Synthesis of 2′,3′-Dideoxy- and 3′- Azido-2′,3′-dideoxy-pyridazine Nucleosides as Potential Antiviral Agents (original) (raw)
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Synthesis and antiviral screening of some novel pyridazine and triazolopyridazine nucleosides
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Some novel cyclic and acyclic pyridazine and triazolopyridazine nucleoside derivatives were prepared. Some of the prepared products were selected and tested for antiviral activity against herpes simplex virus type-1 (HSV-1) and hepatitis-A virus (HAV, MBB-cell culture adapted strain). Plaque reduction infectivity assay was used to determine virus count reduction as a result of treatment with test compounds. Compound 15 showed the highest effect on the HAV than the other tested compounds.
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. #
Journal of Medicinal Chemistry, 1999
Asymmetric syntheses of L-carbocyclic 2′,3′-didehydro-2′,3′-dideoxy-and 2′,3′-dideoxypyrimidine and purine nucleoside analogues were accomplished, and their anti-HIV and anti-HBV activities were evaluated. The key intermediate, (1S,4R)-1-benzoyloxy-4-(tert-butoxymethyl)cyclopent-2-ene (7), was prepared by benzoylation of the alcohol 2, selective deprotection of the isopropylidene group of 3, followed by thermal elimination via cyclic ortho ester or deoxygenation via cyclic thionocarbonate. The target compounds were also synthesized by thermal elimination via cyclic ortho esters from protected nucleosides. It was found that L-carbocyclic 2′,3′-didehydro-2′,3′-dideoxyadenosine (34) exhibited potent anti-HBV activity (EC 50) 0.9 µM) and moderate anti-HIV activity (EC 50) 2.4 µM) in vitro without cytotoxicity up to 100 µM.
Antiviral Chemistry and Chemotherapy, 1993
The syntheses of 4-amino-1-(β-D-ribofuranosyl)-1 H-1,2,3-triazolo[4,5-c]pyridine (8-aza-3-deazaadenosine, 1), 4-amino-1-(2-deoxy-β-D- erythro-pentofuranosyl)-1 H-1,2,3-triazolo[4,5-c]pyridine (2′-deoxy-8-aza-3-deazaadenosine, 2), and their N8and N7glycosylated analogues (12,13, 21,22) and 4-amino-1-(2,3-dideoxy-β-D- erythro-pentof uranosyl)-1 H-1,2,3-triazolo [4,5-c]pyridine (2′,3′-dideoxy-8-aza-3-deazaadenosine, 3) were carried out by glycosylation of the 4-chloro-3 H-1,2,3-triazolo[4,5-c]pyridine anion. The anomeric configuration as well as the position of glycosylation were determined by1H-,13C-NMR, UV and N.O.E. difference spectroscopy. Nucleoside (2) and its parent compound 2′-deoxy-3-deazaadenosine were found active against ASFV and VSV. The 4-chloro-2-(β-D-ribofuranosyl)-2 H-1,2,3-triazolo[4,5-c] pyridine (9) was active against Coxsackie B1, whereas none of the 8-aza-3-deaza purine nucleosides, compound (3) included, was active against HIV-1. The 6-chloro derivatives of 8-aza...
Journal of Medicinal Chemistry, 1979
Several procedures are described for the synthesis of arabinofuranosyl-5-ethylpyrimidine nucleosides: (a) condensation of benzylated a-chloroarabinofuranose (5) with 2,4-bis-O-(trimethylsily1)-5-ethylpyrimidine (6) in the presence of SnCl, or molecular sieves yielded exclusively the @-anomer 7 and proved to be the best pathway to 1-(@-~arabinofuranosyl)-5-ethyluracil (1); (b) condensation of benzoylated a,@-bromoarabinose 9 with 6 led to a mixture of anomeric nucleosides 10 and 11 in the ratio 5:2; (c) condensation of benzoylated a-bromoarabinose 8 with 6 led exclusively to the a-anomer 10 which, on thiation and amination, gave l-(a-~-arabinofuranosyl)-5-ethylcytosine (4); (d) condensation of benzylated a-halogenoarabinose with 2,4-diethoxy-5-ethylpyrimidine (15) in the presence of SnCh or molecular sieves gave exclusively the p anomer of the 4-ethoxy nucleoside 16 which, on amination and reduction, was the most convenient procedure for the synthesis of l-(@-~-arabinofuranosyl)-5-ethylcytosine (2). The mechanisms of the various condensation methods are compared and discussed. CD and NMR data are presented for 1 and 2 and their corresponding a anomers. Antiviral activities of 1 and 2 and their a-anomers 3 and 4 were tested in primary rabbit kidney cells and in human skin fibroblasts. Herpes simplex virus was inhibited by 1 at a concentration as low as 2 FglmL, whereas concentrations exceeding 200 fig/mL were required to inhibit vaccinia virus replication or normal cellular metabolism. Compound 2 was significantly less active as an antiherpes agent than compound
Inhibition of Human Immunodeficiency Virus by a New Class of Pyridine Oxide Derivatives
Antimicrobial Agents and Chemotherapy, 2003
A new class of pyridine oxide derivatives as inhibitors of human immunodeficiency virus type 1 (HIV-1) and/or HIV-2 replication in cell culture has been identified. The compounds, which specifically inhibit HIV-1, behave as typical nonnucleoside reverse transcriptase inhibitors (NNRTIs). The most active congener of this group, JPL-133 (UC-B3096), has a 50% effective concentration of 0.05 μg/ml for HIV-1(IIIB) with a selectivity index of approximately 760 in CEM cell cultures. However, the cytostatic activity of most pyridine oxide derivatives highly depended on the nature of the cell line. All compounds, including those pyridine oxide derivatives that inhibit both HIV-1 and HIV-2 replication, select for NNRTI-characteristic mutations in the HIV-1 reverse transcriptase of HIV-infected cell cultures (i.e., Lys103Asn, Val108Ile, Glu138Lys, Tyr181Cys and Tyr188His). These amino acid mutations emerged mostly through transition of guanine to adenine or adenine to guanine in the correspond...
Tetrahedron Letters, 1994
Abstrack Novel aqclo analogues (L&14) of didehydro dideoxy adenosine (d4A) Iacking C-3'-C-4' bond were synthesized as potential anti-HIV agents. The key step inwIves the brominationof unsaturated isomer 6 with NBS in mono protected ethylene glycol leading to 3',4'-seco-2'-bromo-3'.hydroxy compound lla. ActIvationof 3'-hydroxy group and reductive eliminationof vk5naI bromo tosylate gave 13 whIcIi on deprotectionwas converted Into the target molecule 14.
Journal of Medicinal Chemistry, 2004
The second generation of methylenecyclopropane analogues of nucleosides 5a-5i and 6a-6i was synthesized and evaluated for antiviral activity. The 2,2-bis(hydroxymethyl)methylenecyclopropane (11) was converted to dibromo derivative 7 via acetate 12. Alkylation-elimination of adenine (16) with 7 afforded the Z/E mixture of acetates 17 + 18, which was deacetylated to give analogues 5a and 6a separated by chromatography. A similar reaction with 2-amino-6-chloropurine (19) afforded acetates 20 + 21 and, after deprotection and separation, isomers 5f and 6f. The latter served as starting materials for synthesis of analogues 5b, 5e, 5g-5i and 6b, 6e, 6g-6i. Alkylation-elimination of N 4 -acetylcytosine (22) with 7 afforded a mixture of isomers 5c + 6c which were separated via N 4 -benzoyl derivatives 23 and 24. Deprotection furnished analogues 5c and 6c. Alkylation of 2,4-bis(trimethylsilyloxy)-5-methylpyrimidine with 7 led to bromo derivative 26. Elimination of HBr followed by deacetylation and separation gave thymine analogues 5d and 6d. The guanine Z-isomer 5b was the most effective against human and murine cytomegalovirus (HCMV and MCMV) with EC 50 ) 0.27-0.49 µM and no cytotoxicity. The 6-methoxy analogue 5g was also active (EC 50 ) 2.0-3.5 µM) whereas adenine Z-isomer 5a was less potent (EC 50 ) 3.6-11.7 µM). Cytosine analogue 5c was moderately effective, but 2-amino-6-cyclopropylamino derivative 5e was inactive. All E-isomers were devoid of anti-CMV activity, and none of the analogues was significantly active against herpes simplex viruses (HSV-1 or HSV-2). The potency against Epstein-Barr virus (EBV) was assay-dependent. In Daudi cells, the E-isomers of 2-amino-6-cyclopropylamino-and 2,6-diaminopurine derivatives 6e and 6h were the most potent (EC 50 ≈ 0.3 µM), whereas only the thymine Z-isomer 5d was active (EC 50 ) 4.6 µM). Guanine Z-derivative 5b was the most effective compound in H-1 cells (EC 50 ) 7 µM). In the Z-series, the 2-amino-6-methoxypurine analogue 5g was the most effective against varicella zoster virus (VZV, EC 50 ) 3.3 µM) and 2,6-diaminopurine 5h against hepatitis B virus (HBV, EC 50 ) 4 µM). Adenine analogues 5a and 6a were moderately active as substrates for adenosine deaminase. Scheme 1 a a (a) NBS, (BzO)2, CCl4, illumination. (b) (1) t-BuOK, tBuOH, ∆; (2) separation. (c) LiAlH4, Et2O. (d) Ac2O, pyridine. (e) Br2, CCl4. Scheme 2 a a (a) LiAlH4, Et2O. (b) Ac2O, pyridine. (c) (1) Pyridine‚HBr3, CH2Cl2; (2) separation. Scheme 3 a a (a) K2CO3, DMF, ∆. (b) (1) K2CO3, MeOH/H2O; (2) separation.