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1.
ChemMedChem ; 16(23): 3600-3614, 2021 12 06.
Artículo en Inglés | MEDLINE | ID: mdl-34665510

RESUMEN

Leishmaniasis and Chagas diseases are two of the most important parasitic diseases in the world. Both belong to the category of Neglected Tropical Diseases, and they cannot be prevented by vaccination. Their treatments are founded in outdated drugs that possess many pernicious side-effects and they're not easy to administer. With the aim of discovering new compounds that could serve as anti-trypanosomal drugs, an antiparasitic study of a synthetic compound family has been conducted. A series of new 1,4-bis(alkylamino)- and 1-alkylamino-4-chloroazine and benzoazine derivatives 1-4 containing imidazole rings have been synthesized and identified. Their structures showed a possible interest based on previous work. Their in vitro anti-Leishmania infantum, anti-L. braziliensis, anti-L. donovani and anti-T. cruzi activity were tested, as well as the inhibition of Fe-SOD enzymes. It was found that some of them exhibited quite relevant values indicative of being worthy of future more detailed studies, as most of them showed activity to more than only one parasite species, especially compound 3 c was active for the three studied Leishmania species and also for T. cruzi, which is a very interesting trait as it covers a wide spectrum.


Asunto(s)
Imidazoles/farmacología , Ftalazinas/farmacología , Piridazinas/farmacología , Tripanocidas/farmacología , Animales , Chlorocebus aethiops , Imidazoles/síntesis química , Imidazoles/toxicidad , Leishmania braziliensis/efectos de los fármacos , Leishmania donovani/efectos de los fármacos , Leishmania infantum/efectos de los fármacos , Pruebas de Sensibilidad Parasitaria , Ftalazinas/síntesis química , Ftalazinas/toxicidad , Piridazinas/síntesis química , Piridazinas/toxicidad , Tripanocidas/síntesis química , Tripanocidas/toxicidad , Trypanosoma cruzi/efectos de los fármacos , Células Vero
2.
Eur J Med Chem ; 106: 106-19, 2015 Dec 01.
Artículo en Inglés | MEDLINE | ID: mdl-26523668

RESUMEN

A series of new phthalazine derivatives (1-4) containing imidazole rings and functionalized with nitro groups in the benzene ring of the phthalazine moiety were prepared and identified on the basis of their MS, elemental analyses and bidimensional (1)H and (13)C NMR data, and their trypanocidal activity was tested. The 8-nitrosubstituted compound (3) was more active in vitro against Trypanosoma cruzi and less toxic against Vero cells than the reference drug benznidazole, and showed a SI value that was 47-fold better than the reference drug in amastigote forms. It also remarkably reduced the infectivity rate in Vero cells and decreased the reactivation of parasitemia in immunodeficient mice. Ultrastructural alterations found in epimastigotes treated with 3 confirmed extensive cytoplasm destruction in the parasites, whereas histopathological analysis of the hearts of mice infected and treated with 3 resulted in a decrease in cardiac damage. Biochemical markers showed that livers, hearts, and kidneys of treated mice were substantially unaffected by the administration of 3, despite the presence of the potentially toxic nitro group. It was also found that this compound selectively inhibited the antioxidant parasite enzyme Fe-superoxide dismutase (Fe-SOD) in comparison with human CuZn-SOD, and molecular modeling suggested interaction with the H-bonding system of the iron-based moiety as a feasible mechanism of action against the enzyme.


Asunto(s)
Inhibidores Enzimáticos/farmacología , Imidazoles/química , Imidazoles/farmacología , Parasitemia/tratamiento farmacológico , Ftalazinas/farmacología , Tripanocidas/química , Tripanocidas/farmacología , Trypanosoma cruzi/efectos de los fármacos , Animales , Chlorocebus aethiops , Relación Dosis-Respuesta a Droga , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/química , Femenino , Humanos , Imidazoles/síntesis química , Ratones , Ratones Endogámicos BALB C , Modelos Moleculares , Estructura Molecular , Parasitemia/parasitología , Ftalazinas/síntesis química , Ftalazinas/química , Relación Estructura-Actividad , Superóxido Dismutasa/antagonistas & inhibidores , Superóxido Dismutasa/metabolismo , Tripanocidas/síntesis química , Trypanosoma cruzi/enzimología , Células Vero
3.
J Med Chem ; 55(22): 9900-13, 2012 Nov 26.
Artículo en Inglés | MEDLINE | ID: mdl-23043291

RESUMEN

A series of new phthalazine derivatives 1-4 containing imidazole rings were prepared. The monoalkylamino substituted derivatives 2 and 4 were more active in vitro against T. cruzi and less toxic against Vero cells than both their disubstituted analogues and the reference drug benznidazole. Compounds 2 and 4 highly inhibited the antioxidant parasite enzyme Fe-SOD, and molecular modeling suggested that they interact with the H-bonding system of the iron atom moiety. In vivo tests on the acute phase of Chagas disease gave parasitemia inhibition values twice those of benznidazole, and a remarkable decrease in the reactivation of parasitemia was found in the chronic phase for immunodeficient mice. Glucose metabolism studies showed that compounds 1-4 did not affect the succinate pathway but originated important changes in the excretion of pyruvate metabolites. The morphological alterations found in epimastigotes treated with 1-4 confirmed extensive cytoplasm damage and a high mortality rate of parasites.


Asunto(s)
Enfermedad de Chagas/tratamiento farmacológico , Imidazoles/química , Parasitemia/prevención & control , Ftalazinas/química , Ftalazinas/farmacología , Tripanocidas/farmacología , Trypanosoma cruzi/efectos de los fármacos , Animales , Muerte Celular/efectos de los fármacos , Enfermedad de Chagas/parasitología , Chlorocebus aethiops , Ensayo de Inmunoadsorción Enzimática , Femenino , Imidazoles/síntesis química , Imidazoles/farmacología , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , Modelos Moleculares , Estructura Molecular , Parasitemia/etiología , Ftalazinas/síntesis química , Relación Estructura-Actividad , Superóxido Dismutasa/metabolismo , Tripanocidas/síntesis química , Células Vero
4.
J Antimicrob Chemother ; 67(2): 387-97, 2012 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-22127582

RESUMEN

OBJECTIVES: To evaluate the in vitro leishmanicidal activity of imidazole-based (1-4) and pyrazole-based (5-6) benzo[g]phthalazine derivatives against Leishmania infantum and Leishmania braziliensis. METHODS: The in vitro activity of compounds 1-6 was assayed on extracellular promastigote and axenic amastigote forms, and on intracellular amastigote forms of the parasites. Infectivity and cytotoxicity tests were performed on J774.2 macrophage cells using meglumine antimoniate (Glucantime) as the reference drug. The mechanisms of action were analysed by iron superoxide dismutase (Fe-SOD) and copper/zinc superoxide dismutase (CuZn-SOD) inhibition, metabolite excretion and transmission electronic microscopy (TEM). RESULTS: Compounds 1-6 were more active and less toxic than meglumine antimoniate. Data on infection rates and amastigote mean numbers showed that 2, 4 and 6 were more active than 1, 3 and 5 in both L. infantum and L. braziliensis. The inhibitory effect of these compounds on the antioxidant enzyme Fe-SOD of promastigote forms of the parasites was remarkable, whereas inhibition of human CuZn-SOD was negligible. The ultrastructural alterations observed in treated promastigote forms confirmed the greater cell damage caused by the most active compounds 2, 4 and 6. The modifications observed by (1)H-NMR in the nature and amounts of catabolites excreted by the parasites after treatment with 1-6 suggested that the catabolic mechanisms could depend on the structure of the side chains linked to the benzo[g]phthalazine moiety. CONCLUSIONS: All the compounds assayed were active in vitro against the two Leishmania species and were less toxic against mammalian cells than the reference drug, but the monosubstituted compounds were significantly more effective and less toxic than their disubstituted counterparts.


Asunto(s)
Antiprotozoarios/farmacología , Imidazoles/farmacología , Leishmania braziliensis/efectos de los fármacos , Leishmania infantum/efectos de los fármacos , Ftalazinas/farmacología , Pirazoles/farmacología , Animales , Antiprotozoarios/química , Antiprotozoarios/toxicidad , Supervivencia Celular/efectos de los fármacos , Femenino , Humanos , Imidazoles/química , Imidazoles/toxicidad , Macrófagos/parasitología , Ratones , Ratones Endogámicos BALB C , Microscopía Electrónica de Transmisión , Pruebas de Sensibilidad Parasitaria , Ftalazinas/química , Ftalazinas/toxicidad , Pirazoles/química , Pirazoles/toxicidad , Relación Estructura-Actividad , Superóxido Dismutasa/metabolismo
5.
J Med Chem ; 54(4): 970-9, 2011 Feb 24.
Artículo en Inglés | MEDLINE | ID: mdl-21229977

RESUMEN

The in vivo trypanosomicidal activity of the imidazole-based benzo[g]phthalazine derivatives 1-4 and of the new related pyrazole-based compounds 5 and 6 has been studied in both the acute and chronic phases of Chagas disease. As a rule, compounds 1-6 were more active and less toxic than benznidazole in the two stages of the disease, and the monosubstituted derivatives 2, 4, and 6 were more effective than their disubstituted analogs. Feasible mechanisms of action of compounds 1-6 against the parasite have been explored by considering their inhibitory effect on the Fe-SOD enzyme, the nature of the excreted metabolites and the ultrastructural alterations produced. A complementary histopathological analysis has confirmed that the monosubstituted derivatives are less toxic than the reference drug, with the behavior of the imidazole-based compound 4 being especially noteworthy.


Asunto(s)
Enfermedad de Chagas/tratamiento farmacológico , Imidazoles/síntesis química , Ftalazinas/síntesis química , Pirazoles/síntesis química , Tripanocidas/síntesis química , Tripanocidas/farmacología , Trypanosoma cruzi/efectos de los fármacos , Animales , Chlorocebus aethiops , Femenino , Histocitoquímica , Humanos , Imidazoles/química , Imidazoles/farmacología , Concentración 50 Inhibidora , Espectroscopía de Resonancia Magnética , Ratones , Microscopía Electrónica de Transmisión , Ftalazinas/química , Ftalazinas/farmacología , Pirazoles/química , Pirazoles/farmacología , Espectrometría de Masa por Ionización de Electrospray , Espectrofotometría Infrarroja , Relación Estructura-Actividad , Superóxido Dismutasa/antagonistas & inhibidores , Tripanocidas/química , Trypanosoma cruzi/enzimología , Trypanosoma cruzi/crecimiento & desarrollo , Trypanosoma cruzi/ultraestructura , Células Vero
6.
Bioorg Med Chem ; 18(14): 5301-9, 2010 Jul 15.
Artículo en Inglés | MEDLINE | ID: mdl-20538470

RESUMEN

The synthesis of new 1,4-bisalkylamino (2-4) and 1-alkylamino-4-chloro (5-6) substituted benzo[g]phthalazines is reported. Compounds 2-4 and 6 were prepared both in the free and heteroaromatic ring protonated forms. Bifunctional 6 contains the 1,4-bisaminopropylpiperazine chain as a linker between the two heteroaromatic units, whereas 5 is its monofunctional analogue. The in vitro antitumour activity of the synthesized compounds has been tested against human colon, breast and lung carcinoma cells, and also against human glioblastoma cells. Results obtained show that all of them are active in all cases, but bifunctional 6.2HCl is remarkably effective against the four cell lines tested, exhibiting IC50 values in the range of 10(-7) M, similar to those found for doxorubicin. The bifunctional structure of 6.2HCl enhances activity with respect to the monofunctional related compounds 5 and 7, leading to the highest activity among all the compounds tested. Molecular modelling of 6 suggests that those results could be indicative of DNA bisintercalation, which should be specially favoured in the diprotonated form 6.2HCl, a compound suitable for being studied more in depth in further biological tests. Measure of the DNA thermal melting curves show that the linear rise in Tm for bifunctional 6.2HCl is nearly twice than that one obtained for monofunctional 5, and supports the DNA-binding hypothesis.


Asunto(s)
Antineoplásicos/química , Antineoplásicos/farmacología , ADN/metabolismo , Sustancias Intercalantes/química , Sustancias Intercalantes/farmacología , Piperazinas/química , Piperazinas/farmacología , Antineoplásicos/síntesis química , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Sustancias Intercalantes/síntesis química , Modelos Moleculares , Neoplasias/tratamiento farmacológico , Desnaturalización de Ácido Nucleico/efectos de los fármacos , Ftalazinas/síntesis química , Ftalazinas/química , Ftalazinas/farmacología , Piperazina , Piperazinas/síntesis química
7.
J Med Chem ; 51(6): 1962-6, 2008 Mar 27.
Artículo en Inglés | MEDLINE | ID: mdl-18293910

RESUMEN

The synthesis and trypanosomatic behavior of a new series of 1,4-bis(alkylamino)benzo[g]phthalazines 1- 4 containing the biologically significant imidazole ring are reported. In vitro antiparasitic activity against Trypanosoma cruzi epimastigotes is remarkable, especially for compound 2, whereas toxicity against Vero cells is very low. Conversion of epimastigotes to metacyclic forms in the presence of the tested compounds causes significant decreases in the amastigote and trypomastigote numbers. Fe-SOD inhibition is noteworthy, whereas effect on human Cu/Zn-SOD is negligible.


Asunto(s)
Antiparasitarios/farmacología , Imidazoles/química , Ftalazinas/farmacología , Superóxido Dismutasa/antagonistas & inhibidores , Trypanosoma cruzi/efectos de los fármacos , Animales , Antiparasitarios/síntesis química , Antiparasitarios/química , Chlorocebus aethiops , Humanos , Estructura Molecular , Pruebas de Sensibilidad Parasitaria , Ftalazinas/síntesis química , Ftalazinas/química , Estereoisomerismo , Relación Estructura-Actividad , Trypanosoma cruzi/crecimiento & desarrollo , Células Vero/efectos de los fármacos
8.
Bioorg Med Chem ; 15(5): 2081-91, 2007 Mar 01.
Artículo en Inglés | MEDLINE | ID: mdl-17222558

RESUMEN

The synthesis of a new series of 1,4-bis(alkylamino)benzo[g]phthalazines 1-3 is reported, and their ability to form dinuclear complexes with Cu(II) assayed. The geometry of the complexes is dependent on the nature of the electron-donor sites at the sidechains. Compounds 1 and 2, that contain sp3 or sp2 nitrogens at the end of the alkylamino groups, originate monopodal dinuclear complexes which seem to include endogenous OH bridges, and the sidechains seem to actively participate in complexation. However, the substitution of nitrogen by oxygen in 3 leads to a tripodal dinuclear complex in which the sidechains are not involved. The in vitro antiparasitic activity on Trypanosoma cruzi epimastigotes and amastigotes and the SOD activity inhibition have been evaluated for compounds 1-3, and, as expected, 1 and 2 show in all cases relevant results, whereas 3 is always the less active among the three substrates tested.


Asunto(s)
Cobre/química , Inhibidores Enzimáticos/farmacología , Ftalazinas/farmacología , Superóxido Dismutasa/antagonistas & inhibidores , Trypanosoma cruzi/efectos de los fármacos , Animales , Chlorocebus aethiops , Ligandos , Espectroscopía de Resonancia Magnética , Ftalazinas/química , Ftalazinas/metabolismo , Espectrometría de Masa Bombardeada por Átomos Veloces , Espectrofotometría Infrarroja , Células Vero
9.
J Org Chem ; 62(9): 2684-2693, 1997 May 02.
Artículo en Inglés | MEDLINE | ID: mdl-11671626

RESUMEN

A convenient synthesis of the proton-ionizable crown 3 is reported that uses dibutyltin oxide. In acetonitrile, the reaction of 3 (LH(2)) with phenethylamine and homoveratrylamine (molar ratio 1:2) affords solid dinuclear complexes [LH(2)]2RNH(2) (4a,b), which spectroscopic (FAB-MS, IR, (1)H and (13)C NMR) data point toward a strong participation of the pyrazole nitrogens in the amine complexation. In DMSO-d(6) solution, a (13)C NMR study demonstrates the formation in situ of analogous neutral 4a-d[LH(2)]2RNH(2) or charged 5a-d[L(2)(-)]2RNH(3)(+) dinuclear complexes by reaction of 3 [LH(2)] or 3'[L(2)(-)]2Na(+) with RNH(2) (phenethylamine, homoveratrylamine, dopamine, and norepinephrine) or their RNH(3)(+)Cl(-) salts, respectively. Differences between the structure of complexes 4 and 5 have been evaluated by taking the homoveratrylamine derivatives 4b and 5bas models. An (1)H and (13)C NMR study (by raising the temperature) and measurements of intermolecular NOE effects (from NOESY and ROESY spectra) demonstrate that both complexes behave as prototropic isomers showing different conformations. By increasing the ionic strength, the 4b isomer structure becomes similar to that of 5b. The molecular modeling (GenMol software) of 4a-d and 5a-d shows that the assemblage in which both amine molecules are on the same side of the crown is the more stable. Lipophilic amines afford more stable complexes than hydrophilic ones and charged species are much more stable than the neutral ones.

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