A new class of pyridine oxide derivatives as inhibitors of human immunodeficiency virus type 1 (HIV-1) and/or HIV-2 replication in cell culture has been identified. The compounds, which specifically inhibit HIV-1, behave as typical nonnucleoside reverse transcriptase inhibitors (NNRTIs). The most active congener of this group, JPL-133 (UC-B3096), has a 50% effective concentration of 0.05 microg/ml for HIV-1(III(B)) with a selectivity index of approximately 760 in CEM cell cultures. However, the cytostatic activity of most pyridine oxide derivatives highly depended on the nature of the cell line. All compounds, including those pyridine oxide derivatives that inhibit both HIV-1 and HIV-2 replication, select for NNRTI-characteristic mutations in the HIV-1 reverse transcriptase of HIV-infected cell cultures (i.e., Lys103Asn, Val108Ile, Glu138Lys, Tyr181Cys and Tyr188His). These amino acid mutations emerged mostly through transition of guanine to adenine or adenine to guanine in the corresponding codons of the reverse transcriptase (RT) gene. The HIV-1-specific pyridine oxide derivatives lost their antiviral activity against HIV-1 strains containing these mutations in the RT. However, most compounds retained pronounced antiviral potency against virus strains that contained other NNRTI-characteristic RT mutations, such as Leu100Ile and Val179Asp. Furthermore, the complete lack of inhibitory activity of the pyridine oxide derivatives against recombinant HIV-2 RT and partial retention of anti-HIV-1 activity against HIV-1 strains that contain a variety of HIV-1-characteristic mutations suggest that the pyridine oxide derivatives must have a second target of antiviral action independent from HIV-1 RT.
Abstract Virtually all the compounds that are currently used, or under advanced clinical trial, for the treatment of HIV infections, belong to one of the following classes: (i) nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs): i.e., zidovudine, didanosine, zalcitabine, stavudine, lamivudine, abacavir, emtricitabine, tenofovir (PMPA), and disoproxil fumarate; (ii) non-nucleoside reverse transcriptase inhibitors (NNRTIs): i.e., nevirapine, delavirdine, efavirenz, and emivirine; and (iii) protease inhibitors (PIs): i.e., saquinavir, ritonavir, indinavir, nelfinavir, and amprenavir. In addition, various other events in the HIV replicative cycle are potential targets for chemotherapeutic intervention: (i) viral adsorption, through binding to the viral envelope glycoprotein gp120; (ii) viral entry, through blockade of the viral coreceptors CXCR4 and CCR5; (iii) virus-cell fusion; (iv) viral assembly and disassembly; (v) proviral DNA integration; and (vi) viral mRNA transcription. Also, new NRTIs, NNRTIs, and PIs have been developed that possess respectively improved metabolic characteristics, or increased activity against NNRTI-resistant HIV strains or, as in the case of PIs, a different, nonpeptidic scaffold. Given the multitude of molecular targets with which anti-HIV agents can interact, one should be cautious in extrapolating from cell-free enzymatic assays to the mode of action of these agents in intact cells.
9-[(2-Hydroxyethoxy)methyl]guanine (acyclovir, 1a) and 9-[(1,3-dihydroxy-2-propoxy)methyl]guanine (DHPG, ganciclovir, 1b) were transformed to their respective tricyclic derivatives, 3-substituted 3,9-dihydro-9-oxo-5H-imidazo[1,2-a]purines 2b, 3a, and 3b. The 6-methyl-substituted compound 2b was obtained following reaction of 1b with bromoacetone. A two-step approach via 1-(2,2-diethoxyethyl) intermediates 4a,b was the most effective for the preparation of the derivatives unsubstituted in the appended ring (3a,b). The novel acyclonucleosides, in particular ganciclovir derivative 2b, proved markedly active against herpes simplex virus type 1 and 2, varicella-zoster virus, and cytomegalovirus.
TPS 701: Spatial determinants of population health, Exhibition Hall, Ground floor, August 27, 2019, 3:00 PM - 4:30 PM Background/Aim: Mental health in a broad sense is defined as the ability to cope with problems and fulfill one’s role in society. In this area, Belgium has a poor record, featuring a high number of depressions and anxiety disorders. The NAMED project aims at exploring different dimensions of mental health in Belgium in relation to the (non) built environment. Methods: Data from the Health Interview Survey (HIS) 2008 and 2013 was used. Variables describing mental health and annoyance at home (air pollution, noise, smells, …) for 13.905 participants were analyzed using the R statistical language. Based on mixed factor analysis (FAMD) on mental health variables and environmental stressors, relevant indicators were selected and screened on differences between provinces. Results: Five indicators were selected for both mental health and environmental stressors based on their contribution to the first four dimensions. The state of mental health was similar in the majority of the provinces, but differences in the dimensions of mental health problems could be seen. Psychological distress was lowest in West-Flanders, and highest in Brussels. Subjective health however was highest in Brabant Walloon and lowest in West-Flanders. Suicidal ideation and depression was observed more often in Namur and Hainaut and less so in Limburg and Antwerp. Brussels performed poorly on nearly all dimensions of mental health. When looking at residential annoyances, traffic noise and vibrations were mentioned most often, and densely populated provinces were more affected than others. Airplane noise was most prevalent in Brussels and Flemish Brabant. More than 80% of the participants were not at all annoyed by air pollution at home. In Brussels, this drops to 60%. Conclusions: Provinces with more mention of environmental stressors appear to have more mental health problems, although this association is not always straightforward and depends on the dimension of mental health considered.
Some new isoindol heterocyclic ureas (6a-6i) have been synthesized using N-aminophthalimide (2) and ethyl N-monosubstituted/ethyl N,Ndisubstituted carbamate (5a-5i).All the newly synthesized final compounds have been evaluated for their anti-viral activities against a variety of viruses.The compound (6f) with the methoxy substituent showed reasonably better activity as compared to the standard drugs against all the viruses (cf.Tables 1, 2 and3).Further, all the products (6a-6i) were found to be active against Vesicular stomatitis virus, Coxsackie virus B4 and Respiratory syncytical virus (cf.Table 2) and the compounds (6h) and (6i) displayed better antiviral activity in comparison to Brivudin and (S)-DHPA (cf.Table 3).
No abstract is provided for this article.
