Design, synthesis and SAR analysis of potent BACE1 inhibitors: Possible lead drug candidates for Alzheimer's disease.

We have identified potent isophthalic acid derivatives armed with imidazol and indolyl groups as potent ß-secretase inhibitors. The most effective analogs demonstrated low nano-molar potency for the BACE1 (ß-secretase cleaving enzyme) as measured by FRET (Fluorescence Resonance Energy Transfer) and cell-based (ELISA) assays. Our design strategy followed a traditional SAR approach and was supported by molecular modeling studies based on previously reported hydroxyethylene transition state inhibitor derived from isophthalic acid I. In the FRET assay, the most potent compound, 10a, displayed an IC50 value for BACE1 of 75 nM, and exhibited cellular activity with an EC50 value of 0.81 µM. On the other hand, compound 11b was found to be the most potent compound in the cell-based assay with an EC50 value of 0.29 µM.

Differential detection of Entamoeba histolytica, Entamoeba dispar and Entamoeba moshkovskii in fecal samples by nested PCR in the United Arab Emirates (UAE).

Amoebiasis is one of the most important infectious diseases afflicting mainly tropical and subtropical countries. This study was carried out in the Sharjah Emirate, UAE in order to accurately detect and differentiate Entamoeba histolytica, Entamoeba dispar and E. moshkovskii in fecal samples collected from the Sharjah municipality public health clinic by ELISA and nested polymerase chain reaction (PCR). One hundred and twenty specimens were examined and the PCR was positive for E. histolytica, E. dispar and E. moshkovskii (collectively referred to as Entamoeba complex) in 19.2% (23 out of 120). Of those, 10% (12/120) were mono - infection with E. histolytica; 2.5% (3/120) with E. dispar; and 2.5% (3/120) E. moshkovskii. The nested PCR also detected mixed infections by both E. histolytica and E. dispar in 3.3% (4/120) and E. dispar and E. moshkovskii in 0.8% (1/120). The TechLab ELISA kit failed to detect E. histolytica in any of the E. histolytica PCR positive samples. Overall, the percentage of E. histolytica including those found in mixed infections was 13.3% (16/120). Compared to nested PCR, microscopy was found to have an overall sensitivity of 52.2% and a specificity of 75.2% for detection of Entamoeba complex. The present study indicates that E. histolytica is present in the UAE with an average incidence rate of 13.3%. However, larger studies need to be conducted in order to confirm these findings. We propose the use of PCR in both the routine diagnosis of amoebiasis and epidemiological survey in the UAE.

Rates of infection and phylogenetic analysis of GB virus-C among Kuwaiti and Jordanian blood donors.

OBJECTIVES: GB virus-C/hepatitis G virus (GBV-C/HGV), collectively known as GBV-C, has been reported to be associated with non-A-E hepatitis. The aim of this study was to determine the rate of infection and genotypic characteristics of GBV-C among Kuwaiti and Jordanian blood donors. METHODS: A total of 334 plasma/serum samples from healthy blood donors in Kuwait (n = 130) and Jordan (n = 204) were screened using RT-PCR/nested PCR of the 5'-untranslated region (5'-UTR). Phylogenetic analysis was conducted by sequencing the 5'-UTR region of the randomly picked clones representative of the two populations. RESULTS: The results obtained showed that the rate of GBV-C infection in healthy Kuwaiti and Jordanian blood donors was 24.6 and 9.8%, respectively. Sequence analysis of the 5'-UTR using 4 and 6 clones from healthy Kuwaiti and Jordanian blood donors, respectively, revealed the prevalence of the European/North American genotype 2 when compared to the 6 reference genotypes in GenBank. CONCLUSION: GBV-C/HGV was detectable at rates relatively comparable with other regions in the world in Kuwaiti and Jordanian blood donors, although the significance of which remains controversial. More interesting is the dominance of GBV-C genotype 2 among the two populations, which remains to be explained.