Target compounds 4a- n were obtained by the reaction of 1-substituted phenyl-3-methyl-5-substituted phenylthio-4-pyrazolaldoximes (3) with chloromethylated heterocyclic compounds (ClCH 2-R 3) under reflux conditions in ethanol. Subsequently, the oxidation of 4a- e with KMnO 4 in HOAc at room temperature afforded eight new compounds, 5a- h. The synthesized compounds were characterized by physical constants, and the structures of the title compounds were confirmed by IR, (1)H NMR, (13)C NMR, and elemental analysis. The bioassay revealed that the compounds possessed antiviral activities. It was found that title compounds 4a and 4g had the same inactivation effects against TMV (EC 50 = 58.7 and 65.3 microg/mL) as the commercial product Ningnanmycin (EC 50 = 52.7 microg/mL). To the best of our knowledge, this is the first report on the antiviral activity of pyrazole derivatives containing an oxime moiety.

The alterations induced in gut microbiota by tacrolimus may affect immune function and organ transplantation. Mice were treated with high-dose tacrolimus for 14 days. The fecal microbiota were analyzed by pyrosequencing the 16S rRNA genes, and the effect on metabolism was predicted using the sequence data. The subgroups of T cells in the serum, gut-associated lymphoid tissue, and draining lymph nodes were determined by flow cytometry. Tacrolimus treatment significantly altered the relative abundance of Allobaculum, Bacteroides, and Lactobacillus and CD4 CD25 FoxP3 regulatory T cells in the colonic mucosa and the circulation. These were significantly increased after either tacrolimus treatment or treatment by fecal microbiota transfer from tacrolimus-treated donors. Further, treatment with low-dose tacrolimus plus fecal microbiota transfer from high-dose tacrolimus-altered mice increased skin allograft survival rate in a skin transplantation model. Thus, high-dose tacrolimus alters the compositions and taxa of the gut microbiota. Administration of these conditioned gut microbiota plus low-dose tacrolimus resulted in regulation of colonic and systemic immune responses and an increased allograft survival rate. This study demonstrated a new strategy for controlling allograft rejection by combining an immunosuppressive agent with gut microbiome transplantation.

No abstract

Starting from benzaldehyde 1, the title compounds 8 were synthesized in six steps. Benzaldehyde 1 was reacted with ammonium hydroxide, and the resulting imine was then treated with dialkyl phosphite 3 to give dialkyl N-(arylmethylene)-1-amino-1-aryl methylphosphonates 4. Phosphonates 4 were then easily hydrolyzed to give dialkyl 1-amino-1-aryl-methylphosphonates 6, which on treatment with triethylamine, carbon disulfide, and phosphorus oxychloride provided 7. Target compounds 8 were then prepared by the reaction of 7 with substituted chiral amine. The structures were clearly verified by spectroscopic data (IR, (1)H, (13)C, and (31)P NMR, and elemental analysis). The bioassay of these compounds revealed them as antivirally active. It was found that title compounds 8g, 8e, 8k, and 8m had the same curative effects of TMV (inhibitory rate = 54.8, 50.5, 50.4, and 50.4%, respectively) as the commercial product Ningnanmycin (56.2%). This would appear to be the first report of the synthesis and antiviral activity of chiral thiourea derivatives containing an alpha-aminophosphonate moiety.

No abstract

Approximately 33.6% of nondiabetic solid organ transplant recipients who received tacrolimus developed hyperglycemia. Whether the tacrolimus‐induced gut microbiota is involved in the regulation of hyperglycemia has not been reported. Hyperglycemia was observed in a tacrolimus‐treated mouse model, with reduction in taxonomic abundance of butyrate‐producing bacteria and decreased butyric acid concentration in the cecum. This tacrolimus‐induced glucose metabolic disorder was caused by the gut microbiota, as confirmed by a broad‐spectrum antibiotic model. Furthermore, oral supplementation with butyrate, whether for remedy or prevention, significantly increased the butyric acid content in the cecum and arrested hyperglycemia through the regulation of glucose‐regulating hormones, including glucagon‐like peptide‐1 (GLP‐1), peptide YY (PYY), and insulin, in serum. The butyrate–G‐protein‐coupled receptor 43–GLP‐1 pathway in the intestinal crypts may be involved in the pathogenesis of normalization of hyperglycemia caused by the tacrolimus. Therefore, tacrolimus affects glucose metabolism through the butyrate‐associated GLP‐1 pathway in the gut, and oral supplementation with butyrate provides new insights for the prevention and treatment of tacrolimus‐induced hyperglycemia in transplant recipients.

No abstract

1,4-Pentadien-3-one derivatives derived from curcumin possess excellent inhibitory activity against plant viruses. On the basis of this finding, a series of novel 1,4-pentadien-3-one derivatives containing a 1,3,4-thiadiazole moiety were designed and synthesized, and their structures confirmed by IR, 1H-NMR, and 13C-NMR spectroscopy and elemental analysis. The antiviral activities of the title compounds were evaluated against tobacco mosaic virus (TMV) and cucumber mosaic virus (CMV) in vivo. The assay results showed that most of compounds had remarkable antiviral activities against TMV and CMV, among which compounds 4b, 4h, 4i, 4k, 4o, and 4q exhibited good curative, protection, and inactivation activity against TMV. Compounds 4h, 4i, 4k, 4l, 4o, and 4q exhibited excellent protection activity against TMV, with EC50 values of 105.01, 254.77, 135.38, 297.40, 248.18, and 129.87 μg/mL, respectively, which were superior to that of ribavirin (457.25 µg/mL). In addition, preliminary SARs indicated that small electron-withdrawing groups on the aromatic ring were favorable for anti-TMV activity. This finding suggests that 1,4-pentadien-3-one derivatives containing a 1,3,4-thiadiazole moiety may be considered as potential lead structures for discovering new antiviral agents.