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1.
Chem Biodivers ; 16(11): e1900340, 2019 Nov.
Article in English | MEDLINE | ID: mdl-31647170

ABSTRACT

A series of camphecene and quinolizidine alkaloid (-)-cytisine conjugates has been obtained for the first time using 'click' chemistry methodology. The cytotoxicity and virus-inhibiting activity of compounds were determined against MDCK cells and influenza virus A/Puerto Rico/8/34 (H1N1), correspondingly, in in vitro tests. Based on the results obtained, values of 50 % cytotoxic dose (CC50 ), 50 % inhibition dose (IC50 ) and selectivity index (SI) were determined for each compound. It has been shown that the antiviral activity is affected by the length and nature of linkers between cytisine and camphor units. Conjugate 13 ((1R,5S)-3-(6-{4-[(2-{(E)-[(1R,4R)-1,7,7-trimethylbicyclo[2.2.1]heptan-2-ylidene]amino}ethoxy)methyl]-1H-1,2,3-triazol-1-yl}hexyl)-1,2,3,4,5,6-hexahydro-8H-1,5-methanopyrido[1,2-a][1,5]diazocin-8-one), which contains cytisine fragment separated from triazole ring by -C6 H12 - aliphatic linker, showed the highest activity at relatively low toxicity (CC50 =168 µmol, IC50 =8 µmol, SI=20). Its selectivity index appeared higher than that of reference compound, rimantadine. According to theoretical calculations, the antiviral activity of the lead compound 13 can be explained by its influence on the functioning of neuraminidase.


Subject(s)
Alkaloids/pharmacology , Antiviral Agents/pharmacology , Camphor/analogs & derivatives , Ethanolamines/pharmacology , Influenza A Virus, H1N1 Subtype/drug effects , Alkaloids/chemistry , Animals , Antiviral Agents/chemical synthesis , Antiviral Agents/chemistry , Azocines/chemistry , Azocines/pharmacology , Camphor/chemistry , Camphor/pharmacology , Cell Survival/drug effects , Cells, Cultured , Chickens , Click Chemistry , Dose-Response Relationship, Drug , Ethanolamines/chemistry , Microbial Sensitivity Tests , Molecular Docking Simulation , Molecular Structure , Quinolizines/chemistry , Quinolizines/pharmacology
2.
Bioorg Med Chem Lett ; 29(19): 126617, 2019 10 01.
Article in English | MEDLINE | ID: mdl-31431363

ABSTRACT

The design of hybrid (chimeric) molecules containing two different pharmacophores connected via a spacer (linker) is a promising approach to the functionalization of natural compounds and potentially of drug molecules. These are important examples for the use of this approach with anthracycline antibiotics. The use of this methodology may help to eliminate some of the drawbacks of anthracycline drugs, e.g., high cardiotoxicity and MDR development.


Subject(s)
Antibiotics, Antineoplastic/chemistry , Antibiotics, Antineoplastic/pharmacology , Benzaldehydes/chemistry , Daunorubicin/chemistry , Neoplasms/drug therapy , Antibiotics, Antineoplastic/chemical synthesis , Cell Proliferation , Humans , Neoplasms/pathology , Tumor Cells, Cultured
3.
Bioorg Med Chem Lett ; 27(10): 2181-2184, 2017 05 15.
Article in English | MEDLINE | ID: mdl-28366530

ABSTRACT

A series of seventeen tetrazole derivatives of 1,7,7-trimethyl-[2.2.1]bicycloheptane were synthesized using click chemistry methodology and characterized by spectral data. Studies of cytotoxicity and in vitro antiviral activity against influenza virus A/Puerto Rico/8/34 (H1N1) in MDCK cells of the compounds obtained were performed. The structure-activity relationship analysis suggests that to possess virus-inhibiting activity, the compounds of this group should bear oxygen atom with a short linker (C2-C4), either as a hydroxyl group (18, 19, 29), keto-group (21) or as a part of a heterocycle (24). These compounds demonstrated low cytotoxicity along with high anti-viral activity.


Subject(s)
Antiviral Agents/chemical synthesis , Camphor/analogs & derivatives , Ethanolamines/chemistry , Animals , Antiviral Agents/chemistry , Antiviral Agents/pharmacology , Camphor/chemical synthesis , Camphor/chemistry , Camphor/pharmacology , Click Chemistry , Dogs , Ethanolamines/chemical synthesis , Ethanolamines/pharmacology , Humans , Influenza A Virus, H1N1 Subtype/drug effects , Madin Darby Canine Kidney Cells , Structure-Activity Relationship
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