Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0021051 (immunodeficiency)
 71,517 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

6-Chloropurine arabinoside (3a) was obtained by treatment of the 2'-O-acetylated congener (2) with ammonia in methanol. The 3',5'-di-O-tritylated riboside (6) was allowed to react with diethylaminosulfur trifluoride (DAST) in the presence of pyridine to give the 2'-deoxy-2'-fluoroarabinoside (7), from which 6-chloro-9-(2-deoxy-2-fluoro-beta-D-arabinofuranosyl)purine (3b) was obtained. The antiviral effects of 3a and 3b were assayed against several DNA and RNA viruses. Only 3a displayed potent activity against varicella-zoster virus (VZV). This antiviral activity was dependent on phosphorylation by the VZV-induced thymidine kinase (TK). Compound 3a showed moderate activity against other DNA viruses, herpes simplex type 1 (HSV-1) and type 2 (HSV-2), and vaccinia virus. They were equally active against TK- and TK+ strains of HSV-1, which suggests that the HSV-1-encoded TK does not play a role in the anti-HSV-1 activity. No activity was noted with any of the compounds against various RNA viruses, including human immunodeficiency virus, at subtoxic concentrations.
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PMID:Synthesis and antiviral activity of 6-chloropurine arabinoside and its 2'-deoxy-2'-fluoro derivative. 899 65

The synthesis and antiviral evaluation of 21 prodrugs of 1-[2',3'-dideoxy-3'-C-(hydroxymethyl)-beta-D-erythropentofuranosyl ] cytosine 1 is reported. Cytosine N4-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 trifluoroacetic acid (TFAA) in methylene chloride. Cytosine N4-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 immunodeficiency virus. A number of analogues were found comparable in activity to 1 with the cytosine N4-imine series more active than the amino acid substituted and cytosine N4-amide prodrugs. Slight to moderate cellular toxicity was observed with some analogues.
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PMID:Synthesis and antiviral activity of prodrugs of the nucleoside 1-[2',3'-dideoxy-3'-C-(hydroxymethyl)-beta-D-erythropentofuranosyl] cytosine. 962 71

Atevirdine mesylate (U-87201E) is a highly specific nonnucleoside inhibitor of human immunodeficiency virus type 1 reverse transcriptase. The absorption, metabolism, and excretion of atevirdine were investigated in male and female Sprague-Dawley rats after oral administration of nonradiolabeled atevirdine mesylate at doses of 20 mg/kg/day or 200 mg/kg/day for 8 days, with [14C]atevirdine mesylate single doses of 10 mg/kg or 100 mg/kg on study days 1 and 10. The distribution of [14C]atevirdine mesylate was also evaluated by whole-body autoradiography in male and female Sprague-Dawley, pregnant Sprague-Dawley, and male Long-Evans rats after a single 10 mg/kg oral dose. Plasma levels of atevirdine and its N-desethyl and O-desmethyl metabolites were determined by high-performance liquid chromatography (HPLC) with ultraviolet detection, urine and feces were profiled for atevirdine and metabolites by HPLC with radiochemical detection, major metabolites in urine were isolated and identified by nuclear magnetic resonance and mass spectrometry, and minor urinary metabolites were identified by liquid chromatography/mass spectrometry. Atevirdine was rapidly absorbed. The pharmacokinetics of atevirdine were nonlinear. Gender differences in the pharmacokinetics and metabolism of atevirdine were observed, consistent with the involvement of cytochrome P450 3A. Atevirdine effectively crossed the blood-brain barrier and had a high rate of maternal-fetal transfer. At the low doses, <2% of the dose was excreted as unchanged parent drug, while atevirdine constituted 9%-25% of the dose at the high doses. The metabolism of atevirdine was extensive in the rat and involved N-deethylation, O-demethylation, hydroxylation at the C-6 position of the indole ring, and hydroxylation of the pyridine ring.
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PMID:Absorption, distribution, metabolism, and excretion of atevirdine in the rat. 976 7

A quantitative structure-activity relationship (QSAR) study has been made on different series of cycloalkylpyranones acting as human-immunodeficiency-virus type 1 (HIV-1) protease inhibitors. The results suggest that the enzyme binding affinity of the compounds would be favoured by a cyclooctyl ring, a 3-cyclopropylphenylmethyl substituent at the pyranone ring, and a 4-CN-2-pyridine-, an N-Me-imidazole-, or a 3- or 4-CN-phenyl-sulfonamide group at the meta position of the phenyl ring of the 3-substituent.
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PMID:Quantitative structure-activity relationships of some HIV-protease inhibitors. 1044 38

Pyrrolobenzoxazepinone (PBO) derivatives represent a new class of human immunodeficiency virus type 1 (HIV-1) non-nucleoside reverse transcriptase (RT) inhibitors (NNRTs) whose prototype is (+/-)-6-ethyl-6-phenylpyrrolo[2,1-d][1,5]benzoxazepin-7(6H)- one (6). Docking studies based on the three-dimensional structure of RT prompted the synthesis and biological evaluation of novel derivatives and analogues of 6 featuring a meta-substituted phenyl or a 2-thienyl ring at C-6 and a pyridine system in place of the fused-benzene ring to yield pyrrolopyridooxazepinones (PPOs). Compared with the lead 6 and nevirapine, several of the synthesized compounds (PBOs 13a-d and PPOs 13i-k) displayed higher inhibitory activity against wild-type RT and clinically relevant mutant RTs containing the single amino acid substitutions L100I, K103N, V106A, Y181I, and Y188L. The most potent inhibitors were further evaluated for in vitro antiviral activity on lymphocytes and monocyte-macrophages, for cytotoxicity on a panel of cell lines, and for potential synergistic antiviral activity with AZT. Pharmacokinetic studies performed on 13b, 13c, and 13i showed that these compounds achieve high concentrations in the brain. The results of the biological and pharmacokinetic experiments suggest a potential clinical utility of analogues such as 13b-d, 13i, and 13j, in combination with nucleoside RT inhibitors, against strains of HIV-1 bearing those mutations that confer resistance to known NNRTI.
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PMID:Pyrrolobenzoxazepinone derivatives as non-nucleoside HIV-1 RT inhibitors: further structure-activity relationship studies and identification of more potent broad-spectrum HIV-1 RT inhibitors with antiviral activity. 1054 90

More than 60 human immunodeficiency virus protease inhibitors were examined for the structure-activity relationship between metabolic stability, CYP3A4 inhibitory potency, and substrate-induced binding spectra with a ferric form of P450 in human liver microsomes. A positive relationship was found between CYP3A4 inhibitory potency and metabolic stability; namely, compounds that were more potent for the CYP3A4 inhibition generally were more metabolically stable. In addition, the compounds formed two clusters defined by the distinct type of substrate-induced P450 binding spectra: the compounds with type II binding spectra were more stable metabolically and more potent for the CYP3A4 inhibition than those with type I binding spectra. The structure-activity relationship suggested that the presence and position of heterocyclic nitrogen on the pyridine moiety play an important role in determining the manner of interaction with P450 and the magnitude of CYP3A4 inhibition/metabolic stability in the series of structurally related human immunodeficiency virus protease inhibitors under development.
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PMID:P450 interaction with HIV protease inhibitors: relationship between metabolic stability, inhibitory potency, and P450 binding spectra. 1112 21

Ru(II)/Ru(III) polypyridyl complexes containing 2,6-(2'-benzimidazolyl)-pyridine or chalcone as co-ligands were synthesized and characterized previously (Mishra, L.; Sinha, R. Indian J. Chem., Sec. A 2001, in press. Mishra, L.; Sinha, R. Indian J. Chem., Sec. A, 39A, 2000, 1131). Their interaction with aqueous buffered calf thymus DNA was measured. (Novakova, O.; Kasparkova, J.; Vrana, O.; van Vliet, P. M., Reedijk, J.; Brabec, V., Biochem. 34, 1995, 12369 and these results prompted additional screening for anti-HIV (human immunodeficiency virus) activity against DNA replication in H9 lymphocytes and cytotoxic activity against eight tumor cell lines. The most active compounds were 17 in the former assay (EC(50) < 0.1 microg/mL and TI > 23.1) and 3, 8, 10, and 14 in the latter assay, especially selectively against the 1A9 ovarian cancer cell line (IC(50) = 4.1, 3.8, 3.6, and 2.5 microg/mL, respectively).
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PMID:Anti-HIV and cytotoxic activities of Ru(II)/Ru(III) polypyridyl complexes containing 2,6-(2'-benzimidazolyl)-pyridine/chalcone as co-ligand. 1142 66

Previous investigations of the potential of metal-organic compounds as inhibitors of human immunodeficiency virus type I protease (HIV-1 PR) showed that the copper(II) complex diaqua [bis(2-pyridylcarbonyl)amido] copper(II) nitrate dihydrate and the complex bis[N2-(2,3,6-trimethoxybenzyl)-4-2-pyridinecarboxamide] copper(II) behaved as inhibitors of HIV-1 PR. In a search for similar readily accessible ligands, we synthesised and studied the structural properties of N2-(2-pyridylmethyl)-2-pyridinecarboxamide (L) copper(II) complexes. Three different crystal structures were obtained. Two were found to contain ligand L simultaneously in a tridentate and bidentate conformation [Cu(L(tri)L(bi))]. The other contained two symmetry-related ligands, coordinated through the pyridine nitrogen and the amide oxygen atoms [Cu(L(bi))(2)]. A search of the Cambridge Structural Database indicated that L(tri) resulting from nitrogen bound amide hydrogen metal substitution is favoured over chelation through the amide oxygen atom. In our case, we calculated that the conformation of L(tri) is 11 kcal/mol more favourable than that of L(bi). ESI-MS experiments showed that the Cu(L(bi))(2) structure could not be observed in solution, while Cu(L(tri)L(bi))-related complexes were indeed present. The lack of protease inhibition of the pyridine carboxamide copper(II) complexes was explained by the fact that the Cu(L(bi)L(tri)) complex could not fit into the HIV-1 active site.
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PMID:Synthesis and structural analysis of the copper(II) complexes of N2-(2-pyridylmethyl)-2-pyridinecarboxamide. 1156 26

This work reports the synthesis and the antiviral activities of 3-benzamido, 3-phenylureido and 3-phenylthioureido derivatives in the imidazo[1,2-a]pyridine series. The structure was proven by NMR spectroscopy. The synthesized compounds were evaluated against a large number of viruses. The 3-phenylthioureido derivative 7 showed moderate activity against human cytomegalovirus (HCMV) in vitro. The crystallographic data for 8 are also reported and explain the absence of activity against human immunodeficiency virus (HIV).
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PMID:3-Benzamido, ureido and thioureidoimidazo[1,2-a]pyridine derivatives as potential antiviral agents. 1176 86

For preparation of sulfated polysaccharides isolated from bamboo leaves (Indocalamus tesselatus) with chlorosulfonic acid-pyridine, the experimental conditions as the molar ratio of reactants and temperature and time of reaction were discussed. A homogeneous sulfation method with good yield of more than 80% was obtained and the sufur content was found to be 21.9%. Conformation change in sulfated polysaccharide with changes of intrinsic viscosity, polarimetery and CD spectra were found to be related to the negative charge. The polysaccharide sulfates were shown to have better activity to inhibit cytopathic effect of human immunodeficiency virus(HIV) infection than native polysaccharides. The effective concentration was 10 micrograms.ml-1 while the cytotoxic concentration was 2.5 mg.ml-1.
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PMID:[Sulfation of polysaccharides isolated from Indocalamus tesselatus and their anticytopathic effect on human immunodeficiency virus type I]. 1193 65


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