Design, synthesis, molecular docking, and molecular dynamic studies of novel quinazoline derivatives as phosphodiesterase 7 inhibitors.

Introduction: Phosphodiesterase 7 (PDE7) is a high-affinity cyclic AMP (cAMP)-specific PDE that is expressed in immune and proinflammatory cells. In this work, we explore the possibility that selective small molecule inhibitors of this enzyme family could provide a novel approach to alleviate the inflammation that is associated with many inflammatory diseases. Methods: A series of novel substituted 4-hydrazinoquinazoline derivatives and fused triazoloquinazolines were designed, synthesized, and evaluated in vitro for their PDE7A inhibition activities, in comparison with Theophylline, a non-selective PDE inhibitor, and BRL50481, a selective PDE7A inhibitor. This series of novel quinazoline derivatives were synthesized via multi-step reactions. The reaction sequence began with selective monohydrazinolysis of compounds 2a,b to give 3a,b. Schiff bases 4a-h were synthesized by the reaction of the quinazolylhydrazines 3a,b with various substituted aromatic aldehydes. The reaction of 4a-h with bromine in acetic acid, in turn, gave fused triazoloquinazolines 5a-h. These compounds were characterized by satisfied spectrum analyses mainly including 1HNMR, 13CNMR, and MS together with elemental analyses. Results and discussion: The results of in vitro PDE7A inhibition activity clearly indicated that compounds 4b, 4g, 5c, and 5f exhibited good potency. Molecular docking and molecular dynamic simulation studies further supported our findings and provided the basis of interaction in terms of conventional hydrogen bonds and π-π stacking patterns. The present results lay the groundwork for developing lead compounds with improved phosphodiesterase seven inhibitory activities.

Comparison of three current Clostridioides difficile infection guidelines: IDSA/SHEA, ESCMID, and ACG guidelines.

PURPOSE: Clostridioides difficile infection (CDI) is a widely recognized condition associated with comorbidity and decreased patient quality of life. Certain professional medical organizations develop clinical practice guidelines for major diseases. This is done in an effort to streamline the universal clinical practice and ensure that a more accurate diagnosis and better treatments are offered to respective patients for optimal outcomes. However, as new data evolve, constant update of these guidelines becomes essential. While these guidelines provide up-to-date recommendations, they are not published around the same time; thus, their recommendations may vary depending on evidence available prior to guidelines preparation and publication. METHODS: Recommendations and corresponding justifications from three major CDI guidelines between 2013 and 2017 were pooled and compared, and notable differences were highlighted while providing an insight and a final recommendation from a clinical standpoint. RESULTS: Most recommendations were consistent among all three guidelines. One notable difference was in the specification of candidates for CDI diagnosis, where it would be recommended to mainly test patients with three or more diarrheal episodes over 24 h, if they had no other clear reason for the diarrhea. Another conflicting point was regarding the treatment of non-severe CDI where vancomycin can be considered for older or sicker patients; however, metronidazole still remains a reasonable option based on recent data, some of which were not cited in the most recent guidelines of IDSA/SHEA. CONCLUSION: Overall, it is prudent to follow these guidelines with critical appraisal to fulfill the goal of achieving optimum patient outcomes.