Synthesis and Biological Properties of Amino Acid Amide Ligand-Based Pyridinioalkanoyl Thioesters as Anti-HIV Agents (original) (raw)
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Bioorganic & Medicinal Chemistry, 1998
AbstractÐThe synthesis and antiviral evaluation of 21 prodrugs of 1-[2 H ,3 H -dideoxy-3 H -C-(hydroxymethyl)-b-D-erythropentofuranosyl] cytosine 1 is reported. Cytosine N 4 -imine analogues were prepared by condensation of 1 with selected formamide dimethyl acetals. Amino acid substituted prodrugs were prepared from 1 or imine prodrug 2 by coupling with either N-tert-butoxycarbonyl (t-Boc)-L-valine or N-t-Boc-L-phenylalanine in the presence of dicyclohexycarbodiimide (DCC) and 4-dimethylaminopyridine (4-DMAP). Deprotection of the t-Boc protecting group was achieved with tri¯uoroacetic acid (TFAA) in methylene chloride. Cytosine N 4 -amide analogues were prepared by reaction of 1 with appropriate anhydrides in aqueous dioxane. Triacylated analogue 22 was prepared by reaction of 1 with four equivalents of benzoyl chloride in pyridine. Prodrugs were evaluated for activity against duck hepatitis B virus, herpes simplex virus types 1 and 2, human cytomegalovirus, and human immunode®ciency virus. A number of analogues were found comparable in activity to 1 with the cytosine N 4 -imine series more active than the amino acid substituted and cytosine N 4 -amide prodrugs. Slight to moderate cellular toxicity was observed with some analogues. #
Antiviral Compounds: A Road to Quest for Novel Antiviral Drugs
Viruses exemplify the most common reason of infectious diseases worldwide and those with prompt propagation and high infection rates cause animal and human pandemics. These rapid-spreading diseases are usually treated with antiviral drugs but, often, drug resistance occurs because of the capability of the pathogens to mutate quickly and become less vulnerable to the treatments. Several compounds have been developed and some of them have exposed good antiviral activity. This review provides an overview on some already known compounds, pointing the attention on the running progresses in identifying and designing novel compounds with outstanding antiviral activity.
Recent advances on heterocyclic compounds with antiviral properties
Chemistry of Heterocyclic Compounds, 2021
In recent years several important viral infections have emerged and antiviral chemotherapeutic agents are not sufficiently effective in clinic, leading to serious human diseases and mortality. Therefore, novel antiviral candidates are urgently desirable, which undoubtedly is essential for the therapy of various fatal and debilitating viral infections. Heterocyclic compounds are obtaining importance in the field of medicinal chemistry because of the broad spectrum of their physiological activities. Among N-and S-containing heterocycles, indole, imidazole, thiazole, pyridine, and quinaxoline derivatives are especially attractive. The present review highlights antiviral behavior of these heterocyclic compounds.
Abstract. The synthesis of 4-methoxy-, 4-amino-3-chloro-, and 4-amino- 1-(2,3- dideoxy-B-D-glycero-pentofuranosyl)pyridazin-6-onen ucleosides, 6,19 and 20 is described. The synthesis of 3,4-dichloropyridazin-6-one(1 0) was accomplished in 44% overall yield using bromomaleic anhydride (17) as the starting material. The condensation of the silylated base of 10 with the halogenose 12 in the presence of trimethylsilyl triflate as a catalyst afforded a mixture of 3,4-dichloro-l-(3,5-di-O-p-toluoyl-2-deoxy-RDeryrhro- pentofuranosyl)pyridazin-6-one (13) in 67% and its a-anomer 14 in 12% yield, respectively. A series of 3'-sulfonate esters were prepared to explore the synthesis of 3- chloro-4-hydroxy- 1 -(3-azido-2,3-dideoxy-~-D-erythro-pentofuranosyl)p~dazin-6-one (32) via 6,3-anhydronucleoside analogues. Compounds 15,19 and 20 were evaluated against human immunodeficiency virus, human cytomegalovirus, and herpes simplex virus type 1 but were inactive.
Antimicrobial Agents and Chemotherapy, 2008
Seventy-three analogs of SJ-3366 (1-(3-cyclopenten-1-ylmethyl)-5-ethyl-6-(3,5-dimethylbenzoyl)-2,4(1H,3H)pyrimidinedione) were synthesized and comparatively evaluated for their ability to inhibit the replication of human immunodeficiency virus type 1 (HIV-1) and HIV-2 and for their ability to suppress virus entry and reverse transcription. These studies were performed to identify inhibitors with activity greater than that of the current lead molecule (SJ-3366) and to utilize structure-activity relationships (SAR) to define the chemical features of the pyrimidinedione congeners responsible for their efficacy, toxicity, and dual mechanism of action against HIV. The results of our SAR evaluations have demonstrated that the addition of the homocyclic moiety at the N-1 of the pyrimidinedione results in acquisition of the ability to inhibit virus entry and extends the range of action of the compounds to include HIV-2. In addition, the results demonstrate that analogs with a methyl linker between the homocyclic substitution and the N-1 of the pyrimidinedione had a greater number of highly active molecules than those analogs possessing ethyl linkers. Six molecules were identified with activity equivalent to or greater than that of SJ-3366, and five additional molecules with highly potent inhibition of reverse transcriptase and virus entry and possessing high efficacy against both HIV-1 and HIV-2 were identified. Six molecules exhibited significant inhibition of viruses with the highly problematic nonnucleoside reverse transcriptase inhibitor (NNRTI) resistance engendering amino acid change K103N in the reverse transcriptase. These evaluations indicate that a new class of NNRTIs has been identified and that these NNRTIs possess highly potent inhibition of HIV-1 with an extended range of action, which now includes HIV-2.
3-Benzamido, Ureido and Thioureidoimidazo[1,2-a]pyridine Derivatives as Potential Antiviral Agents
CHEMICAL & PHARMACEUTICAL BULLETIN, 2001
The first antiretroviral agents approved for the treatment of AIDS were nucleosidic inhibitors of reverse transcriptase such as Zidovudine. Later, the human immunodeficiency virus (HIV) protease inhibitors (e.g. saquinavir) were introduced as therapeutics. Recently, a third class of antiretroviral agents, the non-nucleosidic reverse transcriptase inhibitors (NNRTIs) (i.e. nevirapine, delavirdine, efavirenz) have been marketed. Since the discovery of the anti-HIV activity of 1-[(2-hydroxyethoxy)methyl]-6-(phenylthio)thymidine (HEPT) 1) and tetrahydroimidazo[4,5,1-jk][1,4]benzodiazepin-2(1H)-one and thione (TIBO) 2) as the first NNRTIs, numerous additional compounds have been reported as NNRTIs. 3) From all the active compounds, some common characteristics have emerged. First, NNRTIs interact with a non-substrate binding site that is located in the close vicinity of the substrate binding site of HIV-1. As a consequence, all these compounds are deprived of activity against HIV-2. Furthermore, structural studies have shown that these derivatives contain a central hydrophilic part and two hydrophobic moieties, generally an aromatic cycle forming a butterfly-like conformation. 4) Finally, most of these compounds contain an amide, thioamide, urea or thiourea function in their structure. 5) In continuation of our studies on the antiviral activities of bridgehead nitrogen heterocycles, 6) we were interested in the synthesis of amide, urea and thiourea derivatives within the imidazo[1,2-a]pyridine series. In a first approach, we studied the introduction of these functions in the 3-position. Chemistry The 2-aminopyridine 1a was reacted with bromoacetone or bromopinacolone in refluxing ethanol to give the imidazo[1,2-a]pyridines 2a, b (Chart 1). It is now well established that in this series, electrophilic substitution occurs in the 3-position. 7) Thus a cooled solution (Ϫ5°C) of 2a, b in concentrated sulfuric acid was treated with nitric acid, the temperature not rising above 5°C. Then the reaction mixture was allowed to stand at 20°C to give the 3-nitro compounds 3a, b in good yields. Reduction of the nitro compounds using tin in hydrochloric acid at room temperature gave the amino
Journal of Virological Methods, 2008
HIV-1 Env pseudotyped viruses (PV) are an attractive tool for studying the antiviral activities of compounds interfering with virus entry into a target cell. To investigate whether results obtained in PV assays are relevant biologically, the antiviral activity of 6 reference compounds was compared on 5 virus isolates of different clades using three assays: (1) replicating virus in peripheral blood mononuclear cells (PBMCs), (2) PV in CD4 and CCR5-or CXCR4 co-receptor expressing Ghost cells, and (3) PV in PBMCs. A significant linear relationship was found between both single-cycle PV assays (P < 0.0001, R 2 = 0.75). Moreover, both assays showed enhanced sensitivity to the antiretrovirals tested (P = 0.013 and 0.015, respectively) as compared to the PBMC assay with replication-competent virus. Most importantly, results from the latter assay could be predicted significantly from both PV assays, in which either Ghost target cells (P < 0.0001, R 2 = 0.61) or PBMCs (P < 0.0001, R 2 = 0.55) were used. The usefulness of the PV assay was demonstrated further by investigating the impact of the HIV-1 Env subtype on the antiviral activity of five new compounds derived from the entry inhibitor BMS806.