Enantio- and Diastereoselective Two-Pot Synthesis of Isoquinuclidines from Glutaraldehyde and N-Aryl Imines with DFT Calculations.

A pot-economic method for the enantio- and diastereoselective synthesis of a [2.2.2] azabicyclic isoquinuclidine system is developed. This protocol involves the proline-catalyzed direct Mannich reaction-cyclization/IBX-mediated site-selective oxidation/NaBH4-reduction sequence between glutaraldehyde and imines to generate in situ chiral 1,2-DHPs, followed by the diastereoselective Diels-Alder reaction with N-aryl maleimides furnishing isoquinuclidines in overall five steps. A variety of isoquinuclidines having five-contiguous chiral centers, including an all-carbon quaternary, were prepared with high yields (up to 78%) and excellent stereoselectivity (>50:1 dr, and up to >99:1 er). DFT calculations support the observed high stereoselective reaction outcome.

One-Pot Synthesis of Chiral Tetracyclic Dibenzo[ b, f][1,4]oxazepine-Fused 1,2-Dihydropyridines (DHPs) under Metal-Free Conditions.

An efficient protocol for the catalytic asymmetric synthesis of new dibenzo[ b, f][1,4]-oxazepine-fused 1,2-dihydropyridines (DHPs) has been described under metal-free conditions. This reaction proceeds through proline-catalyzed direct Mannich/cyclization between seven-membered dibenzo[ b, f][1,4]-oxazepine-imines and aqueous glutaraldehyde, followed by IBX-mediated site-selective dehydrogenative oxidation in one-pot operation with high yields (up to 92%) and excellent enantioselectivity (up to >99:1 er).

Negative Regulation of Human Pregnane X Receptor by MicroRNA-18a-5p: Evidence for Suppression of MicroRNA-18a-5p Expression by Rifampin and Rilpivirine.

Small noncoding microRNAs act as post-transcriptional regulators of gene expression involved in diverse biologic functions. Pregnane X receptor (PXR, NR1I2), a member of the superfamily of nuclear receptors, is a transcription factor governing the transport and biotransformation of various drugs and other chemicals. In the present study, we identified a specific microRNA (miR) involved in regulating the expression and functionality of human PXR (hPXR). According to bioinformatics analysis employing three commonly used algorithms (TargetScan, miRanda, and DIANA-microT-CDS), miR-18a-5p was predicted to be the top candidate microRNA regulator of hPXR. Consequently, this microRNA was selected for detailed experimental investigation. As shown in cell-based dual-luciferase reporter gene assays, functional interaction occurred between miR-18a-5p and the microRNA recognition element of miR-18a-5p in the 3'-untranslated region of hPXR mRNA. Transfection of LS180 human colorectal adenocarcinoma cells with an miR-18a-5p mimic decreased hPXR mRNA and protein expression, whereas transfection of LS180 cells with an miR-18a-5p inhibitor increased hPXR mRNA and protein expression. The decrease in hPXR expression by the miR-18a-5p mimic was associated with a reduction in the extent of hPXR target gene (CYP3A4) induction by rifampin and rilpivirine. Treatment of untransfected LS180 cells with either of these hPXR agonists decreased endogenous expression of miR-18a-5p, and this preceded the onset of CYP3A4 induction. In conclusion, miR-18a-5p is a negative regulator of hPXR expression and the hPXR agonists rifampin and rilpivirine are chemical suppressors of miR-18a-5p expression.

Seasonal abundance of Henosepilachna vigintioctopunctata (Fab.) on Solanum melongena L. and natural occurrence of its two hymenopteran parasitoids

ABSTRACT The 28-spotted hadda beetle Henosepilachna vigintioctopunctata Fab. (Coleoptera: Coccinellidae) is a poly-phagous pest, commonly infesting solanacious crops including brinjal, Solanum melongena L. Upon its severe infestation on brinjal, it causes considerable damage to the foliage and also to the calyx of fruits. The studies were made to record the seasonal abundance of hadda beetle and identification of its natural enemies present in the region for two consecutive years. The pooled data for two years showed that the maximum number of H. vigintioctopunctata egg clusters on brinjal were recorded in the 27th (0.40 egg cluster/ plant), followed by grub population in 35th (3.78 grubs/ plant), pupae in 33rd and 39th (0.83 pupae/ plant) and adult beetles in 36th (5.48 adults/ plant) standard meteorological weeks, respectively. It was observed that the key meteorological factors had 35.9%, 87.3%, 66.8% and 81.9% effect on the abundance of egg clusters, grubs, pupae and adults respectively in summer planted brinjal crop. Two natural enemies of hadda beetle viz. Tetrastichus sp. (egg parasitoid) and Pediobius foveolatus (pupal parasitoid) were recorded. The maximum parasitisation by Tetrastichus sp. and P. foveolatus on the egg clusters and pupae was recorded 22.64% and 6.62% respectively, during the month of August (34th and 35th standard meteorological week respectively). Further, the morphometric parameters of these two adult parasitoids were recorded and greater morphometric variability was observed in P. foveolatus in comparison to Tetrastichus sp.

Seasonal dynamics and management of whitefly ( Bemesia tabaci Genn.) in tomato ( Solanum esculentum Mill.)

ABSTRACT Studies on seasonal dynamics of white fly (Bemesia tabaci) on tomato (Solanum esculentum var. Pusa Ruby) revealed that it appeared first during the 13th and reached maximum during 21st standard meteorological week. A positive correlation between adult population and abiotic factors viz. temperature (maximum and minimum) and sunshine hours was observed, whereas humidity (maximum and minimum) and rainfall showed a negative correlation with it. Taken together, the key weather parameters studied, caused 89.00 per cent variation in whitefly population (R2 value). Combination of carbofuran (soil application) + imidacloprid (seed treatment ) + imidacloprid (foliar application) proved significantly superior and caused maximum reduction in whitefly population followed by imidacloprid (seed treatment) + thiomethoxam (spray), imidacloprid (seed treatment) + imidacloprid (spray), imidacloprid (seed treatment) + dimetheoate (spray), carbofuran (soil application) + malathion (spray), and imidacloprid (seed treatment) + yellow sticky traps. The highest cost benefit ratio of 1:25.04 was recorded in case of carbofuran (soil application) + imidacloprid (seed treatment ) + imidacloprid (foliar application) followed by 1:22.38 for imidacloprid (seed treatment) + thiomethoxam (spray) ; 1:21.81 for imidacloprid (seed treatment) + imidacloprid (spray); 1:19.27 imidacloprid (seed treatment) + dimetheoate (spray); 1:19.48 carbofuran (soil application) + malathion (spray), and 1:8.33 for imidacloprid (seed treatment) + yellow sticky traps. The soil application of carbofuran + seed treatment with imidacloprid and three foliar sprays of imidacloprid at fortnight interval starting 40 days after transplanting is found effective and is advised for whitefly management in susceptible tomato cultivars.

Differential activation of human constitutive androstane receptor and its SV23 and SV24 splice variants by rilpivirine and etravirine.

BACKGROUND AND PURPOSE: Rilpivirine and etravirine are second-generation non-nucleoside reverse transcriptase inhibitors (NNRTIs) indicated for the treatment of HIV/AIDS. The constitutive androstane receptor (CAR) regulates the expression of genes involved in various biological processes, including the transport and biotransformation of drugs. We investigated the effect of rilpivirine and etravirine on the activity of the wild-type human CAR (hCAR-WT) and its hCAR-SV23 and hCAR-SV24 splice variants, and compared it with first-generation NNRTIs (efavirenz, nevirapine, and delavirdine). EXPERIMENTAL APPROACH: Receptor activation, ligand-binding domain (LBD) transactivation, and co-activator recruitment were investigated in transiently transfected, NNRTI-treated HepG2 cells. Nuclear translocation of green fluorescent protein-tagged hCAR-WT and CYP2B6 gene expression were assessed in NNRTI-treated human hepatocytes. KEY RESULTS: Rilpivirine and etravirine activated hCAR-WT, but not hCAR-SV23 or hCAR-SV24, and without transactivating the LBD or recruiting steroid receptor coactivators SRC-1, SRC-2, or SRC-3. Among the first-generation NNRTIs investigated, only efavirenz activated hCAR-WT, hCAR-SV23, and hCAR-SV24, but none of them transactivated the LBD of these receptors or substantively recruited SRC-1, SRC-2, or SRC-3. Rilpivirine, etravirine, and efavirenz triggered nuclear translocation of hCAR-WT and increased hCAR target gene (CYP2B6) expression. CONCLUSION AND IMPLICATIONS: NNRTIs activate hCAR-WT, hCAR-SV23, and hCAR-SV24 in a drug-specific and isoform-selective manner. The activation occurs by a mechanism that does not appear to involve binding to the LBD or recruitment of SRC-1, SRC-2, or SRC-3.

5-((Meth-oxy-imino)-{2-[(2-methyl-phen-oxy)meth-yl]phen-yl}meth-yl)-N-phenyl-1,3,4-oxa-diazol-2-amine.

In the title mol-ecule, C24H22N4O3, the plane of the oxa-diazole ring forms a dihedral angle of 32.41 (12)° with that of the phenyl ring and dihedral angles of 74.51 (10) and 56.38 (10)° with the planes of the benzene rings. In the crystal, pairs of N-H⋯N hydrogen bonds link molecules into inversion dimers featuring R 2 (2)(8) graph-set motifs.

Agonism of human pregnane X receptor by rilpivirine and etravirine: comparison with first generation non-nucleoside reverse transcriptase inhibitors.

Rilpivirine and etravirine are second generation non-nucleoside reverse transcriptase inhibitors approved recently by the United States Food and Drug Administration for the treatment of human immunodeficiency virus-1 infection. Pregnane X receptor (PXR) is a member of the superfamily of nuclear receptors that regulate the expression of various genes controlling diverse biological functions. The present study investigated the effects of rilpivirine and etravirine on the activity of human PXR (hPXR), including the mode of activation, and compared them to those of efavirenz, nevirapine, and delavirdine, which are first generation non-nucleoside reverse transcriptase inhibitors. In transiently transfected HepG2 cells, rilpivirine, etravirine, and efavirenz, but not nevirapine or delavirdine, activated human, mouse, and rat PXR. Results from mechanistic studies indicated that rilpivirine, etravirine, and efavirenz, but not nevirapine or delavirdine, bound to the ligand-binding domain of hPXR, as assessed by a transactivation assay and by a competitive ligand-binding assay using time-resolved fluorescence resonance energy transfer; triggered nuclear translocation of a green fluorescence protein-tagged hPXR, as visualized by confocal imaging; and recruited steroid receptor coactivator-1 (SRC-1), SRC-2, and SRC-3 to hPXR, as demonstrated by mammalian two-hybrid assays. Rilpivirine, etravirine, and efavirenz, but not nevirapine or delavirdine, increased hPXR target gene (CYP3A4) expression in primary cultures of human hepatocytes. In summary, select non-nucleoside reverse transcriptase inhibitors activated human and rodent PXR. Rilpivirine, etravirine, and efavirenz, but not nevirapine or delavirdine, were identified as agonists of hPXR, as assessed in mechanistic experiments, and inducers of CYP3A4, as determined in primary cultures of human hepatocytes.