RESUMO
A series of 5'-O-[N-(salicyl)sulfamoyl]-2-aryl-8-aza-3-deazaadenosines were designed to block mycobactin biosynthesis in Mycobacterium tuberculosis (Mtb) through inhibition of the essential adenylating enzyme MbtA. The synthesis of the 2-aryl-8-aza-3-deazaadenosine nucleosides featured sequential copper-free palladium-catalyzed Sonogashira coupling of a precursor 4-cyano-5-iodo-1,2,3-triazolonucleoside with terminal alkynes and a Minakawa-Matsuda annulation reaction. These modified nucleosides were shown to inhibit MbtA with apparent Ki values ranging from 6.1 to 25nM and to inhibit Mtb growth under iron-deficient conditions with minimum inhibitory concentrations ranging from 12.5 to >50µM.
Assuntos
Antituberculosos/química , Antituberculosos/farmacologia , Mycobacterium tuberculosis/efeitos dos fármacos , Sideróforos/biossíntese , Tubercidina/química , Mycobacterium tuberculosis/metabolismo , Análise Espectral/métodos , Relação Estrutura-AtividadeRESUMO
The degradation behavior of a tricyclic analog of acyclovir [6-(4-MeOPh)-TACV] was determined in accordance with International Conference on Harmonization guidelines for good clinical practice under different stress conditions (neutral hydrolysis, strong acid/base degradation, oxidative decomposition, photodegradation, and thermal degradation). Accelerated [40±2°C/75%±5% relative humidity (RH)] and intermediate (30±2°C/65%±5% RH) stability tests were also performed. For observation of the degradation of the tested compound the RP-HPLC was used, whereas for the analysis of its degradation products HPLC/MS/MS was used. Degradation of the tested substance allowed its classification as unstable in neutral environment, acidic/alkaline medium, and in the presence of oxidizing agent. The tested compound was also light sensitive and was classified as photolabile both in solution and in the solid phase. However, the observed photodegradation in the solid phase was at a much lower level than in the case of photodegradation in solution. The study showed that both air temperature and RH had no significant effect on the stability of the tested substance during storage for 1 month at 100°C (dry heat) as well as during accelerated and intermediate tests. Based on the HPLC/MS/MS analysis, it can be concluded that acyclovir was formed as a degradation product of 6-(4-MeOPh)-TACV.
Assuntos
Aciclovir/análise , Antivirais/análise , Aciclovir/análogos & derivados , Cromatografia Líquida de Alta Pressão/métodos , Estabilidade de Medicamentos , Guias como Assunto , Temperatura Alta , Humanos , Peróxido de Hidrogênio/química , Concentração de Íons de Hidrogênio , Hidrólise , Oxirredução , Fotólise , Espectrometria de Massas em TandemRESUMO
Efficient Pd(0)-catalysed synthesis of 5-alkynyl-1-ß-D-ribofuranosyl-1H-[1,2,3]triazole-4-carboxylic acid amide depends on the presence of different protecting groups of the ribose moiety. Peracetylated 5-iodo substrate (15) couples with terminal alkynes or trimethyl-[(tributylstannyl)ethynyl]silane in 50-71% and 72% yield (ETCAR), respectively, although its hydrodehalogenation to 19 is noticeable. On the other hand, hydrodehalogenation of acetonide (16) predominates over coupling with terminal alkyne and slightly decreases a yield of cross-coupling reaction with trimethyl[(tributylstannyl)ethynyl]silane. Alternative conditions of reaction with terminal alkynes, to exclude so far identified hydride sources to produce hydridopalladium species, have been established for acetonide 16 and allowed to achieve 72% of coupling. Fluoromethyl derivative (42) was prepared from its 5-hydroxymethyl precursor by fluorination with DAST. Additionally, X-ray structural analysis of 42 was performed. All 1,2,3-triazolonucleosides and two synthesized cycloSal-pronucleotides were evaluated for cytotoxic activity against K562, HeLa and HUVEC cells.
Assuntos
Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Nucleosídeos/síntese química , Nucleosídeos/farmacologia , Triazóis/síntese química , Triazóis/farmacologia , Antineoplásicos/química , Linhagem Celular , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Cristalografia por Raios X , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Células Endoteliais/efeitos dos fármacos , Células HeLa , Humanos , Modelos Moleculares , Estrutura Molecular , Nucleosídeos/química , Estereoisomerismo , Relação Estrutura-Atividade , Triazóis/químicaRESUMO
This review summarizes briefly literature reports on nucleoside analogues containing five-membered aglycones based on imidazole-4-carboxamide, 1,2,4-triazole-3-carboxamide or 1,2,3-triazole-4-carboxamide structural motifs, which exhibit diverse therapeutically useful or promising biological properties. We do not describe synthetic approaches but try to present the essential activities of compounds and their established or postulated mechanisms of action.
Assuntos
Compostos Aza/química , Compostos Heterocíclicos/química , Nucleosídeos/química , Animais , Compostos Aza/farmacologia , Compostos Heterocíclicos/farmacologia , Humanos , Estrutura Molecular , Nucleosídeos/farmacologia , Relação Estrutura-AtividadeRESUMO
Two new types of imidazole derivatives: N-(2-R1-5-R2-1H-imidazol-4-yl) thioureas 7a-g and N-(2-R1-5-R2-1H-imidazol-4-yl) formamides 8b,c,g were obtained in high yields by the hydrolytic degradation of 6-R1-8-R2-2-thioxo-2,3-dihydroimidazo[1,5-a]-1,3,5-triazin-4(1H)-ones 5a-g and 6-R1-8-R2-imidazo[1,5-a]-1,3,5-triazin-4(3H)-ones 6b,c,d, respectively. The tautomeric preferences of the new imidazoles were determined.
Assuntos
Imidazóis/síntese química , Purinas/químicaRESUMO
Knowledge of the lipophilicity of candidate compounds for prodrugs may predict their predetermined course/effect in the body. Acyclovir (ACV) belongs to a class of drugs with low bioavailability. Its tricyclic analogues, the derivatives of 3,9-dihydro-3-[(2-hydroxyethoxy)methyl]-9-oxo-5H-imidazo[1,2-a]purine (TACV) exhibit similar antiviral activities and are more lipophilic as compared with acyclovir itself. In the search for new antiviral prodrugs 6-(4- methoxyphenyl) tricyclic compound (6-(4-MeOPh)-TACV) was modified by esterification of a hydroxyl group in the aliphatic chain. Selected esters (acetyl, isobutyryl, pivaloyl, ethoxycarbonyl and nicotinoyl) were synthesized and their lipophilicity was determined by the HPLC-RP method. The study compared the log kw calculated from the linear and quadratic equations and proved the correctness of the application of the linear relationship log k as a function of the concentration of ACN in the mobile phase (30-60%). Statistical analyses of the comparative values of log kw and clogP were carried out using computational methods. It was proved that the AC logP algorithm can be useful for the analysis of these compounds, which can have a statistically justified application in the assessment of the quantitative structure- activity relationship (QSAR). The lipophilicity determined by the HPLC method appears as follows: 6-(4-MeOPh)-TACV < Ac- < Nic- < Etc- < iBut- < Piv- (log kw = 0.65-2.26). Finally, the HPLC-RP method was developed and validated for simultaneous determination of synthesized esters.
Assuntos
Aciclovir/análogos & derivados , Antivirais/química , Cromatografia Líquida de Alta Pressão/métodos , Desenho de Fármacos , Pró-Fármacos/química , Aciclovir/síntese química , Antivirais/síntese química , Lipídeos/química , Pró-Fármacos/síntese química , SolubilidadeRESUMO
BACKGROUND: Ribavirin is a broad-spectrum antiviral agent that derives some of its activity from inhibition of cellular inosine monophosphate dehydrogenase (IMPDH), resulting in lower guanosine triphosphate (GTP) levels. Here we report the biological activities of three ribavirin analogues. METHODS: Antiviral activities of test compounds were performed by in vitro cytopathic effect inhibition assays against influenza A (H1N1, H3N2 and H5N1), influenza B, measles, parainfluenza type 3 (PIV-3) and respiratory syncytial viruses. Compounds were modelled into the ribavirin 5'-monophosphate binding site of the crystallographic structure of the human type II IMPDH (hIMPDH2) ternary complex. Effects of compounds on intracellular GTP levels were performed by strong anion exchange HPLC analysis. RESULTS: Of the three compounds evaluated, the 5-ethynyl nucleoside (ETCAR) exhibited virus-inhibitory activities (at 1.2-20 µM, depending upon the virus) against most of the viruses, except for weak activity against PIV-3 (62 µM). Antiviral activity of ETCAR was similar to ribavirin; however, cytotoxicity of ETCAR was greater than ribavirin. Replacing the 5-ethynyl group with a 5-propynyl or bromo substituent (BrCAR) considerably reduced antiviral activity. Computational studies of ternary complexes of hIMPDH2 enzyme with 5'-monophosphates of the compounds helped rationalize the observed differences in biological activity. All compounds suppressed GTP levels in cells; additionally, BrCAR suppressed adenosine triphosphate and elevated uridine triphosphate levels. CONCLUSIONS: Three compounds related to ribavirin inhibited IMPDH and had weak to moderate antiviral activity. Cytotoxicity adversely affected the antiviral selectivity of ETCAR. As with ribavirin, reduction in intracellular GTP may play a role in virus inhibition.
Assuntos
Antivirais/química , Antivirais/farmacologia , Nucleosídeos/química , Nucleosídeos/farmacologia , Ribavirina/análogos & derivados , Ribavirina/farmacologia , Animais , Linhagem Celular , Humanos , Vírus da Influenza A Subtipo H1N1/efeitos dos fármacos , Vírus da Influenza A Subtipo H3N2/efeitos dos fármacos , Virus da Influenza A Subtipo H5N1/efeitos dos fármacos , Vírus da Influenza B/efeitos dos fármacos , Influenza Humana/tratamento farmacológico , Sarampo/tratamento farmacológico , Vírus do Sarampo/efeitos dos fármacos , Modelos Moleculares , Infecções por Orthomyxoviridae/tratamento farmacológico , Vírus da Parainfluenza 3 Humana/efeitos dos fármacos , Infecções por Vírus Respiratório Sincicial/tratamento farmacológico , Vírus Sinciciais Respiratórios/efeitos dos fármacos , Infecções por Respirovirus/tratamento farmacológico , Triazóis/química , Triazóis/farmacologiaRESUMO
The synthesis of 5-ethynyl-1H-[1,2,3]triazole-4-carboxylic acid amide riboside 1 and its derivatives exploits Pd(0)-catalyzed cross-coupling reactions. The iodinated key intermediate 3a, when coupled with alkynes affords 5-alkynylated products 1b,c,e,f in diverse yields. Methanolysis of 1b and 1c provides the title compound 1 and the 5-propynyl derivative 1d, respectively. When coupled with methyl acrylate, 3a gives the E-isomer 4c, although in low yield, while the other 5-iodo precursor 3b undergoes reduction to 4b.
Assuntos
Nucleosídeos/síntese química , Ribonucleosídeos/síntese química , Triazóis/síntese química , Nucleosídeos/química , Ribonucleosídeos/química , Triazóis/químicaRESUMO
In the title compound, C(13)H(13)N(5)O(4) x H(2)O (4,5'-cyclowyosine x H(2)O), the cyclization forces a syn arrangement of the aglycon with respect to the sugar moiety. The ribofuranose part of the molecule displays a beta-D configuration with an envelope C1'-endo pucker. The molecules are arranged in columns along the short a axis and are linked to water molecules through O-H...O and O-H...N hydrogen bonds.
Assuntos
Imidazóis/química , Nucleosídeos/química , Nucleosídeos de Purina/química , Cristalografia por Raios X , Ligação de Hidrogênio , Modelos Moleculares , Conformação MolecularRESUMO
Out of a series of twenty 8-substituted or/and 1,N-2-bridged (tricyclic) derivatives of acyclovir (a selective antiherpetic drug), known to be nontoxic to normal cells, seven compounds were found to exhibit moderate cytostatic activity in KB human tumor tissue culture system with ED50 activity values ranging from 0.052-0.094 x 10(-3) mole/l. The structure-activity relationship analysis indicated that the primary factors determining their cytotoxicity were: 1) bromine atom at the C-8 position of the bicyclic derivatives and 2) unsubstituted appended ring in the tricyclic derivatives. Combination of two structural elements carrying the cytotoxicity gave diverse effects, enhancement or decrease in activity depending on particular cases. Two compounds (of four selected), 8-bromoacyclovir and 1,N-2-etheno-acyclovir, having unsubstituted 9-[(2-hydroxyethoxy)methyl] chain, showed approximately 2-fold increase in their cytotoxicity against HeLa tumor cells in the presence of the induced microsomal generating system suggesting that their cytotoxicity depends on the drug metabolic transformation into their active metabolites (intermediates) via MFO-system, and that structural unit of this chain is essential for abovementioned activation. Presently found remarkable cytotoxic selectivity of acyclovir analogues against KB and HeLa tumor cells together with previously reported in the literature specific cytotoxic activity of acyclovir against murine leukemia L 1210 cells seem to be encouraging for further investigation of this class of compounds in other tumor systems.