In vitro Inhibition of the Measles Virus by Novel Ring-Expanded (“Fat”) Nucleoside Analogues Containing the Imidazo[4,5-e][1,3]diazepine Ring System (original) (raw)
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Bioorganic & Medicinal Chemistry Letters, 2002
The synthesis and in vitro anti-measles virus (anti-MV) activity of a class of ring-expanded ('fat') nucleoside analogues (1-4) containing the title heterocyclic ring system are reported. The target compounds were synthesized by base-catalyzed condensations of 4,5-dicarboxylic acid esters of the appropriately substituted imidazole-1-ribosides with suitably substituted guanidine derivatives. Compounds were screened for anti-MV activity in African green monkey kidney cells (CV-1), employing ribavirin as the control standard. While the parent compound 1 itself failed to show any significant antiviral activity against MV, its analogues containing hydrophobic substituents at the 2-position (2) or the 6-position (4) showed promising antiviral activity at submicromolar or micromolar concentration levels with no apparent toxicity to the host cell line. Both compounds showed higher anti-MV activity than the control drug ribavirin. #
Journal of Medicinal Chemistry, 2004
A series of polyhalogenated imidazole nucleosides were designed and synthesized as ringcontracted analogues of 2,5,6-trichloro-1-(-D-ribofuranosyl)benzimidazole (TCRB) and its 2-bromo analogue (BDCRB) in an effort to explore the spatial limitation of the active pocket(s) in the target protein(s). 2,4,5-Trichloro-, 2-bromo-4,5-dichloro-, and 2,4,5-tribromoimidazole nucleosides were prepared by a condensation of the preformed heterocycles with the appropriate sugar precursors. The ribofuranosyl and xylofuranosyl analogues were prepared by a direct glycosylation using the Vorbruggen's silylation method and provided exclusively the-anomers. The arabinofuranosyl analogues were prepared by the sodium salt method to give both the Rand-anomers. The absolute configurations were established by 1 H NMR spectroscopy. Alkylation of the polyhalogenated imidazoles with the appropriate bromomethyl ethers gave the acyclic acyclovir and ganciclovir analogues. In general, the parent polyhalogenated imidazoles showed some activity against human cytomegalovirus (HCMV) (IC 50 ∼ 35 µM). However, with the exception of two tribromo analogues (7c, 13c-), most of their nucleoside derivatives were inactive against both HCMV and herpes simplex virus type-1 (HSV-1) and were not cytotoxic. The results suggest that the ring-contracted nucleoside analogues of TCRB and BDCRB interacted weakly or not at all with viral and cellular targets.
Journal of the Chinese Chemical Society, 1998
Wehave recently found that 2,5,6-trichloro-H~-D-ribofuranosyl)benzimidazole(TCRB) and the corresponding 2-bromo analog have better in vitro activities against HCMV than the clinically used agents ganciclovir and foscarnet, These benzimidazole nucleosides act by a unique mechanism, however, their biological target has not been completely identified. As an approach to probing the target, we have designed imidazo[4,S-b]quinoxaline nucleosides as linear dimensional analogs of the benzimidazole uucleosides to study the spatial limitation of the binding site in the target enzyme. A convenient route was developed for the synthesis of 2-substituted 6,7-dichloroimidazo[4,5-b]quinoxaiines involving a reaction of 2,3,6,7tetrachloroquinoxaliue with ammonia followed by a ring annulation as the key step. This furnished the versatile heterocycle 6,7-dichloroimidazo[4,5-b]quinoxatin-2-one. Ribosylation of 2-substituted imidazo[4,5b]quinoxaiines was influenced by the functional group at the 2-position and the 2-one compound was found to smoothly undergo ribosylation. The 2-one group of the nucleoside was converted into specifically selected 2-substituted compounds. Evaluation of the compounds for activity against two herpesviruses and for cytotoxicity showed they were less active and/or more cytotoxic than TCRB. We conclude therefore, thai the binding pocket on the protein target of TCRB will tolerate some electronic and size changes.
Bioorganic & Medicinal Chemistry, 2007
The attempted removal of the aralkyl group of 2-bromo-1-p-methoxybenzyl-6-octylimidazo [4,5-e] [1,3]diazepine (ZP-33) with trifluoroacetic acid resulted in replacement of the bromo group with a carbonyl at position-2 in addition to the desired deprotection at the 1-position. 2′-Deoxynucleosides of 2-bromo-substituted-imidazole-4,5-diesters (ZP-35 and ZP-103) were synthesized by direct glycosylation of the corresponding heterocycles. The attempted ring-closure of the above nucleosides resulted in deglycosylation to form the starting heterocycles. The 2-phenyl derivatives of the above nucleosides (ZP-45 and ZP-73) were successfully prepared by Suzuki coupling with the appropriate phenylboronic acids, but the attempted ring-closure with guanidines to form the desired 5,7-fused ring-expanded nucleosides (RENs) resulted once again in the formation of the corresponding heterocyclic aglycons (ZP-64 and ZP-75). The first successful 2-substituted REN (ZP-110) was synthesized by replacing the 2-deoxyribose sugar moiety with a ribosyl group and replacing the bromo group with a p-methoxyphenyl substituent at the 2-position. A number of imidazole riboside diester precursors containing a substituted phenyl group at the 2-position were synthesized in order to prepare analogues of ZP-110. The substituents on the phenyl ring included a variety of electrondonating or electron-withdrawing groups operating through inductive and/or resonance effects. However, the final ring-closure of the diesters with guanidines in order to prepare RENs was successful only in a limited number of cases, including the ones containing a p-fluorophenyl (ZP-121), a m-methoxyphenyl (ZP-122), or an unsubstituted phenyl (NZ-53) at the 2-position. Deglycosylation and incomplete ring-closure of the intermediates were the major problems encountered with most other cases. The stability of glycosidic bonds was found to be dependent on several factors including, but not limited to, the electron-donating inductive effect of the 2-phenyl substituents and the temperature of the reaction medium. The three target RENs ZP-110, ZP-121, and ZP-122 were screened for in vitro anti-HCV activity, employing an HCV RNA replicon assay. While ZP-121 was inactive, the other two compounds showed only weak anti-HCV activity.
Molecules, 2021
A series of 1,2,3-triazolyl nucleoside analogues in which 1,2,3-triazol-4-yl-β-d-ribofuranosyl fragments are attached via polymethylene linkers to both nitrogen atoms of the heterocycle moiety (uracil, 6-methyluracil, thymine, quinazoline-2,4-dione, alloxazine) or to the C-5 and N-3 atoms of the 6-methyluracil moiety was synthesized. All compounds synthesized were evaluated for antiviral activity against influenza virus A/PR/8/34/(H1N1) and coxsackievirus B3. Antiviral assays revealed three compounds, 2i, 5i, 11c, which showed moderate activity against influenza virus A H1N1 with IC50 values of 57.5 µM, 24.3 µM, and 29.2 µM, respectively. In the first two nucleoside analogues, 1,2,3-triazol-4-yl-β-d-ribofuranosyl fragments are attached via butylene linkers to N-1 and N-3 atoms of the heterocycle moiety (6-methyluracil and alloxazine, respectively). In nucleoside analogue 11c, two 1,2,3-triazol-4-yl-2′,3′,5′-tri-O-acetyl-β-d-ribofuranose fragments are attached via propylene linkers t...
Synthesis, antiviral activity, and stability of nucleoside analogs containing tricyclic bases
European journal of …, 2009
A series of 3,9-dihydro-9-oxo-5H-imidazo[1,2-A]purine nucleosides (tricylic nucleosides) were synthesized from 9-[4-α-(hydroxymethyl)cyclopent-2-ene-1-α-yl]guanine (CBV) 5, (−)-β-D-(2R ,4R)-1,3-dioxolane-guanosine (DXG) 6, 3′-azido-3′-deoxy-guanosine (AZG) 7, and ...
Design, synthesis, and antiviral activity of new 1H-1,2,3-triazole nucleoside ribavirin analogs
Medicinal Chemistry Research, 2014
Ribavirin is a broad antiviral compound with demonstrated activity against herpes simplex virus (HSV), human immunodeficiency virus HIV-1, influenza virus, respiratory syncytial virus, and hepatitis C virus, among other viruses. However, routine clinical use of ribavirin is limited because this compound is considerably cytotoxic. Herein, we describe the design, synthesis, and antiviral activity of new nucleoside ribavirin analogs based on the following: (1) ring bioisosterism of a 1,2,4-triazole for a 1,2,3-triazole; (2) amide group exchange for other substituents, such as c-propyl, methyl carboxylate, or trifluoromethyl groups; and (3) the ribofuranose remained linked to the triazole ring. Compounds 5a-c were obtained with yields of 65-36 % and tested against Influenza A and HSV-1 replication as well as reverse transcriptase (RT) from human immunodeficiency virus type 1 (HIV-1 RT). Compound 5b (R = CO 2 CH 3) was the most effective analog, with IC 50 values 14 and 3.8 lM for Influenza A and HIV-1 RT, respectively.
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.
Synthesis and broad spectrum antiviral evaluation of bis(POM) prodrugs of novel acyclic nucleosides
European Journal of Medicinal Chemistry, 2013
A series of seventeen hitherto unknown ANP analogs bearing the (E)-but-2-enyl aliphatic side chain and modified heterocyclic base such as cytosine and 5-fluorocytosine, 2-pyrazinecarboxamide, 1,2,4-triazole-3-carboxamide or 4-substituted-1,2,3-triazoles were prepared in a straight approach through an olefin acyclic cross metathesis as key synthetic step. All novel compounds were evaluated for their antiviral activities against a large number of DNA and RNA viruses including herpes simplex virus type 1 and 2, varicella zoster virus, feline herpes virus, human cytomegalovirus, hepatitis C virus (HCV), HIV-1 and HIV-2. Among these molecules, only compound 31 showed activity against human cytomegalovirus in HEL cell cultures with at EC 50 of w10 mM. Compounds 8a, 13, 14, and 24 demonstrated pronounced anti-HCV activity without significant cytotoxicity at 100 mM.