RESUMO
A new series of 4-aminochloroquinoline based sulfonamides were synthesized and evaluated for antiamoebic and antimalarial activities. Out of the eleven compounds evaluated (F1-F11), two of them (F3 and F10) showed good activity against Entamoeba histolytica (IC50 <5 µM). Three of the compounds (F5, F7 and F8) also displayed antimalarial activity against the chloroquine-resistant (FCR-3) strain of Plasmodium falciparum with IC50 values of 2 µM. Compound F7, whose crystal structure was also determined, inhibited ß-haematin formation more potently than quinine. To further understand the action of hybrid molecules F7 and F8, molecular docking was carried out against the homology model of P. falciparum enzyme dihydropteroate synthase (PfDHPS). The complexes showed that the inhibitors place themselves nicely into the active site of the enzyme and exhibit interaction energy which is in accordance with our activity profile data. Application of Lipinski 'rule of five' on all the compounds (F1-F11) suggested high drug likeness of F7 and F8, similar to quinine.
Assuntos
Antiprotozoários/síntese química , Di-Hidropteroato Sintase/antagonistas & inibidores , Entamoeba histolytica/efeitos dos fármacos , Piperazinas/síntese química , Plasmodium falciparum/efeitos dos fármacos , Proteínas de Protozoários/antagonistas & inibidores , Quinolinas/síntese química , Sequência de Aminoácidos , Antiprotozoários/farmacologia , Sobrevivência Celular/efeitos dos fármacos , Cloroquina/farmacologia , Cristalografia por Raios X , Di-Hidropteroato Sintase/química , Resistência a Medicamentos , Entamoeba histolytica/enzimologia , Entamoeba histolytica/crescimento & desenvolvimento , Eritrócitos/efeitos dos fármacos , Eritrócitos/parasitologia , Hemeproteínas/antagonistas & inibidores , Hemeproteínas/química , Hemólise/efeitos dos fármacos , Humanos , Simulação de Acoplamento Molecular , Dados de Sequência Molecular , Piperazinas/farmacologia , Plasmodium falciparum/enzimologia , Plasmodium falciparum/crescimento & desenvolvimento , Proteínas de Protozoários/química , Quinina/farmacologia , Quinolinas/farmacologia , Relação Estrutura-AtividadeRESUMO
Metronidazole thiosalicylate conjugates were synthesized and crystallised in order to discover new molecules having better efficacy than therapeutically administered drug metronidazole, used against Entamoeba histolytica. The three compounds (4-6) showed lower IC(50) values than metronidazole on HM1:IMSS strain of E. histolytica and displayed low cytotoxicity on MCF-7 cell line. In order to get an insight into the mechanisms of action of these compounds, a homology model of E. histolytica thioredoxin reductase (EhTHRase) was constructed and molecular docking was performed into the binding pocket to identify the nature of interactions. The docking studies suggest that the improved inhibitory activity of the newly synthesised metronidazole analogues could be due to involvement of the additional hydrophobic interactions in the binding mode. The result of the present study indicates the molecular fragments that play an essential role in improving the antiamoebic activity.
Assuntos
Antiparasitários/química , Antiparasitários/farmacologia , Entamoeba histolytica/efeitos dos fármacos , Metronidazol/química , Metronidazol/farmacologia , Sequência de Aminoácidos , Antiparasitários/síntese química , Benzoatos/síntese química , Benzoatos/química , Benzoatos/farmacologia , Sobrevivência Celular/efeitos dos fármacos , Entamoeba histolytica/enzimologia , Entamebíase/tratamento farmacológico , Humanos , Concentração Inibidora 50 , Células MCF-7 , Metronidazol/síntese química , Modelos Moleculares , Dados de Sequência Molecular , Alinhamento de Sequência , Compostos de Sulfidrila/síntese química , Compostos de Sulfidrila/química , Compostos de Sulfidrila/farmacologia , Timerosal/síntese química , Timerosal/química , Timerosal/farmacologia , Tiorredoxina Dissulfeto Redutase/química , Tiorredoxina Dissulfeto Redutase/metabolismoRESUMO
A series of 1,2,4-triazole derivatives containing thiosemicarbazone linkage was synthesized and evaluated for their in vitro antiamoebic activity against HM1:IMSS strain of Entamoeba histolytica. All the compounds were capable of inhibiting the growth of E. histolytica out of which four compounds (IC(50)=0.28-1.38 µM) were found to have better efficacy than the standard drug Metronidazole (IC(50)=1.8 µM). Cytotoxicity of the active compounds was assessed by MTT assay using human breast cancer MCF-7 cell line, which revealed that all the compounds were low cytotoxic in the concentration range of 2.5-250 µM.
Assuntos
Antiprotozoários , Entamoeba histolytica/efeitos dos fármacos , Tiossemicarbazonas/química , Triazóis/química , Antiprotozoários/química , Antiprotozoários/farmacologia , Linhagem Celular Tumoral , Feminino , Humanos , Concentração Inibidora 50 , Metronidazol/farmacologia , Estrutura Molecular , Tiossemicarbazonas/farmacologia , Triazóis/farmacologiaRESUMO
In an effort to develop effective antiamoebic agents, some hydrazones and azoles containing pyridyl moiety were synthesized and screened for in vitro antiamoebic activity against HM1:IMSS strain of Entamoeba histolytica. Among all the compounds, only five compounds (1, 3, 5, 9 and 11) were found to be better inhibitors of growth of E. histolytica than the reference drug metronidazole. The cytotoxic studies of these compounds on human breast cancer MCF-7 cell line revealed that all the compounds were low-cytotoxic in the concentration range of 2.5-250 µM.
Assuntos
Antiparasitários/química , Antiparasitários/farmacologia , Azóis/química , Azóis/farmacologia , Entamoeba histolytica/efeitos dos fármacos , Hidrazonas/química , Hidrazonas/farmacologia , Antiparasitários/síntese química , Azóis/síntese química , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Entamebíase/tratamento farmacológico , Humanos , Hidrazonas/síntese química , Metronidazol/farmacologia , Relação Estrutura-AtividadeRESUMO
A new series of 2,4,6-trisubstituted bis-pyrimidines were synthesized and evaluated for in vitro antiamoebic activity against HM1:IMSS strain of Entamoeba histolytica. Out of 16 compounds 8 compounds have shown IC(50) values in the range of 0.10-1.86 µM. Bis-pyrimidine having methyl-, methoxy-, thiomethyl- and dimehyl-phenyl substituents, exhibited higher antiamoebic activity than the reference drug metronidazole (IC(50) = 1.9 µM). The toxicological studies of active compounds on PC12-rat pheochoromocytoma cell line showed that all compounds were non-toxic at a concentration of 100 µM. 4-4'-Benzene-1,3-diylbis[6-(4-methylphenyl-2-(piperidin-1-yl)pyrimidine] (4c) was found most active (IC(50) = 0.10 µM) and least toxic among all the compounds.
Assuntos
Pirimidinas/síntese química , Pirimidinas/farmacologia , Animais , Entamoeba histolytica/efeitos dos fármacos , Concentração Inibidora 50 , Células PC12 , Pirimidinas/química , Ratos , Análise EspectralRESUMO
A new series of chloroquinoline based chalcones were synthesized and evaluated for in vitro antiamoebic and antimalarial activities. The results showed that out of fifteen compounds, four were found to be more active against the Entamoeba histolytica; while one compound was moderatively active compared to the standard drug metronidazole (IC50=1.46 µM). In contrast, in vitro antimalarial activity against the chloroquine-sensitive (3D7) strain of P. falciparum indicated relatively low activity when compared to controls such as chloroquine and quinine (IC50=0.0065 µM and 0.14 µM, respectively). The toxicological studies of these compounds on human breast cancer MCF-7 cell line showed that all the compounds were non-toxic at the concentration range of 1.56-50 µM.
Assuntos
Antiprotozoários/farmacologia , Chalconas/farmacologia , Entamoeba histolytica/efeitos dos fármacos , Plasmodium falciparum/efeitos dos fármacos , Quinolinas/química , Antiprotozoários/síntese química , Antiprotozoários/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Chalconas/síntese química , Chalconas/química , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Estrutura Molecular , Testes de Sensibilidade Parasitária , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
A new series of pyrazolo[3,4-d]pyrimidine-6-one derivatives (2a-2j) were prepared by using the Biginelli multicomponent cyclocondensation of 3-methyl-1-phenyl-1H-pyrazol-5(4H)-one (1a), different aromatic aldehydes, and urea with a catalytic amount of HCl at reflux temperature. These compounds were characterized by IR, (1)H NMR, (13)C NMR, and Mass spectral data. In vitro antiamoebic activity was performed against HM1:IMSS strain of Entamoeba histolytica. The results showed that the compounds 2b, 2i, and 2j with IC(50) values of 0.37 µM, 0.04 µM, and 0.06 µM, respectively, exhibited better antiamoebic activity than the standard drug metronidazole (IC(50) = 1.33 µM). The toxicological studies of these compounds on human breast cancer MCF-7 cell line showed that the compounds 2b, 2i, and 2j exhibited >80% viability at the concentration range of 1.56-50 µM.
Assuntos
Amebicidas/farmacologia , Antineoplásicos/farmacologia , Entamoeba/efeitos dos fármacos , Pirazóis/farmacologia , Pirimidinonas/farmacologia , Amebicidas/síntese química , Amebicidas/química , Antineoplásicos/síntese química , Antineoplásicos/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Estrutura Molecular , Testes de Sensibilidade Parasitária , Pirazóis/síntese química , Pirazóis/química , Pirimidinonas/síntese química , Pirimidinonas/química , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
A series of 1,2,3-thiadiazole and 1,2,3-selenadiazole derivatives were synthesized by the cyclization of novel 2-(quinolin-8-yloxy) acetohydrazones. In vitro antiamoebic activity was performed against HM1: IMSS strain of Entamoeba histolytica. The results showed that all the 2-(quinolin-8-yloxy) acetohydrazones were more active than their cyclized products (1,2,3-thiadiazole and 1,2,3-selenadiazole derivatives). SAR showed that the compounds having quinoline ring and hydrazone linkage with free N-H group are responsible for higher antiamoebic activity. The cytotoxic studies of these compounds on human breast cancer MCF-7 cell line showed that all the compounds were nontoxic at the concentration range of 1.56-50 µM.
Assuntos
Amebicidas/farmacologia , Antineoplásicos/farmacologia , Entamoeba histolytica/efeitos dos fármacos , Compostos Heterocíclicos com 1 Anel/farmacologia , Hidrazonas/farmacologia , Compostos Organosselênicos/farmacologia , Tiadiazóis/farmacologia , Amebicidas/síntese química , Amebicidas/química , Antineoplásicos/síntese química , Antineoplásicos/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Ciclização , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Compostos Heterocíclicos com 1 Anel/síntese química , Compostos Heterocíclicos com 1 Anel/química , Humanos , Hidrazonas/síntese química , Hidrazonas/química , Estrutura Molecular , Compostos Organosselênicos/síntese química , Compostos Organosselênicos/química , Estereoisomerismo , Relação Estrutura-Atividade , Tiadiazóis/síntese química , Tiadiazóis/químicaRESUMO
The cyclization of chalcones (1a-1j) with 2-(quinolin-8-yloxy) acetohydrazide (2) under basic condition led to the formation of new compounds, pyrazoline derivatives (3a-3j). In vitro antiamoebic activity was performed against HM1: IMSS strain of Entamoeba histolytica. The results showed that the compounds 3d, 3g, 3h, and 3j exhibited promising antiamoebic activity (IC(50) = 0.05 microM, 0.31 microM, 0.06 microM, 0.29 microM) respectively than the standard drug metronidazole (IC(50) = 1.84 microM). The toxicological studies of these compounds on human breast cancer MCF-7 cell line showed that all the compounds 3d, 3g, 3h, 3j and metronidazole were nontoxic at the concentration range of 1.56-50 microM.
Assuntos
Amebicidas/química , Amebicidas/farmacologia , Entamoeba histolytica/efeitos dos fármacos , Pirazóis/química , Pirazóis/farmacologia , Quinolinas/química , Quinolinas/farmacologia , Amebicidas/síntese química , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Entamebíase/tratamento farmacológico , Humanos , Pirazóis/síntese química , Quinolinas/síntese química , Relação Estrutura-AtividadeRESUMO
A new series of 6-ferrocenyl-4-aryl-2-substituted pyrimidines were synthesized and evaluated for in vitro antiamoebic activity against HM1:IMSS strain of Entamoeba histolytica. Out of 16 compounds 10 compounds have shown IC(50) values in the range of 0.41-1.73 microM and 1.80 microM. Pyrimidine derivatives having thiomethyl group, chloro group and mono-, di-, and trimethoxy substitution, exhibited higher antiamoebic activity than the reference drug metronidazole (IC(50)=1.80 microM). The toxicological studies of these compounds on human kidney epithelial cell line showed that all compounds were non-toxic. 4-(4-Chlorophenyl)-6-ferrocenyl-2-piperidin-1-yl-pyrimidine (4f) was found most active (IC(50)=0.41 microM) and least toxic among all the compounds.