Impact of a Primary Care Antimicrobial Stewardship Program on Bacterial Resistance Control and Ecological Imprint in Urinary Tract Infections

Antimicrobial stewardship programs (ASPs) are a central component in reducing the overprescription of unnecessary antibiotics, with multiple studies showing benefits in the reduction of bacterial resistance. Less commonly, ASPs have been performed in outpatient settings, but there is a lack of available data in these settings. We implemented an ASP in a large regional outpatient setting to assess its feasibility and effectiveness. Over a 5-year post-implementation period, compared to the pre-intervention period, a significant reduction in antibiotic prescription occurred, with a reduction in resistance in E. coli urinary isolates. ASP activities also were found to be cost-effective, with a reduction in medication prescription

Asymmetric epoxidation of electron-deficient olefins and synthetic applications

Aquest treball expandeix l'utilitat sintètica dels nitroepòxids, fent d'ells excel·lents precursors de 1,4-diazaheterocicles; com per exemple, quinoxalines, tetrahidroquinoxalines, piperazines i pirazines. Mitjançant una metodologia simple i efectiva, es poden sintetitzar fàcilment compostos saturats (piperazines, tetrahidroquinoxalines) o insaturats (quinoxalines, pirazines), controlant que les condicions siguen reductives o oxidants respectivament. També s'ha reportat la síntesi d'altres heterocicles com tiomorfolines i morfolinols. D'altra banda, s'ha exposat l'epoxidació asimètrica de nitroalquens via catàlisi per transferència de fase. S'ha elucidat i proposat un mecanisme d'acció sobre el paper del catalitazador en l'enantioselectivitat, després d'un intensiu estudi sobre les condicions de reacció. Els resultats experimentals s'han recolzat amb estudis computacionals.The present work expands the synthetic versatility of nitroepoxides and the synthesis of diverse 1,4-diazaheterocycles, including quinoxalines, piperazines, tetrahydroquinoxalines and pyrazines, has been reported. In a simple methodology, adding reductive or oxidative agents to the reaction mixture allows the formation of saturated (piperazines, tetrahydroquinoxalines) or unsaturated (quinoxalines, pyrazines) heterocycles, respectively. The synthesis of other heterocycles, such as morpholinols and thiomorpholines, is also described. The first effective asymmetric epoxidation of nitroalkenes via phase transfer catalysis is also reported. Several efforts were made to elucidate the role of the catalyst and other conditions on the enantioselectivity. Experimental observations were supported by DFT studies

Asymmetric Epoxidation of Alkylidenemalononitriles: Key Step for One-Pot Approach to Enantioenriched 3-Substituted Piperazin-2-ones

The first enantioselective epoxidation of readily available alkylidenemalononitriles has been developed by using a multifunctional cinchona derived thiourea as the organocatalyst and cumyl hydroperoxide as the oxidant. A new simple one-pot asymmetric epoxidation/SN2 ring-opening reaction with 1,2-diamines leading to important enantioenriched heterocycles, i.e. 3-substituted piperazin-2-ones, has been established

Dynamic Kinetic Asymmetric Ring-Opening/Reductive Amination Sequence of Racemic Nitroepoxides with Chiral Amines: Enantioselective Synthesis of Chiral Vicinal Diamines

We report a highly diastereoselective synthesis of vicinal diamines by the treatment of nitroepoxides with primary amines and then a reducing agent. When using a chiral primary amine, racemic nitroepoxides are transformed into chiral diamines as a single enantiomers (>95:5 er) through a dynamic kinetic asymmetric transformation (DYKAT). The overall process is a one-pot procedure combining the exposure of nitroepoxides to chiral amines to afford diastereomeric mixtures of aminoimines and subsequent stereoselective imine reduction

Nitroepoxides as Versatile Precursors to 1,4-Diamino Heterocycles

Nitroepoxides are easily transformed into 1,4-diamino heterocycles such as quinoxalines and pyrazines by treatment with 1,2-benzenediamines and ammonia, respectively. Additionally, related saturated heterocycles, such as piperazines and tetrahydroquinoxalines, can be accessed by treatment with 1,2-diamines and a reducing agent. These transformations are efficient, provide access privileged, bioactive structures, and produce minimal waste

Prevalence of Diarylprolinol Silyl Ethers as Catalysts in Total Synthesis and Patents

Diarylprolinol silyl ethers are among the most utilized stereoselective organocatalysts for the construction of complex molecules. With their debut in 2005, these catalysts have been applied in numerous method developments primarily leveraging enamine and iminium-ion catalysis. These strategies have extended into the preparation of complex molecules in both academic and industrial settings. This Review intends to give an overview of the application of the diarylprolinol silyl ether catalysts in total synthesis. Furthermore, integration of these catalysts in patent literature is also disclosed highlighting the versatility of the catalytic system

Catalytic enantioselective epoxidation of nitroalkenes

Nitroepoxides are potentially exploitable as synthons with vicinal electrophilic centers. Nevertheless, although advances have been made in the field, enantioselective epoxidation of nitroalkenes is still a challenging process. Herein we show a convenient procedure for the preparation of optically active nitroepoxides in high enantiomeric excess and high chemical yield. The kinetic data of the best catalyst have been examined using computational methods based on DFT calculations. Interestingly, the results demonstrate that the enantioselectivity of the epoxidation of nitroalkenes by this kind of catalyst is not only kinetically but also thermodynamically controlled.This work was partially supported by Spanish Ministerio de Economia y Competitividad (ref. CTQ2015-66223-C2-1-P), Generalitat Valenciana (PROMETEOII/2014/022), and the Polish Ministry of Science and Higher Education ("Iuventus Plus'' project 0478/IP3/2015/73, 2015-2016). A. V.-A. thanks Generalitat Valenciana for a PhD grant (VALi+D Program). We thank Serveis Centrals d'Instrumentacio Cientifica and the Servei d'Informatica of Universitat Jaume I for technical support and computational resources, respectively

Structure-activity relationships reveal beneficial selectivity profiles of inhibitors targeting acetylcholinesterase of disease-transmitting mosquitoes

Insecticide resistance jeopardizes the prevention of infectious diseases such as malaria and dengue fever by vector control of disease-transmitting mosquitoes. Effective new insecticidal compounds with minimal adverse effects on humans and the environment are therefore urgently needed. Here, we explore noncovalent inhibitors of the well-validated insecticidal target acetylcholinesterase (AChE) based on a 4-thiazolidinone scaffold. The 4-thiazolidinones inhibit AChE1 from the mosquitoes Anopheles gambiae and Aedes aegypti at low micromolar concentrations. Their selectivity depends primarily on the substitution pattern of the phenyl ring; halogen substituents have complex effects. The compounds also feature a pendant aliphatic amine that was important for activity; little variation of this group is tolerated. Molecular docking studies suggested that the tight selectivity profiles of these compounds are due to competition between two binding sites. Three 4-thiazolidinones tested for in vivo insecticidal activity had similar effects on disease-transmitting mosquitoes despite a 10-fold difference in their in vitro activity

Mycorrhiza l tomato plants fine tunes the growth‐defencebalance upon N depleted root environments

In low nutritive environments, the uptake of N by arbuscular mycorrhizal (AM) fungi may confercompetitive advantages for the host. The present study aims to understand how mycorrhizaltomato plants perceive and then prepare for an N depletion in the root environment. Plantscolonized by Rhizophagus irregularis displayed improved responses to a lack of N thannonmycorrhizal (NM) plants. These responses were accomplished by a complex metabolic andtranscriptional rearrangement that mostly affected the gibberellic acid and jasmonic acid path-ways involving DELLA and JAZ1 genes, which were responsive to changes in the C/N imbalanceof the plant. N starved mycorrhizal plants showed lower C/N equilibrium in the shoots thanstarved NM plants and concomitantly a downregulation of the JAZ1 repressor and the increasedexpression of the DELLA gene, which translated into a more active oxylipin pathway in mycorrhi-zal plants. In addition, the results support a priorization in AM plants of stress responses overgrowth. Therefore, these plants were better prepared for an expected stress. Furthermore, mostmetabolites that were severely reduced in NM plants following the N depletion remained unal-tered in starved AM plants compared with those normally fertilized, suggesting that the symbiosisbuffered the stress, improving plant development in a stressed environment

Structure-function study of a Ca2+-independent metacaspase involved in lateral root emergence

Metacaspases are part of an evolutionarily broad family of multifunctional cysteine proteases, involved in disease and normal development. As the structure–function relationship of metacaspases remains poorly understood, we solved the X-ray crystal structure of an Arabidopsis thaliana type II metacaspase (AtMCA-IIf) belonging to a particular subgroup not requiring calcium ions for activation. To study metacaspase activity in plants, we developed an in vitro chemical screen to identify small molecule metacaspase inhibitors and found several hits with a minimal thioxodihydropyrimidine-dione structure, of which some are specific AtMCA-IIf inhibitors. We provide mechanistic insight into the basis of inhibition by the TDP-containing compounds through molecular docking onto the AtMCA-IIf crystal structure. Finally, a TDP-containing compound (TDP6) effectively hampered lateral root emergence in vivo, probably through inhibition of metacaspases specifically expressed in the endodermal cells overlying developing lateral root primordia. In the future, the small compound inhibitors and crystal structure of AtMCA-IIf can be used to study metacaspases in other species, such as important human pathogens, including those causing neglected diseases