RESUMO
Starting from 2-hydroxy-1,4-naphthoquinone (lawsone), we synthesized eight new 6H-dibenzo[b,h]xanthene derivatives selectively under solvent-free conditions. Spectroscopic investigations confirmed that only the isomer 6H-dibenzo[b,h]xanthene was obtained in all eight cases. Computational studies provide a rationalization for the selective appearance of these isomers having as an intermediate an addition product.
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
New oxirane derivatives were synthesized using six naphthoquinones as the starting materials. Our biological results showed that these oxiranes acted as trypanocidal agents against Trypanosoma cruzi with minimal cytotoxicity in the VERO cell line compared to naphthoquinones. In particular, oxirane derivative 14 showed low cytotoxicity in a mammalian cell line and exhibited better activity against epimastigote forms of T.cruzi than the current drug used to treat Chagas disease, benznidazole.
Assuntos
Óxido de Etileno/farmacologia , Naftoquinonas/química , Naftoquinonas/farmacologia , Tripanossomicidas/química , Tripanossomicidas/farmacologia , Trypanosoma cruzi/efeitos dos fármacos , Animais , Morte Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Chlorocebus aethiops , Relação Dose-Resposta a Droga , Avaliação Pré-Clínica de Medicamentos , Óxido de Etileno/análogos & derivados , Óxido de Etileno/química , Modelos Moleculares , Estrutura Molecular , Testes de Sensibilidade Parasitária , Relação Estrutura-Atividade , Tripanossomicidas/síntese química , Trypanosoma cruzi/citologia , Trypanosoma cruzi/crescimento & desenvolvimento , Células VeroRESUMO
A broad-spectrum antibiotic therapy has led to medical complications and emergence of multiresistant bacteria including Enterococcus faecalis. In this study, we designed, synthesized, and evaluated the antibacterial activity of 13 nor-ß-lapachone derivatives against a drug resistant E. faecalis strain. Two triazole substituted compounds (1e = 8 µg/ml and 1c = 16 µg/ml) and the non-substituted derivative (1a = 8 µg/ml) were promising compared to chloramphenicol (12 µg/ml), an antibiotic currently available in the market. We also performed a structure-activity relationship analysis using a molecular modeling approach that pointed the low HOMO energy values; HOMO density concentrated on the nor-ß-lapachone ring, lipophilicity, solubility and number HBA as important stereoelectronic features for the antibacterial profile. In addition the triazole compounds presented low theoretical toxicity profile, and drug-score higher than commercial antibiotics also fulfilling the Lipinski "Rule of Five", which pointed them as promising candidates for further studies in infections caused by multiresistant E. faecalis hospital strains.
Assuntos
Antibacterianos/farmacologia , Enterococcus faecalis/efeitos dos fármacos , Naftoquinonas/farmacologia , Antibacterianos/química , Antibacterianos/toxicidade , Enterococcus faecalis/isolamento & purificação , Infecções por Bactérias Gram-Positivas/microbiologia , Humanos , Testes de Sensibilidade Microbiana , Naftoquinonas/química , Naftoquinonas/toxicidade , Relação Estrutura-AtividadeRESUMO
In continuing our screening program of naphthoquinone activity against Trypanosoma cruzi, the aetiological agent of Chagas' disease, new beta-lapachone-based 1,2,3-triazoles, 3-arylamino-nor-beta-lapachones, 3-alkoxy-nor-beta-lapachones and imidazole anthraquinones were synthesised and evaluated against bloodstream trypomastigote forms of the parasite. Compounds 2,2-dimethyl-3-(2,4-dibromophenylamino)-2,3-dihydro-naphtho[1,2-b]furan-4,5-dione, IC(50)/24h 24.9+/-7.4 and 4-azido-3-bromo-2,2-dimethyl-3,4-dihydro-2H-benzo[h]chromene-5,6-dione with 23.4+/-3.8 microM showed a trypanosomicidal activity higher than benznidazole. These results demonstrate the potential of naphthoquinone derivatives as novel structures for the development of alternative drugs for Chagas' disease.
Assuntos
Antraquinonas , Antiparasitários , Naftoquinonas , Triazóis , Trypanosoma cruzi/efeitos dos fármacos , Animais , Antraquinonas/síntese química , Antraquinonas/química , Antraquinonas/farmacologia , Antiparasitários/síntese química , Antiparasitários/química , Antiparasitários/farmacologia , Cristalografia por Raios X , Imidazóis/síntese química , Imidazóis/química , Imidazóis/farmacologia , Camundongos , Estrutura Molecular , Naftoquinonas/síntese química , Naftoquinonas/química , Naftoquinonas/farmacologia , Testes de Sensibilidade Parasitária , Quinonas/síntese química , Quinonas/química , Quinonas/farmacologia , Triazóis/síntese química , Triazóis/química , Triazóis/farmacologiaRESUMO
New naphthoquinone derivatives were synthesized and assayed against bloodstream trypomastigote forms of Trypanosoma cruzi, the etiological agent of Chagas' disease. The compounds were rationalized based on hybrid drugs and appear as important compounds against this parasite. From nor-lapachol were prepared five substituted ortho-naphthofuranquinones, a non-substituted para-naphthofuranquinone, a new oxyrane and an azide and from alpha-lapachone a new non-substituted para-naphthofuranquinone. Other five substituted ortho-naphthofuranquinones recently designed as cytotoxic, were also evaluated. The most active compounds were the ortho naphthofuranquinones 3-(4-methoxyphenylamino)-2,3-dihydro-2,2-dimethylnaphtho[1,2-b]furan-4,5-dione and 3-(3-nitrophenylamino)-2,3-dihydro-2,2-dimethylnaphtho[1,2-b]furan-4,5-dione with trypanocidal activity higher than that of benznidazole, the standard drug. The compounds were rationalized based on hybrid drugs and appear as important compounds against T. cruzi. The trypanocidal activity of these substances endowed with redox properties representing a good starting point for a medicinal chemistry program aiming the chemotherapy of Chagas' disease.
Assuntos
Antiprotozoários/síntese química , Antiprotozoários/farmacologia , Naftoquinonas/síntese química , Naftoquinonas/farmacologia , Trypanosoma cruzi/efeitos dos fármacos , Animais , Antiprotozoários/química , Cristalografia por Raios X , Modelos Moleculares , Estrutura Molecular , Naftoquinonas/química , Testes de Sensibilidade Parasitária , EstereoisomerismoRESUMO
[1,2,3]-Triazole derivatives of nor-beta-lapachone were synthesized and assayed against the infective bloodstream trypomastigote form of Trypanosoma cruzi, the etiological agent of Chagas disease. All the derivatives were more active than the original quinones, with IC(50)/1 day values in the range of 17 to 359 microM, the apolar phenyl substituted triazole 6 being the most active compound. These triazole derivatives of nor-beta-lapachone emerge as interesting new lead compounds in drug development for Chagas disease.
Assuntos
Naftoquinonas/química , Triazóis/síntese química , Triazóis/farmacologia , Tripanossomicidas/síntese química , Tripanossomicidas/farmacologia , Trypanosoma cruzi/efeitos dos fármacos , Animais , Azidas/química , Cátions/química , Cristalografia por Raios X , Ligação de Hidrogênio , Modelos Moleculares , Estrutura Molecular , Relação Estrutura-Atividade , Triazóis/química , Tripanossomicidas/químicaRESUMO
Six new nor-beta-lapachones have been synthesized from reaction of 3-bromo-nor-beta-lapachone with arylamines. These derivatives have potent anticancer properties against several cell lines. Here, we report complete unambiguous assignments of (1)H and (13)C chemical shifts of the new compounds. The assignments were made using a combination of one- and two-dimensional NMR techniques ((1)H, (13)C, (1)H-(1)H COSY, (1)H-(13)C HSQC, and (1)H-(13)C HMBC).
Assuntos
Espectroscopia de Ressonância Magnética/métodos , Quinonas/química , Aminas/química , Antineoplásicos/química , Isótopos de Carbono , Furanos/química , Naftalenos/químicaRESUMO
This work describes the application of counter-current chromatography (CCC) as a useful, fast and economic alternative for the isolation and purification of heterocyclic derivatives from lapachol and beta-lapachone, two naturally occurring compounds from Tabebuia species, and nor-beta-lapachone, a synthetic congener of lapachol. The discussed data comprise four examples of purification of synthetic reactions with different solvent systems - the mixture of the oxazole and the imidazole from beta-lapachone; the quinoxaline from nor-beta-lapachone; and the purification of the N-oxides from the quinoxaline and the phenazine from nor-beta-lapachone from their respective not fully reacted substrates by means of aqueous reversed- and normal-phase elution modes and non-aqueous solvent systems. Traditional purification of these reaction products by silica gel column chromatography demanded a large amount of solvent and time and, in some cases, serious degradation of the products occurred, leading to low yield of the reaction. High-speed counter-current chromatography (HSCCC) was used as an alternative to optimize the process and raise the yield of the reactions.
Assuntos
Fator 6 Ativador da Transcrição/metabolismo , Distribuição Contracorrente/métodos , Naftoquinonas/química , Fator 6 Ativador da Transcrição/genética , Cromatografia em Camada Fina , Ciclização , Imidazóis/química , Estrutura Molecular , Naftoquinonas/síntese química , Naftoquinonas/isolamento & purificação , Oxazóis/química , Quinoxalinas/químicaRESUMO
The aim of this work was to develop and characterize nanoparticles as carriers of lapazine, a phenazine derived from ß-lapachone; its antimycobacterial activity is described for the first time as a potential treatment for tuberculosis. The lapazine was synthesized, and by using gas chromatography coupled to a flame ionization detector, it was possible to evaluate its purity degree of almost 100%. For better elucidation of the molecular structure, mass spectroscopy and 1H NMR were carried out and compared to the literature values. Lapazine was assayed in vitro against H37Rv Mycobacterium tuberculosis and a rifampicin-resistant strain, with minimum inhibitory concentration values of 3.00 and 1.56 µg mL(-1), respectively. The nanoparticles showed a polydispersity index of 0.16,mean diameter of 188.5 ± 1.7 mm, zeta potential of -15.03 mV, and drug loading of 54.71 mg g(-1) for poly-ε-caprolactone (PCL) nanoparticles and a polydispersity index of 0.318,mean diameter of 197.4 ± 2.7 mm, zeta potential of -13.43 mV and drug loading of 137.07 mg g(-1) for poly(DL-lactide-co-glycolide) (PLGA) nanoparticles. These results indicate that both polymeric formulations have good characteristics as potential lapazine carriers in the treatment of tuberculosis.
Assuntos
Antituberculosos/síntese química , Antituberculosos/farmacologia , Ácido Láctico/química , Nanopartículas/química , Fenazinas/síntese química , Fenazinas/farmacologia , Poliésteres/química , Ácido Poliglicólico/química , Antituberculosos/química , Liberação Controlada de Fármacos , Cinética , Testes de Sensibilidade Microbiana , Mycobacterium tuberculosis/efeitos dos fármacos , Nanopartículas/ultraestrutura , Tamanho da Partícula , Fenazinas/química , Copolímero de Ácido Poliláctico e Ácido Poliglicólico , Eletricidade Estática , Difração de Raios XRESUMO
An intensive effort has been directed toward finding alternative drugs for treatment of Chagas' disease, caused by Trypanosoma cruzi, and prophylaxis of blood in endemic areas. Our research comprises the synthesis and trypanocidal screening of derivatives from naphthoquinones. Herein a new phenazine, obtained from the reaction of beta-lapachone with aniline, has its structure established by physical data and X-ray analysis. It was 9 times more active against T. cruzi trypomastigotes than crystal violet.
Assuntos
Fenazinas/síntese química , Tripanossomicidas/síntese química , Trypanosoma cruzi/efeitos dos fármacos , Compostos de Anilina/química , Animais , Cristalografia por Raios X , Fenazinas/química , Fenazinas/farmacologia , Tripanossomicidas/química , Tripanossomicidas/farmacologiaRESUMO
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.
Assuntos
Anti-Infecciosos/química , Imidazóis/síntese química , Naftoquinonas/química , Parasitemia/tratamento farmacológico , Piranos/síntese química , Tripanossomicidas/síntese química , Trypanosoma cruzi/efeitos dos fármacos , Animais , Imidazóis/química , Imidazóis/farmacologia , Camundongos/parasitologia , Modelos Moleculares , Conformação Molecular , Piranos/química , Piranos/farmacologia , Relação Estrutura-Atividade , Tripanossomicidas/farmacologiaRESUMO
Continuing our screening program for novel anti-parasite compounds, we synthesized seven 1,4-naphthoquinones coupled to 1,2,3-triazoles, five nor-ß-lapachone-based 1,2,3-triazoles and ten α-lapachone-based 1,2,3-triazoles. These and other naphthoquinonoid compounds were evaluated for their activity against promastigote forms of antimony-sensitive and -resistant strains of Leishmania infantum (syn. Leishmania chagasi) and Leishmania amazonensis. The toxicity of these compounds to mammalian cells was also examined. The substances were more potent than an antimonial drug, with IC50 values ranging from 1.0 to 50.7 µM. Nor-α-lapachone derivatives showed the highest antileishmanial activity, with selectivity indices in the range of 10-15. These compounds emerged as important leads for further investigation as antileishmanial agents. Additionally, one of these compounds exhibited cross-resistance in Sb-resistant Leishmania and could provide a molecular tool for investigating the multidrug resistance mechanisms in Leishmania parasites.
Assuntos
Antiprotozoários/síntese química , Reação de Cicloadição/métodos , Naftoquinonas/síntese química , Triazóis/síntese química , Alcinos/química , Animais , Antimônio/farmacologia , Antiprotozoários/química , Antiprotozoários/farmacologia , Azidas/química , Catálise , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Cobre/química , Resistência a Medicamentos/efeitos dos fármacos , Leishmania/efeitos dos fármacos , Leishmania infantum/efeitos dos fármacos , Macrófagos Peritoneais/citologia , Macrófagos Peritoneais/efeitos dos fármacos , Camundongos , Naftoquinonas/química , Naftoquinonas/farmacologia , Testes de Sensibilidade Parasitária , Especificidade da Espécie , Triazóis/química , Triazóis/farmacologiaRESUMO
Thirty two compounds were synthesized in moderate to high yields and showed activity against cancer cells HL-60 (leukemia), MDA-MB435 (melanoma), HCT-8 (colon) and SF295 (central nervous system), with IC(50) below 2 µM for some compounds. The ß-lapachone-based 1,2,3-triazoles showed the best cytoxicity profile and emerge as promising anticancer prototypes. Insights about the reactive oxygen species (ROS) mechanism of anticancer action for some compounds were obtained by addition of 1-bromoheptane that deplete reduced glutathione (GSH) content and by using N-acetylcysteine that protects cells against apoptotic cellular death, as well by analysis of thiobarbituric acid reactive substances (TBARS) formation, and oxidative DNA damage after treatment detected by the comet assay with the bacterial enzymes formamidopyrimidine DNA-glycosylase (FPG) and endonuclease III (ENDOIII).
Assuntos
Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Benzoquinonas/síntese química , Benzoquinonas/farmacologia , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Benzoquinonas/química , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Quebras de DNA/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Concentração Inibidora 50RESUMO
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
Several 3-arylamino and 3-alkoxy-nor-beta-lapachone derivatives were synthesized in moderate to high yields and found to be highly potent against cancer cells SF295 (central nervous system), HCT8 (colon), MDA-MB435 (melanoma), and HL60 (leukemia), with IC(50) below 2 microM. The arylamino para-nitro and the 2,4-dimethoxy substituted naphthoquinones showed the best cytoxicity profile, while the ortho-nitro and the 2,4-dimethoxy substituted ones were more selective than doxorubicin and similar to the precursor lapachones, thus emerging as promising new lead compounds in anticancer drug development.
Assuntos
Naftoquinonas/síntese química , Naftoquinonas/farmacologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Cristalografia por Raios X , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Modelos Moleculares , Estrutura Molecular , Naftoquinonas/química , Naftoquinonas/toxicidade , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
We report here an alternative to the MCPBA or ozonolysis-based oxidation methods of quinoxaline-featuring compounds prepared from beta-lapachones. The use of peracetic acid allowed a simple preparation of the corresponding macrolactones by cleavage of the ring system. These lactones were evaluated for their antimycobacterial potential and compound 4 turned out to have an MIC of 0.62 microg per mL on Mycocabteriumtuberculosis H37Rv. These results justify further research into its value as a potential lead for an original treatment of tuberculosis.
Assuntos
Antituberculosos/síntese química , Lactonas/síntese química , Mycobacterium tuberculosis/efeitos dos fármacos , Fenazinas/química , Testes de Sensibilidade Microbiana , Oxirredução , Quinoxalinas , Relação Estrutura-AtividadeRESUMO
Several arylamino derivatives of nor-beta-lapachone were synthesized in moderate to high yields and found to show very potent cytotoxicity against six neoplastic cancer cells: SF-295 (central nervous system), HCT-8 (colon), MDAMB-435 (breast), HL-60 (leukaemia), PC-3 (prostate), and B-16 (murine melanoma), with IC(50) below 1 microg/mL. Their cytotoxicities were compared to doxorubicin and with their synthetic precursors, beta-lapachone and nor-beta-lapachone. The activity against a normal murine fibroblast L-929 showed that some of the compounds were selective against cancer cells. The absence of hemolytic activity (EC(50)>200 microg/mL), performed with erythrocyte suspensions, suggests that the cytotoxicity of the compounds was not related to membrane damage of mouse erythrocytes. For comparison purposes, one isomeric compound based on nor-alpha-lapachone was also synthesized and showed lower activity than the related ortho-derivative. The modified arylamino quinones appear as interesting new lead compounds in anti-cancer drug development.
Assuntos
Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Naftoquinonas/síntese química , Naftoquinonas/farmacologia , Animais , Antineoplásicos/química , Linhagem Celular Tumoral , Membrana Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Camundongos , Estrutura Molecular , Naftoquinonas/química , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
The antimalarial activity of benzo[a]phenazines synthesized from 1,2-naphthoquinone, lapachol, beta-lapachone and several derivatives have been tested against Plasmodium falciparum in vitro using isolates of parasites with various susceptibilities to chloroquine and/or mefloquine. Parasite growth in the presence of the test drugs was measured by incorporation of [(3)H]-hipoxanthine in comparison to controls with no drugs, always testing in parallel chloroquine, a standard antimalarial. Among seven benzophenazines tested, four had significant in vitro activities; important, the parasites resistant to chloroquine were more susceptible to the active phenazines in vitro. The doses of phenazines causing 50% inhibition of parasite growth varied from 1.67 to 9.44 microM. The two most active ones were also tested in vivo against Plasmodium berghei in mice, in parallel with lapachol and beta-lapachone. The 3-sulfonic acid-beta-lapachone-derived phenazine was the most active causing up to 98% inhibition of parasitaemia in long term treatment (7 doses) subcutaneously, whereas the phenazine from 3-bromo-beta-lapachone was inactive. Thus, these simple phenazines, containing polar (-Br,-I) and ionizable (-SO(3)H, -OH) groups, easily synthesized from cheap, natural or synthetic precursors (lapachol and beta-lapachone), at rather low cost, provide prototypes for development of new antimalarials aiming the chloroquine resistant parasites.