Discovery of Benzothiazol-2-ylthiophenylpyrazole-4-carboxamides as Novel Succinate Dehydrogenase Inhibitors.

Succinate dehydrogenase (SDH) has been considered an ideal target for discovering fungicides. To develop novel SDH inhibitors, in this work, 31 novel benzothiazol-2-ylthiophenylpyrazole-4-carboxamides were designed and synthesized using active fragment exchange and a link approach as promising SDH inhibitors. The findings from the tests on antifungal activity indicated that most of the synthesized compounds displayed remarkable inhibition against the fungi tested. Compound Ig N-(2-(((5-chlorobenzo[d]thiazol-2-yl)thio)methyl)phenyl)-3-(difluoromethyl)-1-methyl-1H-yrazole-4-carboxamide, with EC50 values against four kinds of fungi tested below 10 µg/mL and against Cercospora arachidicola even below 2 µg/mL, showed superior antifungal activity than that of commercial fungicide thifluzamide, and specifically compounds Ig and Im were found to show preventative potency of 90.6% and 81.3% against Rhizoctonia solani Kühn, respectively, similar to the positive fungicide thifluzamide. The molecular simulation studies suggested that hydrophobic interactions were the main driving forces between ligands and SDH. Encouragingly, we found that compound Ig can effectively promote the wheat seedlings and the growth of Arabidopsis thaliana. Our further studies indicated that compound Ig could stimulate nitrate reductase activity in planta and increase the biomass of plants.

Discovery of Benzothiazolylpyrazole-4-Carboxamides as Potent Succinate Dehydrogenase Inhibitors through Active Fragment Exchange and Link Approach.

Succinate dehydrogenase (SDH) is an attractive target for developing green fungicides to manage agricultural pathogens in modern agriculture research. Herein, in this work, we report the discovery of benzothiazolylpyrazole-4-carboxamides I-III as potent SDH inhibitors using active fragment exchange and link approach. The results of the fungicidal activity assays showed that some of the synthesized compounds exhibited excellent inhibition against the tested fungi. Systematic structure-activity relationship studies led to the discovery of compound Ip, N-(1-((4,6-difluorobenzo[d]thiazol-2-yl)thio)propan-2-yl)-3-(difluoromethyl)-N-methoxy-1-methyl-1H-pyrazole-4-carboxamide, which showed higher fungicidal activity against Fusarium graminearum Schw (EC50 = 0.93 µg/mL) than the commercial fungicides thifluzamide (EC50 > 50 µg/mL) and boscalid (EC50 > 50 µg/mL). The molecular simulation studies suggested that hydrophobic interactions were the primary driving forces between ligands and SDH. Promisingly, we found that Ip could stimulate the growth of wheat seedlings and Arabidopsis thaliana and increase the biomass of the treated plants. Preliminary studies on the plant growth promoter mechanism of Ip indicated that it could increase nitrate reductase activity in planta, that, in turn, stimulates the growth of plants.

[Role of hepatitis C virus superinfection in hepatic pathologic changes of patients with chronic hepatitis B: a retrospective short-term and long-term comparative study].

OBJECTIVE: To observe the effect of hepatitis C virus (HCV) superinfection on the short-term and long-term hepatic pathological changes in patients with chronic hepatitis B (CHB). METHODS: HCV-RNA of twice corresponding period serum samples was detected via reverse transcription polymerase chain reaction assay from 230 patients with CHB for whom liver biopsy was performed at an interval of 0.5-15 years, respectively. The hepatic pathological changes of the patients with CHB who were serum HCV-RNA positive at the beginning of observation and persistently positive between the starting and ending of observation were respectively compared with those of serum HCV-RNA negative and persistently negative patients. RESULTS: 41 patients (17.83%) were positive for serum HCV-RNA at the beginning of observation. There were significant differences in the severity of hepatic inflammatory activity grade and fibrosis stage between serum HCV-RNA positive and negative patients with CHB (P < 0.05). Twenty-nine patients were persistently positive for serum HCV-RNA in the beginning and end of observation. Compared with persistently negative patients who were 116 patients selected from the above-mentioned 230 patients and they were comparable with HCV-RNA persistently positive patients in mean follow-up time, age and sex, the long-term progression of hepatic inflammatory activity grade and fibrosis stage in persistently positive patients were more speedy (P < 0.01). CONCLUSION: HCV superinfection worsens the hepatic pathological changes of patients with CHB and speeds up its progression.

[Significance of detecting HBV-DNA by the fluorescence quantitative PCR].

BACKGROUND: To study the correlativity between HBV-DNA and the markers of hepatitis B virus infection and different clinical types of hepatitis B. METHODS: The fluorescence quantitation (FQ) of HBV-DNA of 105 patients with hepatitis B was performed by PCR, and the correlativity between the fluorescence quantitation of HBV-DNA and the markers of hepatitis B virus and different clinical types of hepatitis B was analyzed. RESULTS: Ninety-seven percent of the patients were found HBsAg(+), HBeAg(+), HBcAb(+); 75% were HBsAg(+), HBeAb(+), HBcAb(+); 60% were HBsAg(+), HBcAb(+); 40% were HBsAg(+); in HBsAb(+), HBeAb(+), HBcAb(+) (or both HBsAb and HBcAb were positive) group the HBV DNA was undetectable. The analysis indicated that there was a significant difference among different groups (P less than 0.05).HBV-DNA was detected in 72.2% in acute hepatitis B group, in 75% of chronic hepatitis B group, and in 70% of cases of liver cirrhosis with hepatitis B group. The analysis indicated that there was no significant difference among the different clinical types of hepatitis (P greater than 0.05). CONCLUSION: The levels of viral replication were not correlated with different clinical types of hepatitis B; the concentration of HBV-DNA in serum was related to hepatitis B antigen.