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1.
Chemotherapy ; 51(5): 263-7, 2005 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-16103666

RESUMO

BACKGROUND: A dramatic increase in multiple-drug-resistant (MDR) Gram-positive pathogens has occurred in recent times, leading to increased rates or morbidity and mortality and also associated with high costs for the treatment of these infections. It is clear that there is an urgent need for the development of effective antimicrobial agents. The anti-bacterial activity of seven 2,2,6,6-tetramethylpiperidine (TMP)-substituted phenazines, compared to clofazimine (B663), were tested against 70 clinical isolates of methicillin-resistant Staphylococcus aureus, MDR Streptococcus pneumoniae and resistant Enterococcus sp. METHODS: Standard minimum inhibitory concentration agar dilution susceptibility tests were done on all isolates, including ATCC control strains. RESULTS: All the TMP-substituted phenazines were more active than clofazimine against all isolates tested. Compound B4125 was the most active by inhibiting all growth of the organisms tested, including vancomycin-resistant Enterococcus faecium. CONCLUSION: Clofazimine has been shown to have anti-staphylococcal activity. We demonstrate enhanced anti-bacterial activity of TMP-substituted phenazines against drug-resistant Gram-positive organisms compared to clofazimine.


Assuntos
Resistência a Múltiplos Medicamentos , Enterococcus/efeitos dos fármacos , Fenazinas/farmacologia , Piperidinas/química , Staphylococcus aureus/efeitos dos fármacos , Streptococcus pneumoniae/efeitos dos fármacos , Clofazimina/farmacologia , Hansenostáticos/farmacologia , Resistência a Meticilina , Testes de Sensibilidade Microbiana
2.
Indian J Lepr ; 72(1): 5-20, 2000.
Artigo em Inglês | MEDLINE | ID: mdl-10935183

RESUMO

In 1991 World Health Organization proclaimed the goal of global elimination of leprosy as a public health problem by year 2000 by implementing multidrug therapy (MDT). Since then the prevalence rate has declined by 85%. However, during the same period the incidence rate of leprosy has remained constant or even has been increasing. This suggests that it will take a long time for the eradication of leprosy and that without in-vitro cultivation of M. leprae, eradication of leprosy is not likely to be achieved. While in-vitro cultivation is a long-term goal, as an immediate measure, there is an urgent need for the development of newer drugs and newer multidrug therapy regimens. Using the in-vitro system for screening potential antileprosy drugs and also using the mouse foot-pad system we have evaluated several compounds in four classes of drugs--dihydrofolate reductase inhibitors, fluoroquinolones, rifampicin analogues and phenazines--and identified at least two compounds that appear to be more potent than dapsone, rifampicin and clofazimine. Newer combinations of rifampicin analogues and fluoroquinolones have also been identified that seem to be better than the combination of rifampicin and ofloxacin.


Assuntos
Hansenostáticos/farmacologia , Mycobacterium leprae/efeitos dos fármacos , Animais , Anti-Infecciosos/farmacologia , Fluoroquinolonas , Antagonistas do Ácido Fólico/farmacologia , Pé/microbiologia , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Testes de Sensibilidade Microbiana/métodos , Mycobacterium leprae/crescimento & desenvolvimento , Fenazinas/farmacologia , Rifampina/análogos & derivados , Rifampina/farmacologia , Tetra-Hidrofolato Desidrogenase/metabolismo
3.
J Antimicrob Chemother ; 43(5): 615-23, 1999 May.
Artigo em Inglês | MEDLINE | ID: mdl-10382882

RESUMO

Riminophenazines were specifically developed as drugs active against Mycobacterium tuberculosis but extensive research over several decades has shown that these compounds are also active against many other mycobacterial infections, particularly those caused by Mycobacterium leprae and the Mycobacterium avium complex (MAC). Clofazimine, the lead compound in this series, is included in the regimens that are approved by the WHO for the treatment of leprosy and has contributed significantly to the control of that disease, particularly that caused by dapsone-resistant bacteria. Despite early problems, clofazimine has shown clinical efficacy in tuberculosis, in particular that caused by multiple drug resistant strains. Clofazimine does not induce resistance and also inhibits emergence of resistance to isoniazid in M. tuberculosis. The efficacy of clofazimine against MAC is more varied and the availability of better drugs has limited its use. Newer riminophenazines, such as B746 and B4157, not only showed increased anti-mycobacterial activity but also produced less skin pigmentation, which is the main drawback of this group of compounds. The most important virtues of riminophenazines, such as intracellular accumulation in mononuclear phagocytic cells, anti-inflammatory activity, a low incidence of drug resistance and slow metabolic elimination, make them attractive candidates for the treatment of mycobacterial infections. It is essential, however, to investigate the newer analogues clinically, while continuing the pursuit of alternate candidates that demonstrate higher anti-mycobacterial activity and lower rates of skin pigmentation.


Assuntos
Infecções por Mycobacterium/tratamento farmacológico , Mycobacterium/efeitos dos fármacos , Fenazinas/química , Fenazinas/farmacologia , Animais , Antituberculosos/química , Antituberculosos/farmacologia , Clofazimina/metabolismo , Clofazimina/farmacologia , Humanos , Hansenostáticos/química , Hansenostáticos/farmacologia , Fenazinas/metabolismo
4.
Int J Lepr Other Mycobact Dis ; 61(3): 406-14, 1993 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-8228439

RESUMO

Twenty-five compounds structurally related to clofazimine were tested for their ability to inhibit the growth of Mycobacterium leprae using the kinetic method of drug evaluation in the mouse foot pad model of leprosy. Seven of the phenazine derivatives displayed anti-M. leprae activity comparable to that of clofazimine when administered at a concentration of 0.01% (w/w) in the diet. Three of the compounds, B746, B4087, and B4101, were active when administered at 0.001% in the diet. At a dietary concentration of 0.0001%, B4087 and B4101 were slightly more active than clofazimine, while B746 was less active. In the kinetic method of drug evaluation, greater anti-M. leprae activity of phenazine derivatives was generally associated with greater pigmentation of abdominal fat. Of the compounds which did not cause pigmentation when fed at a concentration of 0.01% in the diet B4090 was the most active. This compound also inhibits the growth of a clofazimine-resistant M. smegmatis strain.


Assuntos
Hanseníase/tratamento farmacológico , Mycobacterium leprae/efeitos dos fármacos , Fenazinas/farmacologia , Abdome , Tecido Adiposo/efeitos dos fármacos , Animais , Clofazimina/química , Clofazimina/farmacologia , Clofazimina/uso terapêutico , Modelos Animais de Doenças , Avaliação Pré-Clínica de Medicamentos , Feminino , Humanos , Cinética , Hanseníase/microbiologia , Camundongos , Estrutura Molecular , Mycobacterium leprae/crescimento & desenvolvimento , Fenazinas/química , Fenazinas/uso terapêutico , Pigmentação
5.
Lepr Rev ; 61(2): 163-70, 1990 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-2165549

RESUMO

In this study the effects of nine dihydrophenazine derivatives, relative to clofazimine (B663), on the N-formyl-L-methionyl-L-leucyl-L-phenylalanine (FMLP) stimulated release of superoxide anion and on the spontaneous generation of arachidonic acid by human neutrophils were investigated. Previous findings that the pro-oxidative activity of the agents depended largely on the substitution in position 2 of the phenazine molecule and on chlorination in the paraposition of the phenyl and anilino rings were confirmed. Only riminophenazines, but not aposafranone derivatives or the imidazophenazine B621, could enhance superoxide release from activated neutrophils. The lack of chlorination of the phenyl and anilino rings could be compensated for by chlorine substitution in position 7 of the phenazine core. The priming effect of the agents on FMLP stimulated superoxide generation was completely prevented by the phospholipase A2 inhibitor 4-p-bromophenacyl bromide. Furthermore pro-oxidative activities correlated closely with a stimulatory effect of the agents on arachidonic acid release. It was therefore concluded that dihydrophenazine derivatives with pro-oxidative properties can prime neutrophils for FMLP-stimulated superoxide release by modulation of phospholipase A2 activity.


Assuntos
Ácidos Araquidônicos/metabolismo , Clofazimina/farmacologia , Neutrófilos/metabolismo , Fenazinas/farmacologia , Superóxidos/metabolismo , Ácido Araquidônico , Fenômenos Químicos , Química , Humanos , Leucócitos Mononucleares/efeitos dos fármacos , Leucócitos Mononucleares/metabolismo , N-Formilmetionina Leucil-Fenilalanina/farmacologia , Neutrófilos/efeitos dos fármacos
6.
Antimicrob Agents Chemother ; 33(11): 2004-5, 1989 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-2692516

RESUMO

In a previous study of structure-activity relationships of selected phenazines against Mycobacterium leprae in vitro, compounds containing a 2,2,6,6-tetramethylpiperidine substitution at the imino nitrogen were most active. Therefore, the effect of substitution at the para positions of the phenyl and anilino groups in tetramethylpiperidine-substituted phenazines was assessed. As determined by radiorespirometry, activity in ascending order was observed in compounds substituted with hydrogens or fluorines, ethoxy groups, methyl groups, chlorines, and bromines and correlated with partition coefficients in octanol-water.


Assuntos
Antibacterianos/farmacologia , Clofazimina/análogos & derivados , Clofazimina/farmacologia , Mycobacterium leprae/efeitos dos fármacos , Testes de Sensibilidade Microbiana , Fenazinas/farmacologia , Piperidinas/farmacologia , Relação Estrutura-Atividade
7.
Antimicrob Agents Chemother ; 32(10): 1583-5, 1988 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-3056241

RESUMO

Structure-activity relationships of phenazines against Mycobacterium leprae were investigated by using an in vitro radiorespirometric assay. In general, activity in ascending order was observed in compounds containing no chlorine atoms, a monochlorinated phenazine nucleus, and chlorines in the para positions of both the anilino and phenyl rings. The most active compounds contained a 2,2,6,6-tetramethylpiperidine substitution at the imino nitrogen. Most of these chlorinated phenazines were considerably more active in vitro than clofazimine (B663).


Assuntos
Hansenostáticos , Mycobacterium leprae/efeitos dos fármacos , Fenazinas/farmacologia , Clofazimina/farmacologia , Testes de Sensibilidade Microbiana , Relação Estrutura-Atividade
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