ABSTRACT
A library of 585 compounds built off a 7-azaindole core was evaluated for anti-HIV-1 activity, and ten hits emerged with submicromolar potency and therapeutic index >100. Of these, three were identified as non-nucleoside reverse transcriptase (RT) inhibitors and were assayed against relevant resistant mutants. Lead compound 8 inhibited RT with submicromolar potency (IC50=0.73µM) and also maintained some activity against the clinically important RT mutants K103N and Y181C (IC50=9.2, 3.5µM) in cell-free assays. Free energy perturbation guided lead optimization resulted in the development of a compound with a two-fold increase in potency against RT (IC50=0.36µM). These data highlight the discovery of a unique scaffold with the potential to move forward as next-generation anti-HIV-1 agents.
Subject(s)
HIV Reverse Transcriptase/antagonists & inhibitors , HIV-1/enzymology , Indoles/chemistry , Reverse Transcriptase Inhibitors/chemistry , Animals , Binding Sites , Cell Survival/drug effects , Chlorocebus aethiops , Drug Evaluation, Preclinical , HIV Reverse Transcriptase/genetics , HIV Reverse Transcriptase/metabolism , HIV-1/drug effects , Humans , Indoles/metabolism , Indoles/pharmacology , Indoles/toxicity , Molecular Docking Simulation , Mutagenesis, Site-Directed , Protein Binding , Protein Structure, Tertiary , Reverse Transcriptase Inhibitors/metabolism , Reverse Transcriptase Inhibitors/pharmacology , Vero CellsABSTRACT
The geometric mean 50% inhibitory concentration (IC50) for Proveblue, a methylene blue complying with the European Pharmacopoeia, was more active on 23 P. falciparum strains than chloroquine, quinine, mefloquine, monodesethylamodiaquine, and lumefantrine. We did not find significant associations between the Proveblue IC50 and polymorphisms in the pfcrt, pfmdr1, pfmdr2, pfmrp, and pfnhe-1 genes or the copy numbers of the pfmdr1 and pfmdr2 genes, all of which are involved in antimalarial resistance.
Subject(s)
Antimalarials/pharmacology , Methylene Blue/pharmacology , Plasmodium falciparum/genetics , Amodiaquine/analogs & derivatives , Amodiaquine/pharmacology , Chloroquine/pharmacology , Ethanolamines/pharmacology , Fluorenes/pharmacology , Inhibitory Concentration 50 , Lumefantrine , Mefloquine/pharmacology , Plasmodium falciparum/drug effects , Polymorphism, Genetic/genetics , Protozoan Proteins/genetics , Quinine/pharmacologyABSTRACT
OBJECTIVES: The aim of this survey was to compare the level of professional stress among seamen--crew members--who work on French oceanographic vessels to the one of technicians and engineers from the oceanographic institute, who board the ships to operate special equipment during sea voyages. METHOD: Two questionnaires were used for collecting data: Langner's total health test (22 items) that investigates the level of psychical stress. Karasek's "Job Content Questionnaire" (38 items) used for investigation of strain at work, psychological pressure, decision latitude and social support. Data were processed by a statistical software: Sphinx, using Chi2 test. RESULTS: two groups of subjects were included: 74 seamen and 74 non seamen, males of comparable ages were questioned. Results showed that there was no significant difference in strain at work and social support between them (41 seamen and 50 non seaman professionals who filled in the questionnaires). There was a very significant difference in the decision latitude: much lower level for seamen as compared to non seamen. 17% compared to zero percent of non seamen were ranked in the heavy strain/low decision latitude category regarded by Karasek as a high risk of stress (compared to 0% of non seaman professionals). 33% of seamen in this group reached a score that indicated psychical stress according to Langner's total health test. CONCLUSION: The results of the survey show that the occupation of seamen includes specific elements regarded by Karasek as leading to a risk of stress.