was simulation, and the most used assessment strategy was feedback and/or debriefing. SUMMARY: Publications involving the development of at least 1 domain of clinical competence have increased in the last decade. Thus, the mapping of studies has provided subsidies for identifying gaps in the teaching-learning process, as well as the identification of methodologies applied in the development and assessment of clinical competence for the referred population.