2-Trifluoromethylthiazole-5-carboxamides: Analogues of a Stilbene-Based Anti-HIV Agent that Impact HIV mRNA Processing.

The observation that stilbene 3 (5350150) blocks HIV replication through its impact on HIV mRNA processing prompted a program to develop non-cytotoxic analogues that maintain its mechanism of action. This initially involved replacement of the central double bond in 3 by an amide function and the quinoline motif by a 2-aminobenzothiazole subunit, as in 12jj (R' = Cl), 12pp (R = NO2), and 12vv (R = CF3). On the basis of the possible CF3 ↔ NO2 bioisostere relationship in 12vv and 12pp, compound 23 was prepared and also found to be active. In the final step, the thiazole compounds 28 (GPS488) (EC50 = 1.66 µM) and 29 (GPS491) (EC50 = 0.47 µM) were prepared and evaluated. Similar activity and cell viability values (therapeutic index (TI = CC50/EC50) values of 50-100) were observed in primary peripheral blood mononuclear cells. Furthermore, they remained active against a panel of HIV mutant strains displaying resistance to individual drugs used in antiretroviral therapy. It was determined that compound 29 suppressed expression of the HIV-1 structural protein Gag and altered HIV-1 RNA accumulation, decreasing the abundance of RNAs encoding the structural proteins while increasing levels of viral RNAs encoding the regulatory proteins, a pattern similar to that seen for compound 3.

A Parallel Synthesis Approach to the Identification of Novel Diheteroarylamide-Based Compounds Blocking HIV Replication: Potential Inhibitors of HIV-1 Pre-mRNA Alternative Splicing.

A 256-compound library was evaluated in an anti-HIV screen to identify structural "mimics" of the fused tetracyclic indole compound 1 (IDC16) that conserve its anti-HIV activity without associated cytotoxicity. Four diheteroarylamide-type compounds, containing a common 5-nitroisobenzothiazole motif, were identified as active. In subsequent screens, the most potent compound 9 (1C8) was active against wild-type HIV-1IIIB (subtype B, X4-tropic) and HIV-1 97USSN54 (subtype A, R5-tropic) with EC50's of 0.6 and 0.9 µM, respectively. Compound 9 also inhibited HIV strains resistant to drugs targeting HIV reverse transcriptase, protease, integrase, and coreceptor CCR5 with EC50's ranging from 0.9 to 1.5 µM. The CC50 value obtained in a cytotoxicity assay for compound 9 was >100 µM, corresponding to a therapeutic index (CC50/EC50) of approximately 100. Further comparison studies revealed that, whereas the anti-HIV activity for compound 9 and the parent molecule 1 are similar, the cytotoxic effect for compound 9 was, as planned, markedly suppressed.

The effects of self-care training on quality of life in patients with multiple sclerosis.

BACKGROUND: Multiple sclerosis (MS) is a chronic and progressive disease of the central nervous system with debilitating symptoms and complications. Therefore, education and appropriate interventions, including self-care education, are necessary to increase the quality of life in these patients. The purpose of this study was to determine the influence of self-care education on quality of life in MS patients affiliated to Iranian MS Association. MATERIALS AND METHODS: This quasi-experimental study assessed a single group of MS patients before and after training. Totally, 50 MS patients were selected non-randomly from the patients referring to Iranian MS Association. A two-part questionnaire was used to collect data. The first part included demographic information and the second part consisted of a quality of life questionnaire (MSQOL-54) including 54 items in 3 sections and 14 subgroups. The scores ranges from zero to a hundred in each subgroup. The reliability of the questionnaire has been confirmed (Cronbach's alpha = 0.96). The questionnaires were filled out by the patients before training. After at least six 50-minute training sessions during three months, the same questionnaire was again completed by the participants. Statistical analyses, including absolute and relative frequency tables and mean and standard deviation for descriptive analysis, and t-test and Pearson correlation for descriptive analysis, were performed by SPSS. FINDINGS: The mean values of quality of life in physical health, pain, fatigue, health conception, changes in health status, sexual activities, as well as overall quality of life scores differed significantly after training. Moreover, except for cognitive activity, there were significant differences in values of mental health before and after training. CONCLUSIONS: Designing and applying the self-care programs based on the educational needs of MS patients has a positive effect on physical and psychological aspects of their quality of life.