RESUMO
Despite being a curable disease, tuberculosis (TB) remains a public health problem worldwide mainly due to lengthy treatment, as well as its toxic effects, TB/HIV co-infection and the emergence of resistant Mycobacterium tuberculosis strains. These barriers reinforcing the need for development of new antimicrobial agents, that ideally should reduce the time of treatment and be active against susceptible and resistant strains. Quinones are compounds found in natural sources and among them, the naphthoquinones show antifungal, antiparasitic, and antimycobacterial activity. Thus, we evaluated the potential antimycobacterial activity of six 1,4-naphthoquinones derivatives. We determined the minimum inhibitory concentration (MIC) of the compounds against three M. tuberculosis strains: a pan-susceptible H37Rv (ATCC 27294); one mono-resistant to isoniazid (ATCC 35822); and one mono-resistant to rifampicin (ATCC 35838); the cytotoxicity in the J774A.1 (ATCC TIB-67) macrophage lineage; performed in silico analysis about absorption, distribution, metabolism, and excretion (ADME) and docking sites. All evaluated naphthoquinones were active against the three strains with MIC between 206.6 and 12.5 µM, and the compounds with lower MIC values have also showed low cytotoxicity. Moreover, two naphthoquinones derivatives 5 and 6 probably do not exhibit cross resistance with isoniazid and rifampicin, respectively, and regarding ADME analysis, no compound violated the Lipinski's rule-of-five. Considering the set of findings in this study, we conclude that these naphthoquinones could be promising scaffolds to develop new therapeutic strategies to TB.
RESUMO
Twenty-three naphthoimidazoles and six naphthoxazoles were synthesised and evaluated against susceptible and rifampicin- and isoniazid-resistant strains of Mycobacterium tuberculosis. Among all the compounds evaluated, fourteen presented MIC values in the range of 0.78 to 6.25 µg/mL against susceptible and resistant strains of M. tuberculosis. Five structures were solved by X-ray crystallographic analysis. These substances are promising antimycobacterial prototypes.
Assuntos
Antituberculosos/síntese química , Antituberculosos/farmacologia , Azóis/farmacologia , Imidazóis/farmacologia , Mycobacterium tuberculosis/efeitos dos fármacos , Naftoquinonas/farmacologia , Oxazóis/farmacologia , Antituberculosos/química , Azóis/síntese química , Azóis/química , Proliferação de Células/efeitos dos fármacos , Cristalografia por Raios X , Relação Dose-Resposta a Droga , Humanos , Imidazóis/síntese química , Imidazóis/química , Leucócitos Mononucleares/citologia , Leucócitos Mononucleares/efeitos dos fármacos , Testes de Sensibilidade Microbiana , Modelos Moleculares , Estrutura Molecular , Naftoquinonas/síntese química , Naftoquinonas/química , Oxazóis/síntese química , Oxazóis/química , Relação Estrutura-AtividadeRESUMO
Several quinonoid and phenazine compounds were synthesized in moderate to high yields and showed activity against H(37)Rv, rifampicin and isoniazid-resistance strains of Mycobacterium tuberculosis. The cytotoxity of the compounds were evaluated against human peripheral blood mononuclear cells (PBMC) and these substances emerge as promising antitubercular prototypes.
Assuntos
Antituberculosos/síntese química , Antituberculosos/farmacologia , Mycobacterium tuberculosis/efeitos dos fármacos , Fenazinas/síntese química , Quinonas/síntese química , Antituberculosos/química , Células Cultivadas , Resistência Microbiana a Medicamentos , Isoniazida/farmacologia , Espectroscopia de Ressonância Magnética , Testes de Sensibilidade Microbiana , Modelos Moleculares , Fenazinas/química , Fenazinas/farmacologia , Quinonas/química , Quinonas/farmacologia , Rifampina/farmacologia , Espectrometria de Massas por Ionização por Electrospray , Espectrofotometria Infravermelho , Difração de Raios XRESUMO
The increase of incidence of tuberculosis (TB) with resistant strains and HIV co-infection has reinforced the necessity of developing new drugs for its treatment. The reaction of naphthoquinones with aromatic or aliphatic aldehydes in the presence of ammonium acetate led to the synthesis of the three ß-lapachone derivatives (naphthoimidazoles) that were tested in this study. Phenazines were prepared by the reaction of the respective naphtoquinone with o-phenylenediamine in acetic acid under reflux. The antimicrobial activity of the derivatives was evaluated in vitro against Mycobacterium tuberculosis H37Rv (ATCC 27294) and the rifampicin-resistant strain (ATCC 35338) containing a His-526-Tir mutation in the rpoB gene. Using the Resazurin Microtiter Assay (REMA) method, bioactive molecules were observed in the susceptible and resistant strains with MICs ranging from 2.2 µM to 17 µM. The naphthoimidazoles with p-toluyl and indolyl group attached to the imidazole ring were more active against the H37Rv strain (MIC 9.12 µM and 4.2 µM, respectively) than the rifampicin-resistant strain (MIC 8.3 µM and 17 µM, respectively). The phenazine with the allyl-pyran group was most active among the two strains and had an MIC of 2.2 mM. These results show the potential of these molecules as prototypes for future drugs used in treating TB.
Assuntos
Antituberculosos/farmacologia , Resistência Microbiana a Medicamentos/efeitos dos fármacos , Mycobacterium tuberculosis/efeitos dos fármacos , Naftoquinonas/farmacologia , Rifampina/farmacologia , Linhagem Celular , Humanos , Testes de Sensibilidade Microbiana , Fenazinas/farmacologiaRESUMO
The reaction of naphthoquinone-oximes (3) and (4) with diazomethane yields directly, in one step, the oxazoles (5) and (6), respectively.
Assuntos
Técnicas de Química Combinatória , Diazometano/química , Naftoquinonas/química , Oxazóis/síntese química , Oximas/química , OxirreduçãoRESUMO
The reaction of naphthoquinone-oximes (3) and (4) with diazomethane yields directly, in one step, the oxazoles (5) and (6), respectively.
A reação das naphthoquinona-oximas (3) e (4) com diazometano fornece diretamente, em uma etapa, os oxazóis (5) e (6), respectivamente.
Assuntos
Técnicas de Química Combinatória , Diazometano/química , Naftoquinonas/química , Oxazóis/síntese química , Oximas/química , OxirreduçãoRESUMO
We synthesized new naphthoimidazoles from beta-lapachone with an aromatic moiety linked to the imidazole ring, using phenylic and heterocyclic aldehydes. The most active compound against Trypanosoma cruzi had a p-methyl group linked to the phenyl ring, presenting an EC(50) value of 15.5 +/- 2.9 microM. No reliable correlation could be established with the biological activity and the structure of in the phenylic series. For the heterocyclic series, activity was associated with a three bond-distance from nitrogen to the imidazole ring, in accordance with our previous work.