Late-Stage Diversification of Pyrazoles as Antileishmanial Agents.

N-Pyrazolylcarboxamides and N-pyrazolylureas represent promising lead compounds for the development of novel antileishmanial drugs. Herein, we report the late-stage diversification of 3-bromopyrazoles 10 A/B and 14 A by Pd-catalyzed Sonogashira and Suzuki-Miyaura cross coupling reactions. The electron-withdrawing properties of the cyano moiety in 4-position of the pyrazole ring limited the acylation of the primary amino moiety in 5-position. A large set of pyrazoles bearing diverse aryl and alkynyl substituents in 3-position was prepared and the antileishmanial and antitrypanosomal activity was recorded. The urea 38 lacking the electron withdrawing cyano moiety in 4-position and containing the large 4-benzylpiperidinoo moiety exhibited a modest antileishmanial (IC50=19 µM) and antitrypanosomal activity (IC50=7.9 µM)). However, its considerable toxicity against the PMM and MRC-5 cells indicates low selectivity, i. e. a small gap between the desired antiparasitic activity and undesired cytotoxicity of <2- to 4-fold.

N-Pyrazolyl- and N-Triazolylamines and -Ureas as Antileishmanial and Antitrypanosomal Drugs.

Three types of modifications of antileishmanial pyrazole lead compounds 7 and 8 were conducted to expand understanding of the relationships between structural features and antileishmanial/antitrypanosomal activity: (1) the pyrazole core was retained or replaced by a 1,2,4-triazole ring; (2) various aryl moieties including 2-fluorophenyl, pyridin-3-yl and pyrazin-2-yl rings were attached at 3-position of the core azole; (3) either arylmethylamino or ureido substituents were introduced at 5-position of the azole core. The synthesis followed established routes starting with esters 9 or 15 and anhydride 21. The synthesized 3-arylpyrazoles and 3-aryl-1,2,4-triazoles had only very low antileishmanial activity. The 2-fluorophenyl-substituted pyrazole 18c revealed the highest antileishmanial activity of this series of compounds, but its IC50 value (20 µM) still indicates low activity. However, low micromolar antitrypanosomal activity was detected for the pyridin-3-yl-substituted pyrazoles 12b (IC50=4.7 µM) and 14a (IC50=2.1 µM). Their IC50 values are comparable with the IC50 values of the reference compounds benznidazole and nifurtimox. Whereas only low unspecific cytotoxicity at the primary peritoneal mouse macrophages (PMM) was detected, considerable cytotoxicity at MRC-5 human fibroblast cells was found for both pyrazoles 12b an 14a. The activity of pyrazole 12b against T. cruzi is 4-fold higher than its unspecific MRC-5 cytotoxicity.

PsychOpen CAMA: Publication of community-augmented meta-analyses in psychology.

To enable optimal decision-making based on the best evidence available, open syntheses are called for. To make data accessible and comprehensible even for decision-makers without proficient knowledge in meta-analysis, a graphical user interface (GUI) provides flexible data visualizations including interpretation aids. Moreover, due to a growing number of research findings, efficient and easy updating of meta-analyses is crucial to prevent waste in research. One label for a concept to meet these needs is community-augmented meta-analysis (CAMA). The research community at the one hand feeds the data repository of a CAMA with new data and on the other hand benefits from easy access to data and meta-analyses on a GUI. PsychOpen CAMA has been released recently to serve the psychological research community as a whole by covering a broad scope of potential research domains. PsychOpen CAMA relies on a web application with an OpenCPU server for the R calculations. To achieve interoperability of different datasets with the analysis functions used in PsychOpen CAMA, a template for meta-analytic data and machine-readable metadata are used. In the future, the automation of workflows, flexibility of analysis options, and the scope of the platform will be further developed by making use of synergies with other resources and tools at ZPID. The article provides an overview on the rationale for the necessity of open syntheses and the CAMA approach, as well as a presentation of the architecture, user interface, functionalities and future challenges of PsychOpen CAMA.

Data and code availability statements in systematic reviews of interventions were often missing or inaccurate: a content analysis.

OBJECTIVES: To estimate the frequency of data and code availability statements in a random sample of systematic reviews with meta-analysis of aggregate data, summarize the content of the statements and investigate how often data and code files were shared. METHODS: We searched for systematic reviews with meta-analysis of aggregate data on the effects of a health, social, behavioral, or educational intervention that were indexed in PubMed, Education Collection via ProQuest, Scopus via Elsevier, or Social Sciences Citation Index and Science Citation Index Expanded via Web of Science during a 4-week period (between November 2, and December 2, 2020). Records were randomly sorted and screened independently by two authors until our target sample of 300 systematic reviews was reached. Two authors independently recorded whether a data or code availability statement (or both) appeared in each review and coded the content of the statements using an inductive approach. RESULTS: Of the 300 included systematic reviews with meta-analysis, 86 (29%) had a data availability statement, and seven (2%) had both a data and code availability statement. In 12/93 (13%) data availability statements, authors stated that data files were available for download from the journal website or a data repository, which we verified as being true. While 39/93 (42%) authors stated data were available upon request, 37/93 (40%) implied that sharing of data files was not necessary or applicable to them, most often because "all data appear in the article" or "no datasets were generated or analyzed". DISCUSSION: Data and code availability statements appear infrequently in systematic review manuscripts. Authors who do provide a data availability statement often incorrectly imply that data sharing is not applicable to systematic reviews. Our results suggest the need for various interventions to increase data and code sharing by systematic reviewers.