Novel 5′-Norcarbocyclic Derivatives of Bicyclic Pyrrolo- and Furano[2,3-d]Pyrimidine Nucleosides

Here we report the synthesis and biological activity of new 5′-norcarbocyclic derivatives of bicyclic pyrrolo- and furano[2,3-d]pyrimidines with different substituents in the heterocyclic ring. Lead compound 3i, containing 6-pentylphenyl substituent, displays inhibitory activity with respect to a number of tumor cells with a moderate selectivity index value. Compound 3i induces cell death by the apoptosis pathway with the dissipation of mitochondrial potential

5’-НОРКАРБОЦИКЛИЧЕСКИЕ АНАЛОГИ НУКЛЕОЗИДОВ КАК ПОТЕНЦИАЛЬНЫЕ ХИМИОТЕРАПЕВТИЧЕСКИЕ АГЕНТЫ

Novel types of the 5’-norcarbocyclic analogues of nucleosides have been designed, and new biological targets and mechanisms of action of these compounds have been found. The first group of the analogues are derived from purine nucleosides. N1-oxide-5’-noraristeromycin derivatives show an antiviral activity in a virus. The isosteric analogues of inosine-5’-monophoshate were weakly inhibitory towards inosine-5’-monophosphate dehydrogenase II and hepatitis C virus, but did not suppress M. Tuberculosis growth. The second group are 1-(4’-hydroxy-2’-cyclopentene-1’-yl)-uracil (HCPU) derivatives having substituents at 4’-hydroxyl and at carbon 3 of the heterocyclic core. The analogues were evaluated as HIV-1 reverse transcriptase inhibitors. It has been shown for the first time that 3,4’-substituted analogues of HCPU can act as the non-nucleoside inhibitors of reverse transcriptase of wild type HIV-1 (Ki 5 to 19 mkM) and HIV-1 mutants L100I (Ki 1 to 11 mkM) and K103N (Ki 8 to 55 mkM) referred to the first generation NNRTI resistant HIV-1 strains. The third group includes HCPU and 1,3-di-(4’-hydroxy-2’-cyclopentene-1’-yl)-uracil derivatives having different substituents (a halogen or 5-arylamine) at carbon 5 of their heterocyclic core. The compounds of this group proved to be potent inhibitors of the laboratory M. Tuberculosis strain H37Rv (MIC90 10 to 40 mg/ml) and the MS-115 strain (MIC90 5 to 20 mkM), which features multiple drug resistance against five first-line anti-tuberculosis: rifampicin, streptomycin, ethambutol, and pyrazinamide. A weak anti-HIV activity of these compounds has also been shown (Ki 60 to 11 mkM). The fourth group of the novel 5’-norcarbocyclic nucleosides are furopyrimidine analogues, which are modified at positions 4 and 5 of their uracil moieties. They were shown to inhibit the growth of different tumor cell lines at IC50 from 3 to 50 mkM.Созданы новые типы 5’-норкарбоциклических аналогов нуклеозидов. Выявлены новые биологические мишени и механизмы проявления активности соединений данного класса. Первой группой соединений стали 5’-норкарбоциклические аналоги пуриновых нуклеозидов. Производные N1-окcида-5’-нораристеромицина показали антивирусную активность на модели вируса осповакцины. Изостерные аналоги инозин-5’-монофосфата проявили слабые ингибиторные свойства по отношению к IMPDH II и ВГС, но не подавляли рост M. Tuberculosis. Вторая группа это производные 1-(4’-гидрокси-2’-цикло-пентен-1’-ил)-урацила с заместителями по 4’-гидроксильной группе и 3 положению гетероциклического основания. Полученные аналоги были оценены в качестве ингибиторов ОТ ВИЧ-1. Впервые показана способность 3,4’-замещенных производных 1-(4’-гидрокси-2’-циклопентенил)урацила выступать в роли ненуклеозидных ингибиторов ОТ ВИЧ-1 дикого типа (КI 5-19 мкМ), а также мутантных форм L100I (КI 1-11 мкМ) и K103N (КI 8-55 мкМ), соответствующих штаммам ВИЧ-1, резистентным к ННИОТ первого поколения. Третья группа включает производные 1-(4’-гидрокси-2’-цикло-пентен-1’-ил)-урацила и 1,3-ди-(4’-гидрокси-2’-циклопентен-1’-ил)-урацила с различными заместителями по 5 положению гетероциклического основания (галлоген или остаток 5-ариламина). Представители данной группы продемонстрировали выраженную способность ингибировать рост лабораторного штамма M. Tuberculosis H37Rv(MIC90 10-40 мкг/мл) и штамма MS-115 с множественной лекарственной устойчивостью, резистентного к пяти основным противотуберкулезным препаратам первой линии: изониазиду, рифампицину, стрептомицину, этамбутолу и пиразинамиду (MIC90 5-20 мкг/мл). Показано также наличие слабой анти-ВИЧ активности соединений (К / 60-119 мкМ). Последней группой синтезированных 5’-норкар-боциклических нуклеозидов являются фуропиримидиновые аналоги - соединения, модифицированные по 4 и 5 положениям урацильного фрагмента, проявившие способность ингибировать рост различных линий опухолевых клеток (IC50 3-50 мкМ)

Toward the discovery of dual HCMV-VZV inhibitors: Synthesis, structure activity relationship analysis, and cytotoxicity studies of long chained 2-uracil-3-yl-N-(4-phenoxyphenyl)acetamides

The need for novel therapeutic options to fight herpesvirus infections still persists. Herein we report the design, synthesis and antiviral evaluation of a new family of non-nucleoside antivirals, derived from 1-[ω-(4-bromophenoxy)alkyl]uracil derivatives - previously reported inhibitors of human cytomegalovirus (HCMV). Introduction of the N-(4-phenoxyphenyl)acetamide side chain at N(3) increased their potency and widened activity spectrum. The most active compounds in the series exhibit submicromolar activity against different viral strains of HCMV and varicella zoster virus (VZV) replication in HEL cell cultures. Inactivity against other DNA and RNA viruses, including herpes simplex virus 1/2, points to a novel mechanism of antiviral action.publisher: Elsevier articletitle: Toward the discovery of dual HCMV–VZV inhibitors: Synthesis, structure activity relationship analysis, and cytotoxicity studies of long chained 2-uracil-3-yl-N-(4-phenoxyphenyl)acetamides journaltitle: Bioorganic & Medicinal Chemistry articlelink: http://dx.doi.org/10.1016/j.bmc.2015.09.033 content_type: article copyright: Copyright © 2015 Elsevier Ltd. All rights reserved.status: publishe

Synthesis of uracil-coumarin conjugates as potential inhibitors of virus replication

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New Derivatives of 5-Substituted Uracils: Potential Agents with a Wide Spectrum of Biological Activity

Pyrimidine nucleoside analogues are widely used to treat infections caused by the human immunodeficiency virus (HIV) and DNA viruses from the herpes family. It has been shown that 5-substituted uracil derivatives can inhibit HIV-1, herpes family viruses, mycobacteria and other pathogens through various mechanisms. Among the 5-substituted pyrimidine nucleosides, there are not only the classical nucleoside inhibitors of the herpes family viruses, 2′-deoxy-5-iodocytidine and 5-bromovinyl-2′-deoxyuridine, but also derivatives of 1-(benzyl)-5-(phenylamino)uracil, which proved to be non-nucleoside inhibitors of HIV-1 and EBV. It made this modification of nucleoside analogues very promising in connection with the emergence of new viruses and the crisis of drug resistance when the task of creating effective antiviral agents of new types that act on other targets or exhibit activity by other mechanisms is very urgent. In this paper, we present the design, synthesis and primary screening of the biological activity of new nucleoside analogues, namely, 5′-norcarbocyclic derivatives of substituted 5-arylamino- and 5-aryloxyuracils, against RNA viruses

Synthesis and anti-HCMV activity of 1-[ω-(phenoxy)alkyl]uracil derivatives and analogues thereof

HCMV infection represents a life-threatening condition for immunocompromised patients and newborn infants and novel anti-HCMV agents are clearly needed. In this regard, a series of 1-[ω-(phenoxy)alkyl]uracil derivatives were synthesized and examined for antiviral properties. Compounds 17, 20, 24 and 28 were found to exhibit highly specific and promising inhibitory activity against HCMV replication in HEL cell cultures with EC50 values within 5.5-12μM range. Further studies should be undertaken to elucidate the mechanism of action of these compounds and the structure-activity relationship for the linker region.publisher: Elsevier articletitle: Synthesis and anti-HCMV activity of 1-[ω-(phenoxy)alkyl]uracil derivatives and analogues thereof journaltitle: Bioorganic & Medicinal Chemistry articlelink: http://dx.doi.org/10.1016/j.bmc.2013.05.009 content_type: article copyright: Copyright © 2013 Elsevier Ltd. All rights reserved.status: publishe

1,6-Bis[(benzyloxy)methyl]uracil derivatives-Novel antivirals with activity against HIV-1 and influenza H1N1 virus

A series of 1,6-bis[(benzyloxy)methyl]uracil derivatives combining structural features of both diphenyl ether and pyridone types of NNRTIs were synthesized. Target compounds were found to inhibit HIV-1 reverse transcriptase at micro- and submicromolar levels of concentrations and exhibited anti-HIV-1 activity in MT-4 cell culture, demonstrating resistance profile similar to first generation NNRTIs. The synthesized compounds also showed profound activity against influenza virus (H1N1) in MDCK cell culture without detectable cytotoxicity. The lead compound of this assay appeared to exceed rimantadine, amantadine, ribavirin and oseltamivir carboxylate in activity. The mechanism of action of 1,6-bis[(benzyloxy)methyl]uracils against influenza virus is currently under investigation.publisher: Elsevier articletitle: 1,6-Bis[(benzyloxy)methyl]uracil derivatives—Novel antivirals with activity against HIV-1 and influenza H1N1 virus journaltitle: Bioorganic & Medicinal Chemistry articlelink: http://dx.doi.org/10.1016/j.bmc.2016.04.010 content_type: article copyright: © 2016 Elsevier Ltd. All rights reserved.status: publishe