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Six series of (+)-usnic acid derivatives were synthesized. The IC50values of these compounds were determined in T. gondiiinfected HeLa cells (μM) and in HeLa cells (μM), and their selectivity indexes (SI) were calculated. In vitro, most of the derivatives tested in this study exhibited more anti activity than that of the parent compound (+)-usnic acid and the positive control drugs. Among these derivatives, methyl (E)-(1-(6-acetyl-7,9-dihydroxy-8,9b-dimethyl-1,3-dioxo-3,9b-dihydrodibenzo[b,d]furan-2(1H)-ylidene)ethyl)phenylalaninate (D3) showed the most effective anti-T. gondiiactivity (selectivity >2.77). In comparison with the clinically used positive control drugs sulfadiazine (selectivity 1.15), pyrimethamine (selectivity 0.89), spiramycin (selectivity 0.72), and the lead compound (+)-usnic acid (selectivity 0.96), D3showed better results in vitro. Furthermore, D3and (E)-6-acetyl-7,9-dihydroxy-8,9b-dimethyl-2-(1-(quinolin-6-ylamino)ethylidene)dibenzo[b,d]furan-1,3(2H,9bH)-dione (F3) had greater inhibitory effects on T. gondii(inhibition rates 76.0% and 64.6%) in vivo in comparison to spiramycin (inhibition rate 55.2%); in the peritoneal cavity of mice, the number of tachyzoites was significantly reduced (p< 0.001) in vivo. Additionally, some biochemical parameters were measured and spleen indexes were comprehensively evaluated, and the results indicated that mice treated with both compound D3and compound F3showed reduced hepatotoxicity and significantly enhanced antioxidative effects in comparison to the normal group. Granuloma and cyst formation were effected by the inhibition of compound D3and compound F3in liver sections. Overall, these results indicated that D3and F3for use as anti-T. gondiiagents are promising lead compounds.

Introduction:A lot of in vitrotechnologies have been developed to screen drugs for toxoplasmosis, which is caused by Toxoplasma gondiiand is one of the most serious infectious diseases in the world. However, developed screening methods still have limitation such as inaccuracy, labor-intensive and time-consuming procedure. Therefore, the development of simpler, more efficient and accurate high-throughput screening assay is needed.Areas covered:The present review gives the overview of in vitroscreening technologies described in literatures so far including morphological assay, incorporation of [3H]uracil assay, enzyme-linked immunosorbent assay (ELISA), colorimetric microtiter assay (β-galactosidase assay), flow cytometric quantification assay, yellow fluorescent protein assay and cell viability assay. The authors discuss how these methods are efficient and/or limited for screening anti-T. gondiidrugs. The authors further suggest brand-new technologies which are faster, simpler, more effective and available for high-throughput screening.Expert opinion:Options for clinical treatment of toxoplasmosis are currently very limited. Thus, more accurate in vitroscreening methods must be established to identify the most effective anti-T. gondiidrugs from random screening of compounds. At the same time, based on genome information, combination of an appropriate screening technology, combinatorial chemistry and computational biology may increase the efficiency of target-based drug discovery against T. gondii.

Data for a total of 164 bloodstream infection cases due to carbapenem-resistant Enterobacteriaceae(CRE) from 2013 to 2017 were retrospectively collected from 36 tertiary hospitals in 19 provinces in China to evaluate the outcomes and risk factors for mortality by univariable and multivariable analysis. The most frequent infecting species was Klebsiella pneumoniae(69.5%, 114/164).