Synthesis and discovery of novel hexacyclic cage compounds as inhibitors of acetylcholinesterase

Hexacyclic derivatives share vital pharmacological properties, considered useful in Alzheimer’s disease. The aim of this study was synthesis and its evaluation for acetyl cholinesterase inhibitory activity of novel hexacyclic analogues. Compound 4f, showed potent inhibitory activity against acetyl cholinesterase enzyme with IC₅₀ 0.72 μmol/L.     

Substituted spiro [2.3'] oxindolespiro [3.2″]-5,6-dimethoxy-indane-1″-one-pyrrolidine analogue as inhibitors of acetylcholinesterase

Series of pyrolidine analogues were synthesized and examined as acetylcholinesterase (AChE) inhibitors. Among the compounds, compounds 4k and 6k were the most potent inhibitors of the series. Compound 4k, showed potent inhibitory activity against acetyl cholinesterase enzyme with IC(50) 0.10 μmol/L. Pyrolidine analogues might be potential acetyl cholinesterase agents for AD.     

Synthesis and biological evaluation of novel 6, 7-dimethoxy-3-(4-pyridyl)-2,3,3a,4-tetrahydroindeno[1,2-c]pyrazol-2-yl-4-substituted phenylmethanone/ethanone derivatives

A series of 6,7-dimethoxy-3-(4-pyridyl)-2,3,3a,4-tetrahydroindeno[1,2-c]pyrazol-2-yl-4-substituted phenylmethanone/ethanone derivatives were synthesized and in vitro activity against mycobacterium tuberculosis (MTB) and INHR-MTB were carried out. Among the synthesized compounds, compound (4h) 6,7-dimethoxy-3-(4-pyridyl)-2,3,3a,4-tetrahydroindeno[1,2-c]pyrazol-2-yl-4-pyridyl methanone was found to be the most active agent against MTB and INHR-MTB with a minimum inhibitory concentration of 0.22 μM.     

Effects of X-irradiation on adventitious bud regeneration from in vitro leaf explants of Rosa hybrida

The effectiveness of X-radiation on regeneration of adventitious buds on in vitro leaf explants of three Rosa hybrida L. genotypes was studied. In vitro leaflet explants of roses produced adventitious buds when cultured in the dark for 1 week on Murashige and Skoog (MS) induction medium containing 6.8 μM thidiazuron (TDZ) + 0.49 μM indole-3-butyric acid (IBA) and subsequently transferred to MS regeneration medium containing 2.2 μM benzyladenine (BA) + 0.049 μM IBA in the presence of reduced light, at 15 μmol m-2 s-1 photosynthetically active radiation (PAR). Analysis of radiosensitivity by irradiating leaf explants with increasing doses of X-rays between 25 and 100 Gray (Gy) resulted in a decreasing rate of leaf explants regenerating buds from 47% to 0% respectively. The lethal dose for 50% of the regenerating explants (LD₅₀) in all the three genotypes was estimated to be 25 Gy at a dose rate 2 Gy/s. For the main experiment, doses of 5 and 15 Gy were selected and variations were observed between genotypes. Clone RUI 317 had the highest rate of adventitious bud regeneration, with 83.6% (2.5 buds/explant) at 5 Gy and 64% (1.8 buds/explant) at 15 Gy, compared to 89% (3.4 buds/explant) with the untreated control. Significant differences in the percentage of bud regeneration of the three genotypes were only observed at 15 Gy in comparison to the control and the number of buds formed per regenerating explant varied between 1 to 4. This revised version was published online in June 2006 with corrections to the Cover Date.     

High Prevalence of HIV-1 CRF01_AE Viruses among Female Commercial Sex Workers Residing in Surabaya,Indonesia

Background

Human immunodeficiency virus (HIV) infection and acquired immune deficiency syndrome (AIDS) cause serious health problems and have an impact on the Indonesian economy. In addition, the rapid epidemic growth of HIV is continuing in Indonesia. Commercial sex plays a significant role in the spread of HIV; therefore, in order to reveal the current HIV prevalence rate among commercial sex workers (CSWs), we conducted an epidemiological study on HIV infection among CSWs residing in Surabaya, the capital of East Java province of Indonesia with large communities of CSWs.

Methodology/Principal Findings

The prevalence of HIV infection among 200 CSWs was studied. In addition, the subtype of HIV type 1 (HIV-1) and the prevalence of other blood-borne viruses, hepatitis B virus (HBV), hepatitis C virus (HCV) and GB virus C (GBV-C), were studied. The prevalence rates of HIV, hepatitis B core antibody, hepatitis B surface antigen, anti-HCV antibodies and anti-GBV-C antibodies were 11%, 64%, 4%, 0.5% and 0% among CSWs involved in this study, respectively. HIV-1 CRF01_AE viral gene fragments were detected in most HIV-positive samples. In addition, most CSWs showed low awareness of sexually transmitted diseases and had unprotected sex with their clients.

Conclusions/Significance

The HIV prevalence rate among CSWs was significantly higher than that among the general population in Indonesia (0.2–0.4%). In addition, CSWs were at a high risk of exposure to HBV, although chronic HBV infection was less frequently established. Our results suggest the necessity of efficient prevention programs for HIV and other blood-borne viral infections among CSWs in Surabaya, Indonesia.     

Discovery of novel methanone derivatives acting as antimycobacterial agents

A series of pyrazoline derivatives were synthesized and in vitro activity against Mycobacterium tuberculosis H37Rv was carried out. Among the synthesized compounds, compounds (4d) and (4f) 4-aminophenyl-3-(3,4-dimethoxyphenyl)-6,7-dimethoxy-2,3,3a,4-tetrahydroindeno[1,2-c]pyrazol-2-ylmethanone and 4-aminophenyl-6,7-dimethoxy-3-phenyl-2,3,3a,4-tetrahydroindeno[1,2-c]pyrazol-2-ylmethanone were found to be the most active agent against M. tuberculosis H37Rv with a minimum inhibitory concentration of 10 μg/mL.     

Stress transfer in cellulose nanowhisker composites--influence of whisker aspect ratio and surface charge

The mechanically induced molecular deformation of cellulose nanowhiskers embedded in subpercolation concentration in an epoxy resin matrix was monitored through Raman spectroscopy. Cellulose nanowhiskers isolated by sulfuric acid hydrolysis from tunicates and by sulfuric acid hydrolysis and hydrochloric acid hydrolysis from cotton were used to study how the aspect ratio (ca. 76 for tunicate and 19 for cotton) and surface charges (38 and 85 mmol SO(4)(-)/kg for sulfuric acid hydrolysis of cotton and tunicate, respectively; no detectable surface charges for hydrochloric acid hydrolysis) originating from the isolation process influence stress transfer in such systems. Atomic force microscopy confirmed that uncharged cellulose nanowhiskers produced by hydrochloric acid hydrolysis have a much higher tendency to aggregate than the charged cotton or tunicate nanowhiskers. Each of these nanowhisker types was incorporated in a concentration of 0.7 vol % in a thermosetting epoxy resin matrix. Mechanically induced shifts of the Raman peak initially located at 1095 cm(-1) were used to express the level of deformation imparted to the nanowhiskers embedded in the resin. Much larger shifts of the diagnostic Raman band were observed for nanocomposites with tunicate nanowhiskers than for the corresponding samples comprising cotton nanowhiskers. In the case of nanocomposites comprising nanowhiskers produced by hydrochloric acid hydrolysis, no significant Raman band shift was observed. These results are indicative of different modes of stress transfer, which in turn appear to originate from the different sample morphologies.     

Inhibitory Potency of 8-Methoxypsoralen on Cytochrome P450 2A6 (CYP2A6) Allelic Variants CYP2A6*15, CYP2A6*16, CYP2A6*21 and CYP2A6*22: Differential Susceptibility Due to Different Sequence Locations of the Mutations

Human cytochrome P450 2A6 (CYP2A6) is a highly polymorphic isoform of CYP2A subfamily. Our previous kinetic study on four CYP2A6 allelic variants (CYP2A6*15, CYP2A6*16, CYP2A6*21 and CYP2A6*22) have unveiled the functional significance of sequence mutations in these variants on coumarin 7-hydroxylation activity. In the present study, we further explored the ability of a typical CYP2A6 inhibitor, 8-methoxypsoralen (8-MOP), in inhibition of these alleles and we hypothesized that translational mutations in these variants are likely to give impact on 8-MOP inhibitory potency. The CYP2A6 variant and the wild type proteins were subjected to 8-MOP inhibition to yield IC₅₀ values. In general, a similar trend of change in the IC₅₀ and K_m values was noted among the four mutants towards coumarin oxidation. With the exception of CYP2A6*16, differences in IC₅₀ values were highly significant which implied compromised interaction of the mutants with 8-MOP. Molecular models of CYP2A6 were subsequently constructed and ligand-docking experiments were performed to rationalize experimental data. Our docking study has shown that mutations have induced enlargement of the active site volume in all mutants with the exception of CYP2A6*16. Furthermore, loss of hydrogen bond between 8-MOP and active site residue Asn297 was evidenced in all mutants. Our data indicate that the structural changes elicited by the sequence mutations could affect 8-MOP binding to yield differential enzymatic activities in the mutant CYP2A6 proteins.     

A facile three-component [3+2]-cycloaddition for the regioselective synthesis of highly functionalised dispiropyrrolidines acting as antimycobacterial agents

A series of fourteen dispiropyrrolidines were synthesized using [3+2]-cycloaddition reactions and were screened for their antimycobacterial activity against Mycobacterium tuberculosis H₃₇Rv in HTS (High Throughput Screen). Most of the compounds showed moderate to good activity with MIC of less than 20 μM. Compound 4′-(4-bromophenyl)-1′-methyldispiro[acenaphthylene-1,2′-pyrrolidine-3′,2″-indane]-2,1″(1H)-dione (4c) was found to be the most active with MIC of 12.50 μM.     

Characterization of the nuclear envelope, pore complexes, and dense lamina of mouse liver nuclei by high resolution scanning electron microscopy

We have used high resolution scanning electron microscopy (SEM) to study the nuclear envelope components of isolated mouse liver nuclei. The surfaces of intact nuclei are covered by closely packed ribosomes which are distinguishable by SEM from nuclear pore complexes. After removal of nuclear membranes with the nonionic detergent Triton X-100, the pore complexes remain attached to an underlying, peripheral nuclear lamina, as described by others. The surface of this dense lamina is composed of particulate granules, 75-150 A in diameter, which are contiguous over the entire periphery. We did not observe the pore-to-pore fibril network suggested by other investigators, but such a structure might be the framework upon which the dense lamina is formed. Morphometric analysis of pores and pore complexes shows their size, structure, and density to be similar to that of other mammalian cells. In addition, several types of pore complex-associated structures, not previously reported by other electron microscope (EM) techniques, are observed by SEM. Our studies suggest that the major role of the dense lamina is associated with the distribution, stability, and perhaps, biogenesis of nuclear pore complexes. Treatment of isolated nuclei with a combination of Triton X-100 and sodium deoxycholate removes membranes, dense lamina, and nuclear pore complexes. The resulting "chromatin nuclei" retain their integrity despite the absence of any limiting peripheral structures.