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1.
Bioorg Med Chem ; 21(7): 1685-95, 2013 Apr 01.
Artículo en Inglés | MEDLINE | ID: mdl-23434367

RESUMEN

6-Oxo and 6-thio analogs of purine were prepared based on the initial activity screening of a small, diverse purine library against Mycobacterium tuberculosis (Mtb). Certain 6-oxo and 6-thio-substituted purine analogs described herein showed moderate to good inhibitory activity. N(9)-substitution apparently enhances the anti-mycobacterial activity in the purine series described herein. Several 2-amino and 2-chloro purine analogs were also synthesized that showed moderate inhibitory activity against Mtb.


Asunto(s)
Antituberculosos/química , Antituberculosos/uso terapéutico , Mycobacterium tuberculosis/efectos de los fármacos , Purinas/química , Purinas/uso terapéutico , Tuberculosis/tratamiento farmacológico , Animales , Antituberculosos/farmacología , Antituberculosos/toxicidad , Supervivencia Celular/efectos de los fármacos , Chlorocebus aethiops , Humanos , Ratones , Pruebas de Sensibilidad Microbiana , Purinas/farmacología , Purinas/toxicidad , Compuestos de Sulfhidrilo/química , Compuestos de Sulfhidrilo/farmacología , Compuestos de Sulfhidrilo/uso terapéutico , Compuestos de Sulfhidrilo/toxicidad , Células Vero
3.
Bioorg Med Chem ; 17(2): 872-81, 2009 Jan 15.
Artículo en Inglés | MEDLINE | ID: mdl-19056279

RESUMEN

Arabinosyltransferases (AraTs) play a critical role in mycobacterial cell wall biosynthesis and are potential drug targets for the treatment of tuberculosis, especially multi-drug resistant forms of M. tuberculosis (MTB). Herein, we report the synthesis and acceptor/inhibitory activity of Araf alpha(1-->5) Araf disaccharides possessing deoxygenation at the reducing sugar of the disaccharide. Deoxygenation at either the C-2 or C-3 position of Araf was achieved via a free radical procedure using xanthate derivatives of the hydroxyl group. The alpha(1-->5)-linked disaccharides were produced by coupling n-octyl alpha-Araf 2-/3-deoxy, 2-fluoro glycosyl acceptors with an Araf thioglycosyl donor. The target disaccharides were tested in a cell free mycobacterial AraTs assay as well as an in vitro assay against MTB H(37)Ra and M. avium complex strains.


Asunto(s)
Arabinosa/análogos & derivados , Disacáridos/síntesis química , Mycobacterium tuberculosis/efectos de los fármacos , Pentosiltransferasa/antagonistas & inhibidores , Antibacterianos/síntesis química , Antibacterianos/farmacología , Arabinosa/química , Arabinosa/farmacología , Disacáridos/farmacología , Mycobacterium tuberculosis/enzimología , Pentosiltransferasa/metabolismo , Especificidad por Sustrato
4.
J Med Chem ; 50(14): 3283-9, 2007 Jul 12.
Artículo en Inglés | MEDLINE | ID: mdl-17569517

RESUMEN

Two boron-containing, ortho-icosahedral carborane lipophilic antifolates were synthesized, and the crystal structures of their ternary complexes with human dihydrofolate reductase (DHFR) and dihydronicotinamide adenine dinucleotide phosphate were determined. The compounds were screened for activity against DHFR from six sources (human, rat liver, Pneumocystis carinii, Toxoplasma gondii, Mycobacterium avium, and Lactobacillus casei) and showed good to modest activity against these enzymes. The compounds were also tested for antibacterial activity against L. casei, M. tuberculosis H37Ra, and three M. avium strains and for cytotoxic activity against seven different human tumor cell lines. Antibacterial and cytotoxic activity was modest, with one sample, the closo-carborane 4, showing about 10-fold greater activity. The less toxic nido-carborane 2 was also tested as a candidate for boron neutron capture therapy, but showed poor tumor retention and low selectivity ratios for boron distribution in tumor tissue versus normal tissue.


Asunto(s)
Boro/química , Antagonistas del Ácido Fólico/síntesis química , Antagonistas del Ácido Fólico/farmacología , Animales , Terapia por Captura de Neutrón de Boro , Línea Celular Tumoral , Cristalografía por Rayos X , Antagonistas del Ácido Fólico/química , Humanos , Pruebas de Sensibilidad Microbiana , Modelos Moleculares , Estructura Molecular , Ratas , Tetrahidrofolato Deshidrogenasa/efectos de los fármacos
5.
J Med Chem ; 45(25): 5604-6, 2002 Dec 05.
Artículo en Inglés | MEDLINE | ID: mdl-12459027

RESUMEN

A series of pyrazine and quinoxaline derivatives have been synthesized, and their activity against M. tuberculosis (Mtb) and Mycobacterium avium (MAC) are reported. The 4-acetoxybenzyl ester of pyrazinoic acid and 4'-acetoxybenzyl 2-quinoxalinecarboxylate showed excellent activity against Mtb (MIC ranges of less than 1-6.25 microg/mL) but only modest activity against MAC (MICs of 4-32 microg/mL).


Asunto(s)
Antibacterianos/síntesis química , Mycobacterium avium/efectos de los fármacos , Mycobacterium tuberculosis/efectos de los fármacos , Pirazinamida/síntesis química , Pirazinas/síntesis química , Quinoxalinas/síntesis química , Antibacterianos/química , Antibacterianos/farmacología , Pruebas de Sensibilidad Microbiana , Pirazinamida/análogos & derivados , Pirazinamida/química , Pirazinamida/farmacología , Pirazinas/química , Pirazinas/farmacología , Quinoxalinas/química , Quinoxalinas/farmacología , Relación Estructura-Actividad
6.
J Med Chem ; 47(1): 273-6, 2004 Jan 01.
Artículo en Inglés | MEDLINE | ID: mdl-14695841

RESUMEN

Thio analogues of purine, pyridine, and pyrimidine were prepared based on the initial activity screening of several analogues of these heterocycles against Mycobacterium tuberculosis (Mtb). Certain 6-thio-substituted purine analogues described herein showed moderate to good inhibitory activity. In particular, two purine analogues 9-(ethylcarboxymethyl)-6-(decylthio)-9H-purine (20) and 9-(ethylcarboxymethyl)-6-(dodecylthio)-9H-purine (21) exhibited MIC values of 1.56 and 0.78 microg/mL respectively against the Mtb H(37)Rv strain. N(9)-Substitution apparently enhances the antimycobacterial activity in the purine series described herein.


Asunto(s)
Antituberculosos/síntesis química , Purinas/síntesis química , Sulfuros/síntesis química , Antituberculosos/química , Antituberculosos/farmacología , Pruebas de Sensibilidad Microbiana , Mycobacterium tuberculosis/efectos de los fármacos , Purinas/química , Purinas/farmacología , Piridinas/síntesis química , Piridinas/química , Piridinas/farmacología , Pirimidinas/síntesis química , Pirimidinas/química , Pirimidinas/farmacología , Sulfuros/química , Sulfuros/farmacología
7.
Carbohydr Res ; 337(2): 105-20, 2002 Feb 05.
Artículo en Inglés | MEDLINE | ID: mdl-11814442

RESUMEN

Analogs of trehalose are reported that were designed to interfere with mycolylation pathways in the mycobacterial cell wall. Several derivatives of 6,6'-dideoxytrehalose, including N,N'-dialkylamino and 6,6'-bis(sulfonamido) analogs, were prepared and evaluated for antimycobacterial activity against Mycobacterium tuberculosis H(37)Ra and a panel of clinical isolates of Mycobacterium avium. 6,6'-Diaminotrehalose and its diazido precursor were both inactive, but significant activity apparently related to aliphatic chain length was found among the sulfonamides, N-alkylamines, and one of the amidines.


Asunto(s)
Antituberculosos/síntesis química , Pared Celular/metabolismo , Factores Cordón/síntesis química , Mycobacterium tuberculosis/efectos de los fármacos , Antituberculosos/química , Antituberculosos/farmacología , Pared Celular/efectos de los fármacos , Factores Cordón/química , Factores Cordón/farmacología , Pruebas de Sensibilidad Microbiana , Mycobacterium tuberculosis/metabolismo , Sulfonamidas/química , Sulfonamidas/farmacología
8.
Tuberculosis (Edinb) ; 89(5): 334-53, 2009 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-19758845

RESUMEN

There is an urgent need for the discovery and development of new antitubercular agents that target new biochemical pathways and treat drug resistant forms of the disease. One approach to addressing this need is through high-throughput screening of medicinally relevant libraries against the whole bacterium in order to discover a variety of new, active scaffolds that will stimulate new biological research and drug discovery. Through the Tuberculosis Antimicrobial Acquisition and Coordinating Facility (www.taacf.org), a large, medicinally relevant chemical library was screened against M. tuberculosis strain H37Rv. The screening methods and a medicinal chemistry analysis of the results are reported herein.


Asunto(s)
Antituberculosos/farmacología , Proteínas Bacterianas/efectos de los fármacos , Evaluación Preclínica de Medicamentos , Factores Inmunológicos/farmacología , Inmunoterapia/métodos , Mycobacterium tuberculosis/efectos de los fármacos , Tuberculosis/tratamiento farmacológico , Relación Dosis-Respuesta a Droga , Diseño de Fármacos , Humanos , Mycobacterium tuberculosis/aislamiento & purificación , Bibliotecas de Moléculas Pequeñas , Tuberculosis/genética , Tuberculosis/terapia
9.
Bioorg Med Chem Lett ; 17(16): 4527-30, 2007 Aug 15.
Artículo en Inglés | MEDLINE | ID: mdl-17566735

RESUMEN

Herein we report the synthesis of symmetrical C-linked and pseudo-symmetrical O-linked disaccharides structurally related to Araf motifs present in the cell wall of MTB. Their activity in a competition-based arabinosyltransferase assay using [14C]-DPA as the glycosyl donor is also presented. In addition, in vitro inhibitory activity for the disaccharides was determined in a colorimetric broth microdilution assay system against MTB H37Ra and Mycobacterium avium.


Asunto(s)
Antituberculosos/síntesis química , Disacáridos/síntesis química , Disacáridos/farmacología , Mycobacterium tuberculosis/enzimología , Pentosiltransferasa/antagonistas & inhibidores , Antituberculosos/farmacología
10.
Bioorg Med Chem ; 14(13): 4610-26, 2006 Jul 01.
Artículo en Inglés | MEDLINE | ID: mdl-16513358

RESUMEN

Pyranocoumarin compounds were identified to embody a novel and unique pharmacophore for anti-TB activity. A systematic approach was taken to investigate the structural characteristics. Focused libraries of compounds were synthesized and evaluated for their anti-TB activity in primary screening assays. Compounds shown to be active were further determined for MIC and MBC values. Three of the four bactericidal compounds (16, 17c, and 18f) were amino derivatives, with MIC values of 16 microg/mL and respective MBC values of 32, 32, and 64 microg/mL.


Asunto(s)
Antibióticos Antituberculosos/química , Antibióticos Antituberculosos/farmacología , Mycobacterium tuberculosis/efectos de los fármacos , Piranocumarinas/química , Piranocumarinas/farmacología , Antibióticos Antituberculosos/síntesis química , Pruebas de Sensibilidad Microbiana , Piranocumarinas/síntesis química
11.
J Antimicrob Chemother ; 50(1): 111-4, 2002 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-12096015

RESUMEN

Compounds originally designed as putative tubulin inhibitors were tested as antitubercular agents for inhibition of the Mycobacterium tuberculosis analogue of tubulin, FtsZ. Initial screening of 200 2-alkoxycarbonylpyridines found several that inhibited M. tuberculosis growth. Two compounds, SRI-3072 and SRI-7614, inhibited FtsZ polymerization and were equipotent against susceptible and single-drug-resistant strains of M. tuberculosis. In addition, SRI-3072 reduced the growth of M. tuberculosis in mouse bone marrow macrophages. Our results suggest that these types of compound might be developed into antitubercular drugs effective against the current multidrug-resistant strains of M. tuberculosis.


Asunto(s)
Antituberculosos/farmacología , Azepinas/farmacología , Proteínas Bacterianas/efectos de los fármacos , Carbamatos/farmacología , Proteínas del Citoesqueleto , Mycobacterium tuberculosis/efectos de los fármacos , Pteridinas/farmacología , Tuberculosis Resistente a Múltiples Medicamentos/tratamiento farmacológico , Animales , Antituberculosos/uso terapéutico , Antituberculosos/toxicidad , Azepinas/uso terapéutico , Azepinas/toxicidad , Proteínas Bacterianas/metabolismo , Células de la Médula Ósea/efectos de los fármacos , Células de la Médula Ósea/microbiología , Carbamatos/uso terapéutico , Carbamatos/toxicidad , Chlorocebus aethiops , GTP Fosfohidrolasas/metabolismo , Concentración 50 Inhibidora , Macrófagos/efectos de los fármacos , Macrófagos/microbiología , Ratones , Pruebas de Sensibilidad Microbiana , Mycobacterium tuberculosis/metabolismo , Pteridinas/uso terapéutico , Pteridinas/toxicidad , Células Vero
12.
Bioorg Med Chem ; 12(5): 1199-207, 2004 Mar 01.
Artículo en Inglés | MEDLINE | ID: mdl-14980631

RESUMEN

Naturally occurring anti-HIV-1 agent (+)-calanolide A was found to be active against all of the strains of Mycobacterium tuberculosis tested, including those resistant to the standard antitubercular drugs. Efficacy evaluations in macrophages revealed that (+)-calanolide A significantly inhibited intracellular replication of M. tuberculosis H37Rv at concentrations below the MIC observed in vitro. Preliminary mechanistic studies indicated that (+)-calanolide A rapidly inhibits RNA and DNA synthesis followed by an inhibition of protein synthesis. Compared with known inhibitors, this scenario is more similar to effects observed with rifampin, an inhibitor of RNA synthesis. Since (+)-calanolide A was active against a rifampin-resistant strain, it is believed that these two agents may involve different targets. (+)-Calanolide A and its related pyranocoumarins are the first class of compounds identified to possess antimycobacterial and antiretroviral activities, representing a new pharmacophore for anti-TB activity.


Asunto(s)
Fármacos Anti-VIH/farmacología , Antituberculosos/farmacología , Cumarinas/farmacología , Mycobacterium tuberculosis/efectos de los fármacos , Animales , Protocolos de Quimioterapia Combinada Antineoplásica , Línea Celular , Chlorocebus aethiops , Cisplatino , ADN/biosíntesis , Farmacorresistencia Bacteriana , Ifosfamida , Concentración 50 Inhibidora , Macrófagos/microbiología , Pruebas de Sensibilidad Microbiana , Mitomicina , Piranocumarinas/química , Piranocumarinas/farmacología , ARN/biosíntesis , Rifampin , Células Vero , Replicación Viral/efectos de los fármacos
13.
Microbiology (Reading) ; 148(Pt 1): 289-295, 2002 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-11782521

RESUMEN

2-Methyladenosine (methyl-ado) has demonstrated selective activity against Mycobacterium tuberculosis, which indicates that differences in the substrate preferences between mycobacterial and human purine metabolic enzymes can be exploited to develop novel drugs for the treatment of mycobacterial diseases. Therefore, in an effort to better understand the reasons for the anti-mycobacterial activity of methyl-ado, its metabolism has been characterized in Mycobacterium smegmatis. In a wild-type strain, methyl-ado was phosphorylated by adenosine kinase to methyl-AMP, which was further converted to methyl-ATP and incorporated into RNA. In contrast, a mutant strain of M. smegmatis was isolated that was resistant to methyl-ado, deficient in adenosine kinase activity and was not able to generate methyl-ado metabolites in cells treated with methyl-ado. These results indicated that phosphorylated metabolites of methyl-ado were responsible for the cytotoxic activity of this compound. Methyl-ado was not a substrate for either adenosine deaminase or purine-nucleoside phosphorylase from M. smegmatis. Treatment of M. smegmatis with methyl-ado resulted in the inhibition of ATP synthesis, which indicated that a metabolite of methyl-ado inhibited one of the enzymes involved in de novo purine synthesis. These studies demonstrated the importance of adenosine kinase in the activation of methyl-ado to toxic metabolites in M. smegmatis.


Asunto(s)
Adenosina Quinasa/metabolismo , Adenosina/análogos & derivados , Adenosina/metabolismo , Mycobacterium smegmatis/metabolismo , Adenosina/farmacología , Adenosina Trifosfato/metabolismo , Medios de Cultivo , Farmacorresistencia Bacteriana , Mycobacterium smegmatis/efectos de los fármacos , Mycobacterium smegmatis/genética , Mycobacterium smegmatis/crecimiento & desarrollo
14.
J Antimicrob Chemother ; 52(5): 801-8, 2003 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-14563890

RESUMEN

OBJECTIVES: The aims of this study were to assess the in vitro activity of 2-methyl-adenosine against Mycobacterium tuberculosis and evaluate, and to intracellular efficacy, and to evaluate its effectiveness against M. tuberculosis in a persistent state model and examine its potential mechanism of action. METHODS: In vitro activity was determined by means of a colorimetric microdilution broth assay. Intracellular activity was assessed with a Mono Mac 6 human monocytic cell line. A hypoxic shift-down model was used to evaluate the effect of 2-methyl-adenosine on M. tuberculosis in a persistent state. Mechanism-of-action studies were conducted by examining the effect of 2-methyl-adenosine on the uptake of appropriate radiolabelled precursors into respective mycobacterial macromolecular components. RESULTS: Studies confirmed the in vitro activity of 2-methyl-adenosine against M. tuberculosis and demonstrated intracellular efficacy against M. tuberculosis within macrophages. 2-Methyl-adenosine was able to significantly affect the viability of M. tuberculosis in a hypoxic shift-down model previously described to simulate the persistent state that results during tuberculosis. Mechanism-of-action studies revealed that the immediate inhibitory effects of 2-methyl-adenosine were associated with protein and DNA synthesis and not RNA synthesis. CONCLUSIONS: Results indicate that 2-methyl-adenosine, or similar derivatives, might be effective against M. tuberculosis infections during latency. This information should be helpful in understanding purine metabolism of M. tuberculosis and also the metabolic activity of this important human pathogen in the persistent state.


Asunto(s)
Adenosina/análogos & derivados , Adenosina/farmacología , Mycobacterium tuberculosis/efectos de los fármacos , Proteínas Bacterianas/biosíntesis , Línea Celular , Recuento de Colonia Microbiana , ADN Bacteriano/biosíntesis , Humanos , Pruebas de Sensibilidad Microbiana , Monocitos , Mycobacterium tuberculosis/crecimiento & desarrollo , Mycobacterium tuberculosis/fisiología , ARN Bacteriano/biosíntesis , Latencia del Virus
15.
Bioorg Med Chem ; 10(4): 923-8, 2002 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-11836099

RESUMEN

The mycobacterial cell wall is a potential target for new drug development. Herein we report the preparation and activity of several n-octyl-5-(alpha-D-arabinofuranosyl)-beta-D-galactofuranoside derivatives. A cell-free assay system has been utilized for determination of the ability of disaccharide analogues to act as arabinosyltransferase acceptors using [14C]-DPA as the glycosyl donor. In addition, in vitro inhibitory activity has been determined in a colorimetric broth microdilution assay system against MTB H37Ra and three clinical isolates of Mycobacterium avium complex (MAC). One of these disaccharides showed moderate activity against MTB. The biological evaluation of these disaccharides suggests that more hydrophobic analogues with a blocked reducing end showed better activity as compared to a totally deprotected disaccharide that more closely resembles the natural substrates in cell wall biosynthesis.


Asunto(s)
Antituberculosos/farmacología , Disacáridos/farmacología , Glicosiltransferasas/metabolismo , Mycobacterium/enzimología , Antituberculosos/síntesis química , Antituberculosos/química , Secuencia de Carbohidratos , Disacáridos/síntesis química , Disacáridos/química , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacología , Glicosiltransferasas/antagonistas & inhibidores , Pruebas de Sensibilidad Microbiana , Datos de Secuencia Molecular , Mycobacterium/efectos de los fármacos , Mycobacterium tuberculosis/efectos de los fármacos , Mycobacterium tuberculosis/enzimología , Pentosiltransferasa/antagonistas & inhibidores , Pentosiltransferasa/metabolismo , Polisacáridos Bacterianos/química , Especificidad por Sustrato
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