RESUMO
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.
Assuntos
Antituberculosos/química , Antituberculosos/uso terapêutico , Mycobacterium tuberculosis/efeitos dos fármacos , Purinas/química , Purinas/uso terapêutico , Tuberculose/tratamento farmacológico , Animais , Antituberculosos/farmacologia , Antituberculosos/toxicidade , Sobrevivência Celular/efeitos dos fármacos , Chlorocebus aethiops , Humanos , Camundongos , Testes de Sensibilidade Microbiana , Purinas/farmacologia , Purinas/toxicidade , Compostos de Sulfidrila/química , Compostos de Sulfidrila/farmacologia , Compostos de Sulfidrila/uso terapêutico , Compostos de Sulfidrila/toxicidade , Células VeroRESUMO
A series of pyridopyrazine and pyrimidothiazine derivatives have been synthesized and their activity against FtsZ from Mycobacterium tuberculosis (Mtb) and in vitro antibacterial activity against Mtb H(37)Ra and Mtb H(37)Rv are reported. Certain analogs described herein showed moderate to good inhibitory activity.
Assuntos
Antituberculosos/farmacologia , Proteínas de Bactérias/antagonistas & inibidores , Proteínas do Citoesqueleto/antagonistas & inibidores , Pirazinas/farmacologia , Tiazinas/farmacologia , Animais , Antituberculosos/síntese química , Antituberculosos/química , Modelos Animais de Doenças , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Mycobacterium tuberculosis/química , Mycobacterium tuberculosis/efeitos dos fármacos , Mycobacterium tuberculosis/metabolismo , Pirazinas/síntese química , Pirazinas/química , Piridinas/síntese química , Piridinas/química , Piridinas/farmacologia , Pirimidinas/síntese química , Pirimidinas/química , Pirimidinas/farmacologia , Relação Estrutura-Atividade , Tiazinas/síntese química , Tiazinas/químicaRESUMO
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.
Assuntos
Arabinose/análogos & derivados , Dissacarídeos/síntese química , Mycobacterium tuberculosis/efeitos dos fármacos , Pentosiltransferases/antagonistas & inibidores , Antibacterianos/síntese química , Antibacterianos/farmacologia , Arabinose/química , Arabinose/farmacologia , Dissacarídeos/farmacologia , Mycobacterium tuberculosis/enzimologia , Pentosiltransferases/metabolismo , Especificidade por SubstratoRESUMO
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.
Assuntos
Boro/química , Antagonistas do Ácido Fólico/síntese química , Antagonistas do Ácido Fólico/farmacologia , Animais , Terapia por Captura de Nêutron de Boro , Linhagem Celular Tumoral , Cristalografia por Raios X , Antagonistas do Ácido Fólico/química , Humanos , Testes de Sensibilidade Microbiana , Modelos Moleculares , Estrutura Molecular , Ratos , Tetra-Hidrofolato Desidrogenase/efeitos dos fármacosRESUMO
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).
Assuntos
Antibacterianos/síntese química , Mycobacterium avium/efeitos dos fármacos , Mycobacterium tuberculosis/efeitos dos fármacos , Pirazinamida/síntese química , Pirazinas/síntese química , Quinoxalinas/síntese química , Antibacterianos/química , Antibacterianos/farmacologia , Testes de Sensibilidade Microbiana , Pirazinamida/análogos & derivados , Pirazinamida/química , Pirazinamida/farmacologia , Pirazinas/química , Pirazinas/farmacologia , Quinoxalinas/química , Quinoxalinas/farmacologia , Relação Estrutura-AtividadeRESUMO
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.
Assuntos
Antituberculosos/síntese química , Purinas/síntese química , Sulfetos/síntese química , Antituberculosos/química , Antituberculosos/farmacologia , Testes de Sensibilidade Microbiana , Mycobacterium tuberculosis/efeitos dos fármacos , Purinas/química , Purinas/farmacologia , Piridinas/síntese química , Piridinas/química , Piridinas/farmacologia , Pirimidinas/síntese química , Pirimidinas/química , Pirimidinas/farmacologia , Sulfetos/química , Sulfetos/farmacologiaRESUMO
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.
Assuntos
Antituberculosos/síntese química , Parede Celular/metabolismo , Fatores Corda/síntese química , Mycobacterium tuberculosis/efeitos dos fármacos , Antituberculosos/química , Antituberculosos/farmacologia , Parede Celular/efeitos dos fármacos , Fatores Corda/química , Fatores Corda/farmacologia , Testes de Sensibilidade Microbiana , Mycobacterium tuberculosis/metabolismo , Sulfonamidas/química , Sulfonamidas/farmacologiaRESUMO
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.
Assuntos
Antituberculosos/farmacologia , Proteínas de Bactérias/efeitos dos fármacos , Avaliação Pré-Clínica de Medicamentos , Fatores Imunológicos/farmacologia , Imunoterapia/métodos , Mycobacterium tuberculosis/efeitos dos fármacos , Tuberculose/tratamento farmacológico , Relação Dose-Resposta a Droga , Desenho de Fármacos , Humanos , Mycobacterium tuberculosis/isolamento & purificação , Bibliotecas de Moléculas Pequenas , Tuberculose/genética , Tuberculose/terapiaRESUMO
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.
Assuntos
Antituberculosos/síntese química , Dissacarídeos/síntese química , Dissacarídeos/farmacologia , Mycobacterium tuberculosis/enzimologia , Pentosiltransferases/antagonistas & inibidores , Antituberculosos/farmacologiaRESUMO
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.
Assuntos
Antibióticos Antituberculose/química , Antibióticos Antituberculose/farmacologia , Mycobacterium tuberculosis/efeitos dos fármacos , Piranocumarinas/química , Piranocumarinas/farmacologia , Antibióticos Antituberculose/síntese química , Testes de Sensibilidade Microbiana , Piranocumarinas/síntese químicaRESUMO
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.
Assuntos
Antituberculosos/farmacologia , Azepinas/farmacologia , Proteínas de Bactérias/efeitos dos fármacos , Carbamatos/farmacologia , Proteínas do Citoesqueleto , Mycobacterium tuberculosis/efeitos dos fármacos , Pteridinas/farmacologia , Tuberculose Resistente a Múltiplos Medicamentos/tratamento farmacológico , Animais , Antituberculosos/uso terapêutico , Antituberculosos/toxicidade , Azepinas/uso terapêutico , Azepinas/toxicidade , Proteínas de Bactérias/metabolismo , Células da Medula Óssea/efeitos dos fármacos , Células da Medula Óssea/microbiologia , Carbamatos/uso terapêutico , Carbamatos/toxicidade , Chlorocebus aethiops , GTP Fosfo-Hidrolases/metabolismo , Concentração Inibidora 50 , Macrófagos/efeitos dos fármacos , Macrófagos/microbiologia , Camundongos , Testes de Sensibilidade Microbiana , Mycobacterium tuberculosis/metabolismo , Pteridinas/uso terapêutico , Pteridinas/toxicidade , Células VeroRESUMO
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.
Assuntos
Adenosina/análogos & derivados , Adenosina/farmacologia , Mycobacterium tuberculosis/efeitos dos fármacos , Proteínas de Bactérias/biossíntese , Linhagem Celular , Contagem de Colônia Microbiana , DNA Bacteriano/biossíntese , Humanos , Testes de Sensibilidade Microbiana , Monócitos , Mycobacterium tuberculosis/crescimento & desenvolvimento , Mycobacterium tuberculosis/fisiologia , RNA Bacteriano/biossíntese , Latência ViralRESUMO
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.
Assuntos
Fármacos Anti-HIV/farmacologia , Antituberculosos/farmacologia , Cumarínicos/farmacologia , Mycobacterium tuberculosis/efeitos dos fármacos , Animais , Protocolos de Quimioterapia Combinada Antineoplásica , Linhagem Celular , Chlorocebus aethiops , Cisplatino , DNA/biossíntese , Farmacorresistência Bacteriana , Ifosfamida , Concentração Inibidora 50 , Macrófagos/microbiologia , Testes de Sensibilidade Microbiana , Mitomicina , Piranocumarinas/química , Piranocumarinas/farmacologia , RNA/biossíntese , Rifampina , Células Vero , Replicação Viral/efeitos dos fármacosRESUMO
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.
Assuntos
Adenosina Quinase/metabolismo , Adenosina/análogos & derivados , Adenosina/metabolismo , Mycobacterium smegmatis/metabolismo , Adenosina/farmacologia , Trifosfato de Adenosina/metabolismo , Meios de Cultura , Farmacorresistência Bacteriana , Mycobacterium smegmatis/efeitos dos fármacos , Mycobacterium smegmatis/genética , Mycobacterium smegmatis/crescimento & desenvolvimentoRESUMO
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.