No abstract is provided for this article.
A series of 2-arylidene-1-indanones, 1, had been shown previously to display cytotoxic properties towards Molt 4/C8, CEM and L1210 cells. In the present study, two series of analogues of 1 were prepared namely various 2-arylidene-1,3-indandiones, 2, and chalcones, 3. In general, the potencies of compounds 2 and 3 were greater than the analogues bearing the same aryl substituents in series 1. Molecular modeling was undertaken in order to seek explanations for the variation in bioactivities.
Over 70 alkyl derivatives of purine bases were examined for their inhibitory effects toward rat liver S-adenosyl-L-homocysteine hydrolase and their antiviral activity. The following structural features must be fulfilled by an inhibitor of SAH-hydrolase: an intact adenine moiety, an alkyl chain bound at the 9-position and bearing a vicinal diol at the 2',3'-position, with 2 S configuration. An additional substitution at the 3-position lowers or annihilates the inhibitory activity. The enzyme inhibition is reversible. Some of the compounds are substrates of adenosine aminohydrolase. All inhibitors of SAH-hydrolase exhibit antiviral activity, e.g. against vesicular stomatitis virus and vaccinia virus in cell culture, and this antiviral correlates with the inhibition of SAH-hydrolase.
The importance of human adenovirus infections in immunocompromised patients urges for new and adequate antiadenovirus compounds. Since human adenoviruses are species specific, animal models for systemic adenovirus infections rely on a nonhuman adenovirus. We established mouse adenovirus type 1 (MAV-1) infection of BALB/c SCID mice as a model for the evaluation of antiadenovirus therapy. In vitro studies with mouse embryonic fibroblasts pointed to the acyclic nucleoside phosphonate cidofovir and the N-7-substituted acyclic derivative 2-amino-7-(1,3-dihydroxy-2-propoxymethyl)purine (S-2242) as markedly active compounds against MAV-1. SCID mice, infected intranasally with MAV-1, developed a fatal disseminated infection after approximately 19 days, characterized by hemorrhagic enteritis. Several techniques were optimized to monitor viral, immunological, and pathological aspects of MAV-1 infection. Real-time PCR quantification of viral DNA revealed that after replication in the lungs, virus disseminated to several organs, including the brain, liver, spleen, intestine, heart, and kidneys (resulting in viruria). Immunohistochemical staining showed that MAV-1 was localized in the endothelial cells of the affected organs. Using reverse transcription-PCR, tissue levels of proinflammatory cytokines (i.e., interleukin-1beta and tumor necrosis factor alpha) were found to be markedly increased. The MAV-1/SCID model appears to be an appropriate model for in vivo evaluation of antiadenovirus agents. Treatment with cidofovir or S-2242 at a dose of 100 mg per kg of body weight resulted in a significant delay in MAV-1-related death, although these antivirals were unable to completely suppress virus replication despite continued drug treatment. These findings suggest that complete virus clearance during antiviral therapy for disseminated adenovirus infection may require an efficient adaptive immune response from the host.
A large variety of antiherpes compounds was compared for their inhibitory activity against laboratory strains and clinical isolates of herpes simplex virus (HSV) type 1 and type 2. From studies performed in primary rabbit kidney cell cultures, six, E-5-(2-bromovinyl)-2'-deoxyuridine, E-5-(2-iodovinyl)-2'-deoxyuridine, 5-vinyl-2'-deoxyuridine, 2'-fluoro-5-iodoaracytosine, acycloguanosine, and 5-iodo-2'-deoxycytidine, emerged as the most potent and selective antiherpes agents. For HSV type 1, the 50% inhibitory doses (ID50) were 0.008, 0.012, 0.018, 0.017, 0.04, and 0.06 micrograms/ml, respectively; those for HSV type 2 were 1, 2, 0.1, 0.05, 0.04, and 0.3 microgram/ml, respectively. These compounds did not inhibit host-cell metabolism or replication of vaccinia virus except at concentrations 100--10,000 times greater than the ID50 for any HSV. All were significantly less inhibitory for a thymidine kinase (TK)-deficient mutant of HSV type 1 than for normal strains, suggesting that phosphorylation by virus-induced TK was required to produce specific inhibition of HSV replication.
Currently the long-term usage of traditional anti-HIV drugs, such as nucleoside reverse transcriptase inhibitors (NRTIs), nonnucleoside reverse transcriptase inhibitors (NNRTIs) and protease inhibitors (PIs), eventually leads to the emergence of drug resistance and severe side effects. Thus it is imperative to design and develop more promising HIV-1 inhibitors to overcome these drawbacks. Fortunately, with the identification of some fascinating targets in the entry process of viral life cycle, HIV-1 entry inhibitors (EIs) with low cytotoxicity and mild side effects turned out as novel and effective anti-HIV agents. Especially, of these potent EIs, small molecule CCR5 antagonist maraviroc was approved by US FDA in 2007, which significantly increased the therapeutic options for the clinical treatment of HIV-infected patients. Subsequently, as promising anti-HIV drug candidates, kinds of small molecule CCR5 antagonists have been synthesized and evaluated in clinical trials. In this article, current progress in the development of novel small molecule CCR5 antagonists will be reviewed on the basis of their chemical structures with a special attention to their discovery stories. Simultaneously, binding mode analysis based on molecular modeling studies will also be introduced.
The effects of systemic administration of E-5-(2-bromovinyl)-2'-deoxyuridine (BVDU) and interferon (IFN)--mouse IFN type I (MuIFN-alpha plus -beta), mouse IFN type II (MuIFN-gamma), and polyriboinosinic-polyribocytidylic acid (an IFN inducer)--on the development of herpetic skin lesions and associated mortality were studied in athymic nude (nu/nu) mice inoculated intracutaneously with herpes simplex virus (HSV) type 1 (strain KOS). BVDU was given intraperitoneally or orally at dosages of up to 5 mg per mouse per day; IFN and polyriboinosinic-polyribocytidylic acid were given intraperitoneally at dosages of up to 10(6) units per mouse per day and 100 microgram per mouse per day, respectively. Under conditions in which BVDU effectively suppressed the progression of the disease, IFN and polyriboinosinic-polyribocytidylic acid failed to suppress the disease. Thus, BVDU was superior to IFN in the treatment of HSV infection in immunologically compromised mice.
