p-(3-Amino-1-adamantyl)calix [4]arenes with free and alkylated lower rim, representing conjugates of the aminoadamantane pharmacophore fragment and the calixarene platform, were synthesized for the first time by the Curtius rearrangement route starting from p-(3-carboxy-1-adamantyl)calix [4]arenes. The synthesized compounds were evaluated for activity against herpes simplex virus 2 (HSV-2). The nonalkylated compound with free phenol hydroxy groups is the first aminoadamantylcalixarene reported to possess antiviral properties (chemotherapeutic safety index, SI » 12.5). Alkylation at the lower rim of the calixarene platform leads to an increase in cytotoxicity and to the disappearance of anti-HSV activity.Calix[4]arenes (I) represent cyclic metacyclophanes, which are composed of phenol fragments bridged by methylene groups. These compounds have recently received much attention for their ability to serve as receptors of metal ions and neutral molecules, which opens up ways to using them as carriers, sensors, chromatographic media, ligands in homogeneous catalysis, etc.[1].Although the antituberculous activity of p-tert-octylcalix[8]arene modified at the lower rim with poly(oxyethylene) substituents (I with R = tert-octyl, X = (CH 2 CH 2 O) n H, n = 8) was observed as long ago as in 1955 (then it was considered a tetramer) [2 -4], data available on the pharmacological properties of calixarene derivatives are still rather restricted. In 1996, Casnati et al. reported on the antimicrobial activity of vancomycin antibiotic mimetics based on calix[4]arenes modified with dipeptide bridges at the upper rim [5]. Various calixarene derivatives with sulfonate, carboxylate, phosphoryl, and sulfamide groups at the upper rim were patented as antithrombotic [6], antiviral [7 -9], antimicrobial [10], and antibacterial, antifungal, and antitumor [11] agents. Among calix[n]arenes (n = 4, 6, 8), derivatives with R = SO 3 Na, (CH 2 ) m CO 2 H (m = 0 -2), PO 3
The interest of researchers toward the synthesis of nucleoside compounds is explained to a considerable extent by the successful use of these preparations for the treatment of viral and oncological disorders. In particular, 3'-azido-2',3'-dideoxythymidine (azidothymidine) is capable of strongly inhibiting HIV-1 infection and is widely used under clinical conditions for the therapy of AIDS patients. 2-Amino-9-[(2-hydroxyethoxy)methyl]-6,9-dihydro-lH-purine (acyclovir or aciclovir) has proved to be an effective remedy against HSV infection [1 -3]. Also synthesized and tested were numerous pyrimidine derivatives (in particular, 2'-deoxyuridine analogs) modified with respect to both the nucleic acid residue and the sugar fragment [4 -8]. The synthesis of acyctovir has stimulated the search for new antiviral agents in the series of acyclic ufidine analogs [9]. However, we failed to find any published data on the synthesis and biological properties of nucleoside analogs with framework subsfituents in the nucleic base. At the same time, one may expect that an adamantane fragment would significantly modify the conformation and physicochemical properties of these compounds, thus affecting their interactions with cell membranes as well, which could markedly change the substrate properties of the initial substances [10,11]. As for adamantylated nucleic bases as such, several 5-and 6-adamantylpyridines possessing antiherpetic activity were reported in [12 -14].The purpose of this work was to synthesize a 2'-deoxyuridine derivative (I), modified with a lipophilic adamantyl fragment in position 5, and the corresponding acyclic analogs (II-V), containing (2-hydroxyethoxy)methyl-and isopropoxymethyl substituents in position N1 of the pyrimidine nucleus, and study the effect of these structural changes upon the antiviral properties of the compounds.The synthesis of nucleoside analogs I-V was based on the use of 5-(3-R-1-adamantyl)uracils VI and VII as the initial compounds. Although there is a considerable number of adamantane-eontaining heterocycles [15], the number of re- Recently, we have developed a new effective method for the Cs-adamatylation of hydroxy-, amino-, and chloropyfimidines using a reaction with hydroxyadamantanes in trifluoroacetic acid (TFA) [ 18]. The 5-(1-adamantyl) uracil VII used in this work were synthesized by reactions of uracil with 1-adamantanol (VIII) or 3-iso-propyl-l-adamantanol (IX) in TFA with a yield of 96 and 93%, respectively. As was demonstrated previously [19], 2-(1-adamantyl)-2-propanol (X) is completely isomerized in TFA to 3-iso-propyl-l-adamantanol (IX). It was also found that interaction between equimolar amounts of uracil and alcohol X on boiling in TFA leads to (3-iso-propyl-1-adamantyl)uracil VII with a 69% yield.
Introduction. A significant increase in the incidence of various forms of herpesvirus infection (HVI) determines the need to search for new approaches to the modification of one of the basic antiviral drugs aciclovir (ACV) and its dosage forms to improve their biopharmaceutical characteristics and increase the effectiveness of therapy. In this aspect, an innovative organic germanium complex with aciclovir (OGCA) is promising.The aim of the study was to assess the antiviral activity of OGCA against the herpes simplex virus (HSV) (human herpes virus, HHV) on the HVI models both in vitro and in vivo.Material and methods. We studied the activity of OGCA in a therapeutic regimen against HSV-1 (HHV-1) (Kl strain), HSV-2 (HHV-2) (VN strain) using virological and statistical research methods in the in vitro model of HVI on Vero cell culture and the model of genital herpes (GH) caused by HHV-2 (VN strain) in male guinea pigs (Canis porcellus).Results and discussion. It was found OGCA inhibits the replication of HHV-1 and HHV-2 in Vero cells, and has anti-HHV activity in the GH model in male guinea pigs, leading to a decrease in the severity and duration of the disease, the intensity and duration of viral shedding. The most pronounced activity was detected when preparation was applied topically 5 times a day for 5 days at the early stages of infection (3% gel). The delayed use of OGCA (48 hours after infection) also had statistically significant efficacy compared to commercial reference drugs containing aciclovir or its pro-drugs: aciclovir (5% cream), AIL (acyclovir+interferon alfa-2b+lidocaine, 3% ointment), penciclovir (1% cream). OGCA significantly reduced the number of days of the pathogen shedding, as well as its infectivity, compared to animals in the control group and ones receiving placebo. The activity of OGCA, apparently, is due to its improved biopharmaceutical characteristics compared to aciclovir, as well as the presence of a number of biological activities of its constituent components.Conclusion. The results of the study allow us to consider OGCA as the basis for the development of antiviral agents for the treatment of HVI.
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