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1.
Stamatiou G Foscolos GB Fytas G Kolocouris A Kolocouris N Pannecouque C Witvrouw M Padalko E Neyts J De Clercq E 《Bioorganic & medicinal chemistry》2003,11(24):5485-5492
2-(1-Adamantyl)pyrrolidines 6, 7, 2-(1-adamantyl)piperidines 10, 12a–c, 15a,b and 2-(1-adamantyl)hexahydroazepines 19, 21, 22 were synthesized and tested for their antiviral activity against influenza A, B viruses and the human immunodeficiency virus type 1 (HIV-1) and type 2 (HIV-2). The synthetic procedure followed for the preparation of the parent piperidine 10 represents a general method for the synthesis of 2-alkyl- or cycloalkyl-substituted piperidine alkaloids. Parent aminoadamantanes 6, 10 and 19 contain the 1-aminoethyl pharmacophore group of rimantadine drug 2, extended into a saturated nitrogen heterocycle: pyrrolidine, piperidine and hexahydroazepine, respectively. The ring size effect in anti-influenza A activity was investigated. Rimantadine analogues 6 and 10 were, respectively, 6- and 4-fold more active than the drug Rimantadine 2, whereas the hexahydroazepine derivative 19 was inactive. Thus, enlargement from a 5-(pyrrolidine)- or 6-(piperidine)- to a 7-(hexahydroazepine)- membered heterocyclic ring dramatically reduced the anti-influenza virus A activity. Substitution of piperidine 10 with a dialkyaminoethyl group led to the active compounds 15a and 15b: compound 15a was active against influenza A virus whereas both 15a and 15b were active against HIV-1. 相似文献
2.
Zoidis G Fytas C Papanastasiou I Foscolos GB Fytas G Padalko E De Clercq E Naesens L Neyts J Kolocouris N 《Bioorganic & medicinal chemistry》2006,14(10):3341-3348
2-(1-Adamantyl)-2-methyl-pyrrolidines 3 and 4, 2-(1-adamantyl)-2-methyl-azetidines 5 and 6, and 2-(1-adamantyl)-2-methyl-aziridines 7 and 8 were synthesized and tested for their antiviral activity against influenza A. Parent molecules 3, 5, and 7 contain the alpha-methyl-1-adamantan-methanamine 2 pharmacophoric moiety (rimantadine). The ring size effect on anti-influenza A activity was investigated. Pyrrolidine 3 was the most potent anti-influenza virus A compound, 9-fold more potent than rimantadine 2, 27-fold more potent than amantadine 1, and 22-fold more potent than ribavirin. Azetidines 5 and 6 were both markedly active against influenza A H2N2 virus, 10- to 20-fold more potent than amantadine. Aziridine 7 was almost devoid of any activity against H2N2 virus but exhibited borderline activity against H3N2 influenza A strain. Thus, it appears that changing the five-, to four- to a three-membered ring results in a drop of activity against influenza A virus. 相似文献
3.
Zhang X Amer A Fan X Balzarini J Neyts J De Clercq E Prichard M Kern E Torrence PF 《Bioorganic chemistry》2007,35(3):221-232
To develop an understanding of the structure-activity relationships for the inhibition of orthopoxviruses by nucleoside analogues, a variety of novel chemical entities were synthesized. These included a series of pyrimidine 5-hypermodified acyclic nucleoside analogues based upon recently discovered new leads, and some previously unknown "double-headed" or "abbreviated" nucleosides. None of the synthetic products possessed significant activity against two representative orthopoxviruses; namely, vaccinia virus and cowpox virus. They were also devoid of significant activity against a battery of other DNA and RNA viruses. So far as the results with the orthopoxviruses and herpes viruses, the results may point to the necessity for nucleoside analogues 5'-phosphorylation for antiviral efficacy. 相似文献
4.
Al-Masoudi NA Al-Soud YA Eherman M De Clercq E 《Bioorganic & medicinal chemistry》2000,8(6):1407-1413
Reaction of the quinolone carboxylic acids 1 and 2 with (2-acetoxyethoxy)methyl chloride 3 in the presence of n-Bu4NI afforded the N-alkylated products 4 and 6, which could be deblocked to the free nucleoside analogues 5 and 7, respectively. The alkylated quinolone carboxylic acids 9 and 10 were obtained by condensation of I and 2 with 1,4-dichlorobut-2-ene 8 in the presence of NaH. Hydrolysis of 9 gave the alcohol 11. Similar treatment of 1 with 8 in the presence of K2CO3 at relatively high temperature furnished 12. Prolonged heating of the ester 13 with 8 in NaH/DMF afforded the conjugated-diene 15. Treatment of 1 and 2 with dimethyl acetylenedicarboxylate 16 furnished the pyrano[4,3-b]quinolones 17 and 18, respectively. Antibacterial and antiviral evaluations of the new products are reported. 相似文献
5.
6.
Tang YB Peng ZG Liu ZY Li YP Jiang JD Li ZR 《Bioorganic & medicinal chemistry letters》2007,17(22):6350-6353
A series of ester analogues of acyclic nucleotide PMPA and PMEA were synthesized as potent antiviral agents. The antiviral evaluation results indicated that bis benzyl ester prodrug of PMPA 5f and bis allyl ester prodrug of PMEA 5g exhibited potent antiviral activities. The IC(50) of 5f for HBV was 2.15 microM, and the IC(50) of 5g for HIV-1 was 1.61 microM. 相似文献
7.
Novel acyclic nucleoside analogues were designed and synthesized as open-chain analogues of neplanocin A. The coupling of the allylic bromide with pyrimidine bases using cesium carbonate afforded a series of novel acyclic nucleosides. The synthesized compounds 15-22 were evaluated for their antiviral activity against various viruses such as HIV, HSV-1, HSV-2, and HCMV. 相似文献
8.
A Brancale C McGuigan B Algain P Savy R Benhida J L Fourrey G Andrei R Snoeck E De Clercq J Balzarini 《Bioorganic & medicinal chemistry letters》2001,11(18):2507-2510
Thieno analogues of the potent and selective furo-pyrimidine anti-VZV nucleoside family are herein reported. The compounds retain full antiviral potency in comparison to the furo parent. 相似文献
9.
Wang R Ksebati MB Drach JC Zemlicka J 《Nucleosides, nucleotides & nucleic acids》2001,20(4-7):329-332
Synthesis and antiviral activity of methylenedifluorocyclopropane analogues 8a, 8b and 9a, 9b are described. 相似文献
10.
De Clercq E 《Nucleosides, nucleotides & nucleic acids》2004,23(1-2):457-470
In analogy with maribavir [1-(beta-L-ribofuranosyl)-isopropylamino-5,6-dichlorobenzimidazole], a nucleoside analogue that acts against human cytomegalovirus (HCMV) by a non-nucleoside mechanism, here I present three other examples of classes of nucleoside analogues (i.e. bicyclic furo[2,3-d]pyrimidine as well as HEPT and TSAO derivatives) that act against either HCMV or human immunodeficiency virus (HIV) through a non-nucleoside mode of action. 相似文献
11.
A practical 7-step synthesis of benzyl 3,5-di-O-benzyl-2-deoxy-1,4-dithio-D-erythro-pentofuranoside is described and the product has been used in the synthesis of some 4'-thio-2'-deoxynucleosides. These novel nucleoside analogues have potentially useful biological activity and are resistant to phosphorolysis. 相似文献
12.
Santosh B. Mhaske Bashar Ksebati Mark N. Prichard John C. Drach Jiri Zemlicka 《Bioorganic & medicinal chemistry》2009,17(11):3892-3899
Z- and E-Phosphonate analogues 12 and 13 derived from cyclopropavir and the corresponding cyclic phosphonates 14 and 15 were synthesized and their antiviral activity was investigated. The 2,2-bis(hydroxymethylmethylenecyclopropane acetate (17) was transformed to tetrahydropyranyl acetate 18. Deacetylation gave intermediate 19 which was converted to bromide 20. Alkylation with diisopropyl methylphosphonate afforded after protecting group exchange (21 to 22) acetylated phosphonate intermediate 22. Addition of bromine gave the dibromo derivative 16 which was used in the alkylation–elimination procedure with 2-amino-6-chloropurine to give Z- and E-isomers 23 and 24. Hydrolytic dechlorination coupled with removal of all protecting groups gave the guanine phosphonates 12 and 13. Cyclization afforded the cyclic phosphonates 14 and 15. Z-Phosphonate 12 was a potent and non-cytotoxic inhibitor of human and murine cytomegalovirus (HCMV and MCMV) with EC50 2.2–2.7 and 0.13 μM, respectively. It was also an effective agent against Epstein-Barr virus (EBV, EC50 3.1 μM). The cyclic phosphonate 14 inhibited HCMV (EC50 2.4–11.5 μM) and MCMV (EC50 0.4 μM) but it was ineffective against EBV. Both phosphonates 12 and 14 were as active against two HCMV Towne strains with mutations in UL97 as they were against wild-type HCMV thereby circumventing resistance due to such mutations. Z-Phosphonate 12 was a moderate inhibitor of replication of herpes simplex virus types 1 and 2 (HSV-1 and HSV-2) but it was a potent agent against varicella zoster virus (VZV, EC50 2.9 μM). The cyclic phosphonate 14 lacked significant potency against these viruses. E-isomers 13 and 15 were devoid of antiviral activity. 相似文献
13.
Bis-phosphoimidazolides of an analogue of adenosine (in which ribose is replaced by an acyclic chain) and of two related analogues of guanosine undergo oligomerization in the presence of complementary polynucleotide templates. Data on the template- and nontemplate-directed reactions are presented, and the possible relevance to origins of life is discussed. 相似文献
14.
15.
Novel neplanocin A analogues modified at the 6'-position, i.e. 6'-deoxy derivatives (2, 3, 5, 6, 14), 6'-O-methylneplanocin A (10) and 6'-C-methylneplanocin A (16a and 16b) were synthesized and evaluated for their antiviral activity in a wide variety of virus systems. Compound 16a (TJ-13025) surpassed neplanocin A both in antiviral potency and selectivity. 相似文献
16.
Mariola Kuczer Anna Midak‐Siewirska Renata Zahorska Mirosław Łuczak Danuta Konopińska 《Journal of peptide science》2011,17(11):715-719
The subject of our studies was the synthesis, biological evaluation, and conformational studies of insect tridecapeptide alloferon (H‐His‐Gly‐Val‐Ser‐Gly‐His‐Gly‐Gln‐His‐Gly‐Val‐His‐Gly‐OH) and its analogues such as: [des‐His1]‐, [Lys1]‐, [Arg1]‐, and [Ala1]‐alloferon. These peptides were synthesized to check the influence of the His residue at position 1 of the alloferon chain on its antiviral activity. Two aspects of the biological effects of these peptides were determined: (i) the cytotoxicity in vitro in the Vero, LLC‐MK2, and HEp‐2 cell lines, and (ii) the antiviral activity in vitro in respect to DNA and RNA viruses. We found that alloferon inhibited the herpes virus multiplication and failed to affect the coxsackie virus replication, whereas [Lys1]‐alloferon exhibited a high inhibitory action towards both viruses. Moreover, the peptides did not show any cytotoxic activity against the Vero, LLC‐MK2, and HEp‐2 cells. The preliminary circular dichroism conformational studies showed that the peptides investigated seem to prefer an unordered conformation. Copyright © 2011 European Peptide Society and John Wiley & Sons, Ltd. 相似文献
17.
Michał Gładysz Piotr Ruszkowski Jan Milecki 《Nucleosides, nucleotides & nucleic acids》2018,37(1):53-66
We describe synthesis of novel acyclic nucleoside analogues which are building blocks for CuAAC reaction and their activity against two types of human cancer cell lines (HeLa, KB). Three of chosen compounds show promising cytotoxic activity. Synthesis pathway starting from simple and easily accessible substrates employing DMT or TBDPS protective groups is described. Adenosine and thymidine analogues containing alkyne moiety and adenosine analogue containing azido group were synthesized. The obtained units showed ability of forming triazole motif under the CuAAC reaction conditions. 相似文献
18.
The conformations of oligopeptides derived from L -alanine and co-oligomers of L -alanine with γ-methyl-L -glutamate were studied in several solvents via optical rotation and far-ultraviolet spectroscopy. Calculated values for optical rotation based on model compounds were compared with experimental values for the oligomers. In trifluoroacetic and dichloroacetic acids, the oligomers and co-oligomers exhibit rotations in close agreement with predicted values based on model compounds. Thus, in these solvents only nonhelical conformations exist. In trifluoroethanol, the experimental points of molar rotation for the pentamer and larger oligomers no longer follow the predicted values. In addition, the benzyloxycarbonyl and acetyl cononamers show b0 values of about ?150, which demonstrates the presence of stable helical forms for these peptides. We also examined the molar extinction coefficients of oligopeptides in the 190 mμ region and determined the values for nonhelical peptide groups. The molar extinction coefficients per amide bond for the benzyloxycarbonyl and acetyl cononamers show extensive hypo-chromism, once again indicating the presence of stable helices for these compounds in trifluoroethanol. 相似文献
19.
Avanov AIa 《Molekuliarnaia biologiia》1999,33(5):725-739
20.
A Ia Avanov 《Molekuliarnaia biologiia》1991,25(2):293-308
The stereochemical conditions of the enzymatic process of carbohydrate chain addition to the amino acid sequence are reviewed. A particular attention is given to the process of N-glycosylation, which was studied by the method of theoretical conformational analysis. 相似文献