Antiviral activity against HIV

Dideoxynucleosides are of interest because several members of this group exhibit potent antiviral activity against HIV, for example 169 and 170.246... 

By screening corporate databases Chan and co-workers [5] identified 6-arylthio-2-aminobenzonitriles with micromolar antiviral activity against HIV-1 modification to 6-arylsulfmyl- and 6-arylsulfonyl-2-aminobenzonitriles yielded classes with nanomolar activity. These data have recently been used [6] for a comparison of ligand- and structure-based GRID-derived procedures. Herein the same set is used to test the procedure. 

Examples of sulphated PS with anti-HIV activity also included sulphated a-D(l—>3)-linked mannans from Nothogenia fastigiata [24], from Schizymenia dubyi [25], anti-HIV PS from the brown seaweed Fucus vesiculosus [26] and from the marine microalga Cochlodinium polykrikoides [27]. Sulphated PS displaying antiviral activities against HIV-1 and human immunodeficiency virus type 2 (HIV-2) were also isolated from marine Pseudomonas and Dinoflagellata [28]. 

Certonardosides A-E (23-27), Fig. (9) are sulfated at C-3 of the xylopyranose unit attached to C-26 of the steroidal side chain, while certonardosides F-I (28a, 28b, 29a, 29b), Fig. (10) contain a sulfate group at C-6 (a) of the steroidal aglycone. The isolated compounds were evaluated for their antiviral activity against HIV, HSV, CoxB, EMCV and VSV viruses. Certonardosides A-J were inactive within the range of non cytotoxic concentrations. Only weak antiviral activity against HSV was observed in compounds 29a and 29b and the desulfated analog of 28b. 

Some 3 -5 e-substituted dideoxynucleosides in racemic forms, as well as the a- and p-anomers of oxaselenolane nucleosides have been synthesized and exhibited potent anti-HIV and anti-HBV activities. The synthesized racemic nucleosides (125, 126) were evaluated for antiviral activity against HIV virus type-1 and hepatitis B virus in peripheral blood... 

This chapter describes the procedures that can be used to determine compounds that have antiviral activity against HIV. These include maintenance of lymphoblastoid cell lines, preparation of peripheral blood mononuclear cells (PMMCs), and determination of the infectivity of the HIV stock-supernatant and antiviral assays. The assays described use both acutely and chronically infected cells. Toxicity of compounds is assessed by measuring 14C uptake. These protocols are used for the evaluation of compounds that can be carried out by a single individual in a Category 3 containment laboratory. The number of compounds analyzed would be about 10, which is a convenient number to fill a single 96-well p24 enzyme-linked immunosorbent assay (ELISA) plate. 

Oxanosine, a novel guanosine analogue antibiotic has been phosphorylated according to the Yoshikawa procedure to yield (17) and evaluated for in vitro antiviral activity against HIV proliferation. Compound (17) reduced the number of HIV particles in CEM cells to almost the same level as ddl. 

The isothiazolo[4,5-d]pyrimidin-3-yl C-nucleoside analogs of adenine and guanosine, 559 and 560, respectively, were also synthesized (94JOC1912). C-Nucleosides 552,558,559, and 560 were tested for antiviral activity against HIV, HCMV, HSV, and rhinoviruses and found inactive (93JOC5181 94JOC1912). 

Zidovudine (200 mg every 4 hours) is indicated in the management of patients with HIV infection who show evidence of impaired immunity. Trimethoprim-sulfamethoxazole, pyrimethamine, and acyclovir may be necessary for the management or prevention of opportunistic infections. Zidovudine (3 -azido-3 -deoxythymidine, commonly referred to as AZT) is a thymidine analog with antiviral activity against HIV-1, HIV-2, human T-lymphotropic (or leukemia) virus (HTLV)-I, and other retroviruses. Low concentrations (<0.001 to 0.04 pg/ml) inhibit acute HIV-1 infection in human T-cell lines and peripheral blood lymphocytes. Zidovudine is less active in human monocyte-macrophages or quiescent cells but inhibits HIV replication in human brain macrophages. Zidovudine is also inhibitory for HBV and EBV... 

Mechanism of Action. The drug is a nueleoside analogue structurally related to guanosine having distinct antiviral activity against HIV-1. Its acts as an inhibitor of viral reverse transcryptase and is under investigation in the treatment of AIDS. 

C6H.3N04, Mr 163.17, mp. 192-195 °C, [a] +47.5° (H2O). D. is a glucose-like piperidine derivative from the bark of the mulberry tree Moms). It can also be obtained by fermentation from Streptomyces species. On account of their ability to inhibit intestinal a-glu-cosidases, D. derivatives have been developed as oral antidiabetic drugs (e.g., Miglitol , Emiglitate ). D. derivatives also exhibit antiviral activity against Hiv (inhibition of the glycosylation of viral proteins). 

The boranophosphinate 18 was screened in vitro for antiviral activity against HIV -1, HIV -1 (IIIb) and HIV-2(ROD) but no activity was observed, even at 200 pM concentrations. Similar results were reported for hepatitis C virus (HCV) and herpes simplex virus. 

L-Ascorbic acid can be converted to the separable epimers 219 and 220 (Scheme 22) sequential oxidative degradation of each of them then gave routes to both the L-(-)- and D-(+)-enantiomers, 221 and 222 respectively, of dioxolane-C, together with the a-anomers.306 Other workers have also describe fully the synthesis of 222 and its thymidine analogue firom 1,6-anhydro-D-mannose (see Vol. 25, p. 211), and have used a similar approach, with 1,6-anhydro-L-gulose as precursor, to L-(-)-dioxolane-C 221, and to L-(+)-dioxolane-T. The L-(-)-isomer 221 of dioxolane-C was found to have higher antiviral activity against HIV and hepatitis B virus than the enantiomer... 

Extracts of balm have shown in vitro antiviral activity against HIV-1, herpes simplex, Newcastle disease virus, paramyxovirus (mumps vims), vaccinia, and other vimses. The active constituents include polyphenols (other than caffeic acid) and tannin. Extracts of balm have also shown in vitro antioxidant activity against lipid peroxida-tion m vitro antithyrotropic activity and antiulcerogenic activity in rats against indomethicin-induced ulcer formation. ... 

A series of novel acyclic nucleoside phosphonates (819) with various nucleobases in the oo-position and variously substituted in the p-position of alkylphosphonate chain, have been prepared by Hockowa et al. Several derivatives exhibited antiviral activity against HIV and vaccinia virus, HSV-1, HSV-2, VZV and CMV, although the parent unsubstituted derivatives were anti vitally inactive. Adenine as a nucleobase and the p-methyl group attached to the alkylphosphonate chain proved to be a prerequisite to afford pronounced antiviral activity. " ... 

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