RESUMO
Resumen La dopamina 1, está implicada en trastornos neurodegenerativos que afectan al sistema nervioso central (SNC) tales como la enfermedad de Parkinson, entre otros. Aunque no se dispone aún de ningún fármaco capaz de prevenir, detener o curar la progresión de estas enfermedades, son numerosos los compuestos que han sido diseñados, sintetizados y evaluados farmacológicamente, que han aportado las generalizaciones farmacofóricas del receptor dopaminérgico, necesarias para la búsqueda de un fármaco capaz de mejorar o curar estas patologías. Los derivados 2-aminoindano-N-aralquílicos han mostrado tener actividad selectiva en el sistema dopaminérgico central, de modo tal que los compuestos clorhidratos de N-[(2,4-diclorofenil)-1-metil- etil]-2-aminoindano 2 y N-[(3,4-diclorofenil)-1-metil-etil]-2-aminoindano 3 demostraron tener actividad agonística mediada por mecanismos dopaminérgicos centrales. Con el propósito de contribuir en la búsqueda de nuevos fármacos que permitan restablecer la homeostasis de la transmisión dopaminérgica en la enfermedad de Parkinson, el compuesto N-2,6-dicloro-aralquil-2-aminoindano 4 fue diseñado a través de estrategias de la química medicinal, que contienen las aproximaciones farmacofóricas de los profármacos. La evaluación farmacológica del compuesto 4, en la conducta estereotipada en ratas macho de la cepa Sprague Dawley, demostró tener actividad agonística a través de la activación de los mecanismos dopaminérgicos centrales y mostró mayor selectividad en las respuestas de conductas estereotipadas propias de los ganglios basales sobre las respuestas conductuales propias de las estructuras límbicas.
Abstract Dopamine 1 is involved in neurodegenerative disorders affecting the central nervous system (CNS), such as Parkinson's disease. Despite the absence of some available drugs capable of preventing, stopping or curing the progression of such diseases, there are numerous compounds designed, synthesized, and pharmacologically tested which give rise to pharmacophoric generalizations about the dopaminergic receptor required for the search of a drug able to improve or cure those pathologies. N-aralkyl-2-aminoindane derivatives have shown selective activity in the central dopaminergic system. Both the N-[(2,4-dichlorophenyl)-1-methyl-ethyl]-2-aminoindane hydrochloride 2 and N-[(3,4-dichlorophenyl)-1-methyl-ethyl]-2-aminoindane hydrochloride 3 showed an agonistic activity mediated by central dopaminergic mechanisms. To contribute to the search of new drugs able to re-establish homeostasis in the dopaminergic transmission in Parkinson's disease, the compound N-2,6- dichloro-aralkyl-2-aminoindane 4 was designed through medicinal chemistry strategies that contain pharmacophoric approximations of prodrugs. The pharmacological evaluation of compound 4 in the stereotyped behavior of male Sprague Dawley rats showed agonistic activity through the activation of central dopaminergic mechanisms and a higher selectivity in the responses of stereo- typed behavior characteristic of the basal ganglia over the typical responses from limbic structures.
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Diverse models of intramolecular charge transfer (ICT) have been proposed for interpreting the origin of the charge-transfer (CT) state in donor-acceptor (D-A) dyes. However, a large variety of fused-heterocyclic dyes containing a pseudo-aromatic ring in the rigid structure have shown to be incompatible with them. To approximate a solution within the ICT concept, we reported a novel ICT model called partially aromatized intramolecular charge transfer (PAICT). PAICT involves the generation of a CT state from an ICT that occurred within a pre-excited D-A fused-heterocyclic structure possessing a pseudo-aromatic or unstable aromatic ring as the acceptor moiety. The model was proposed from the multiple-emissive mesomeric D-A N1-aryl-2-(trifluoromethyl)benzo[b][1,8]naphthyridin-4(1H)-one, whose excited mesomeric states, which are defined by the aromatic and pseudo-aromatic forms of the pyrindin-4(1H)-one ring, led to a common partial aromatized CT state upon excitation via PAICT. The latter was supported through theoretical calculations on the excited mesomeric states, one-dimensional (1D) and two-dimensional (2D) excitation-emission measurements in different solvents, and the detection of three excited states by lifetime measurements upon 370 nm excitation. The existence of mesomerism was supposed from: (i) two overlapping bands at 370-390 (or 400-420 nm) in UV-vis spectra, (ii) the direct interaction between the pyridinic nitrogen of one molecule and the carbonylic oxygen of the other found in the solid state and, (iii) the detection of three excited states by lifetime measurements. The PAICT opens new perspectives for interpreting the charge-transfer phenomenon in fused-heterocyclic dyes, in particular, those containing a pseudo-aromatic or unstable aromatic ring as an acceptor moiety.
Assuntos
Corantes/química , SolventesRESUMO
To identify new agents for the treatment of American cutaneous leishmaniasis, a series of eight 1,4-bis(substituted benzalhydrazino)phthalazines was evaluated against Leishmania braziliensis and Leishmania mexicana parasites. These compounds represent a disubstituted version of the 1-chloro-4-(monoaryl/heteroarylhydranizyl)phthalazine that exhibited a significant response against L. braziliensis according to our previous findings. Two disubstituted phthalazines 3b and 3f were identified as potential antileishmanial agents against L. braziliensis parasites, exhibiting a submicromolar IC50 response of 2.37 and 7.90 µM on the promastigote form, and of 1.82 and 4.56 µM against intracellular amastigotes, respectively. In particular, compound 3b showed interesting responses against amastigote isolates from reference, glucantime-resistant and clinical human strains, which were by far superior to the biological response found for the glucantime drug. With regard to the toxicity results, both 3b and 3f exhibited moderate LD50 values against murine macrophages (BMDM), with good selectivity indexes on promastigotes and intracellular amastigotes of L. braziliensis. A comparison of biological response was established between the monosubstituted and disubstituted versions of these benzalhydrazino-phthalazines. Easy synthetic procedure and significant response against amastigote strains including against resistant lines made compound 3b a potential candidate for further pharmacokinetic and in vivo experiments as antileishmanial agent, and as a platform for further structural optimization. Mechanism-of-action studies and molecular docking simulations discarded to inhibition of superoxide dismutase as possible mode of action.
Assuntos
Antiprotozoários/farmacologia , Leishmania braziliensis/efeitos dos fármacos , Leishmania mexicana/efeitos dos fármacos , Leishmania/efeitos dos fármacos , Ftalazinas/farmacologia , Animais , Antiprotozoários/química , Antiprotozoários/toxicidade , Células Cultivadas , Leishmania braziliensis/crescimento & desenvolvimento , Leishmania braziliensis/metabolismo , Leishmania mexicana/crescimento & desenvolvimento , Leishmania mexicana/metabolismo , Dose Letal Mediana , Macrófagos/efeitos dos fármacos , Macrófagos/parasitologia , Camundongos , Simulação de Acoplamento Molecular , Estrutura Molecular , Ftalazinas/química , Ftalazinas/toxicidade , Relação Estrutura-Atividade , Superóxido Dismutase/metabolismoRESUMO
Traditional antimalarial drugs based on 4-aminoquinolines have exhibited good antiproliferative activities against Leishmania parasites; however, their clinical use is currently limited. To identify new 4-aminoquinolines to combat American cutaneous leishmaniasis, we carried out a full in vitro evaluation of a series of dehydroxy isoquines and isotebuquines against two Leishmania parasites such as Leishmania braziliensis and Leishmania mexicana. First, the antiproliferative activity of the quinolines was studied against the promastigote forms of L. braziliensis and L. mexicana parasites, finding that five of them exhibited good antileishmanial responses with micromolar IC50 values ranging from 3.84 to 10 µM. A structure-activity relationship analysis gave evidence that a piperidine or a morpholine attached as N-alkyamino terminal substituent as well as the inclusion of an extra phenyl ring attached at the aniline ring of the isotebuquine core constitute important pharmacophores to generate the most active derivatives, with antileishmanial responses by far superior to those found for the reference drug, glucantime. All compounds showed a relatively low toxicity on human dermis fibroblasts, with CC50 ranging from 69 to >250 µM. The five most active compounds displayed moderate to good antileishmanial activity against the intracellular amastigote form of L. braziliensis, compared to the reference drug. In particular, compound 2j was identified as the most potent agent against antimony-resistant amastigotes of L. braziliensis with acceptable biological response and selectivity, emerging as a promising candidate for further in vivo antileishmanial evaluation. Diverse mechanism-of-action studies and molecular docking simulations were performed for the most active 4-aminoquinoline.
Assuntos
Aminoquinolinas/farmacologia , Antimaláricos/farmacologia , Leishmania/efeitos dos fármacos , Quinolinas/farmacologia , Aminoquinolinas/síntese química , Aminoquinolinas/química , Antimaláricos/síntese química , Antimaláricos/química , Relação Dose-Resposta a Droga , Simulação de Acoplamento Molecular , Estrutura Molecular , Testes de Sensibilidade Parasitária , Quinolinas/síntese química , Quinolinas/química , Relação Estrutura-AtividadeRESUMO
Traditional antimalarial drugs based on 4-aminoquinolines have exhibited good antiproliferative activities against human tumor cells; however, their low relative efficacy has limited their corresponding clinical uses. In order to identify new potent anticancer agents based on 4-aminoquinoline, we evaluated the antiproliferative activity of a series of dehydroxy isoquines and isotebuquines against five human cancer lines. HeLa and SKBr3 were significantly more sensitive to the action of tested quinolines than the A549, MCF-7, and PC-3 cancer lines. Compound 2h was by far the most potent derivative against four of the tested lines (except to PC3 line), exhibiting low micromolar or nanomolar IC50 values superior to adriamycin reference, low toxicities on dermis human fibroblasts (LD50 > 250 µM), and excellent selectivity indexes against the mentioned cancer cells. A structure-activity relationship analysis put in evidence that a pyrrolidine or morpholine moiety as N-alkyl terminal substitution and the incorporation of the extra phenyl attached to aniline ring are pharmacophore essentials for improvement the anticancer activity of the studied dehydroxy isoquines and isotebuquines. From the results, compound 2h emerged as a promising anticancer candidate for further in vitro assays against resistant-strain and in vivo studies as well as pharmacokinetic and genotoxicity studies. Mechanistic assays suggested that the most active quinoline 2h act as calcium-activated potassium channel activator.
Assuntos
Aminoquinolinas/química , Antineoplásicos/química , Canais de Potássio/química , Potenciais de Ação/efeitos dos fármacos , Aminoquinolinas/metabolismo , Aminoquinolinas/farmacologia , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Desenho de Fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Canais de Potássio/metabolismo , Relação Estrutura-AtividadeRESUMO
Trifluoromethyl-substituted quinolones and their analogues have emerged as an interesting platform in the last 6 years to design antiparasite agents. Many of their derivatives have been demonstrated to display excellent efficacy against flagellate parasites such as Plasmodium spp. In order to identify new analogues of trifluoromethyl-substituted quinolones to treat the American cutaneous leishmaniasis, we evaluated the antiproliferative activity of a series of 2-(trifluoromethyl)benzo[b]-[1,8]naphthyridin-4(1H)-ones on the Leishmania braziliensis and Leishmania mexicana parasites. The mentioned derivatives have never been evaluated against any parasite strain. In general, an in vitro evaluation on L.(L)mexicana and L.(V)braziliensis showed that L.(L)mexicana was more sensitive to the action of the compounds than L.(V)braziliensis, either in the promastigote or in the amastigote form. Five compounds exhibited moderate efficacy against L.(L)mexicana promastigotes, with IC50 values ranging from 9.65 to 14.76 µM. From the mentioned molecules, three compounds, 1e, 1f, and 1h, showed a discrete response against axenic and intracellular amastigotes, with LD50 values between 19 and 24 µM. Moreover, an in vitro evaluation was performed on an antimony-resistant amastigote strain and a human isolate amastigote strain. These three compounds showed discrete toxicity on peritoneal macrophages; however, their relatively good antiamastigote response compared to the drug glucantime promoted our trifluoromethyl-substituted benzo[b][1,8]naphthyridin-4(1H)-ones as a potential platform to design potent antileishmanial agents.
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Many people are affected by Malaria around the world, and the parasite is developing resistance against available drugs. Currently, isoquine and N-tert-butyl isoquine are some of the most promising antimalarial candidates that have already reached Phase I and II clinical trials, respectively. Nevertheless, pharmacodynamic studies have demonstrated that isoquine is highly sensitive to form O-glucuronide metabolite, which may affect its accumulation in tissues. To avoid the O-glucuronide formation and its negative influence in the accumulation process, a series of novel five dehydroxy isoquine derivatives were designed and prepared herein as potential antimalarial agents. By a simple three-step procedure, five dehydroxy isoquines were prepared and subsequently examined on the inhibition of haemozoin formation, the main target of the 4-aminoquinolines. Four derivatives displayed significant inhibitory activities at low IC50 values from 1.66 to 1.86 µM comparable to CQ. On the basis of the results, these four compounds were subsequently tested against Plasmodium berghei ANKA model in mice, showing to be as active as CQ with significant curative responses and parasitemia suppression in mice infected. On the other hand, these four compounds showed an acceptable non specific cytotoxicity on murine peritoneal macrophague and human erythrocyte cells. Thus, the presented data indicate that the dehydroxy isoquines 4b, 4c and 4e constitute promising cost-effective leads for the development of new antiplasmodial targeted at blood-stage malaria parasites.
Assuntos
Antimaláricos/química , Plasmodium berghei/efeitos dos fármacos , Aminoquinolinas , Amodiaquina/análogos & derivados , Animais , Antimaláricos/farmacologia , Eritrócitos/efeitos dos fármacos , Eritrócitos/parasitologia , Humanos , Macrófagos/efeitos dos fármacos , Macrófagos/parasitologia , Camundongos , Parasitemia/tratamento farmacológicoRESUMO
With the aim to identify a potential drug candidate to treat cutaneous leishmaniasis, a series of 1-phthalazinyl hydrazones were synthesized and tested against Leishmania braziliensis parasite, one of the main responsible of this disease in the world. A structure-activity relationship permitted to identify two phthalazines containing nitroheterocyclic moiety 3l and 3m as promising new lead compounds. These compounds showed a significant antileishmanial activity against promastigote form of L. braziliensis, with EC50 values in sub-micromolar and nanomolar ranges. The phthalazine 3l also displayed a selective and excellent activity against the clinically relevant intracellular amastigotes form, with a EC50 value in sub-micromolar range (0.59 µM), without affecting the viability of the host cells. Oxidative stress was identified as the possible mode of action of the most active phthalazine. Considering their significant antileishmanial activity and ease synthesis, the phthalazine containing nitroheterocyclic represents a promising agent against Leishmania braziliensis for the rational design of new leads.
Assuntos
Antiprotozoários/síntese química , Antiprotozoários/farmacologia , Desenho de Fármacos , Hidrazonas/síntese química , Hidrazonas/farmacologia , Leishmania braziliensis/efeitos dos fármacos , Ftalazinas/química , Animais , Antiprotozoários/química , Antiprotozoários/toxicidade , Linhagem Celular , Hidrazonas/química , Hidrazonas/toxicidade , Leishmania braziliensis/enzimologia , Leishmania braziliensis/crescimento & desenvolvimento , Macrófagos/efeitos dos fármacos , Camundongos , Modelos Moleculares , Conformação Proteica , Relação Estrutura-Atividade , Superóxido Dismutase/química , Superóxido Dismutase/metabolismoRESUMO
Diverse dehydroxy-isotebuquine derivatives were prepared by using a five step synthetic sequence in good yields. All these new 4-aminoquinolines were evaluated as inhibitors of haemozoin formation, where most of them showed a significant inhibition value (% IHF >97). The best inhibitors were tested in vivo as potential antimalarials in mice infected with Plasmodium berghei ANKA chloroquine susceptible strain, three of them (11b, 11d and 11h) displayed an antimalarial activity comparable to that of chloroquine.
Assuntos
Aminoquinolinas/química , Antimaláricos/síntese química , Hemeproteínas/antagonistas & inibidores , Aminoquinolinas/farmacologia , Aminoquinolinas/uso terapêutico , Animais , Antimaláricos/farmacologia , Antimaláricos/uso terapêutico , Cloroquina/farmacologia , Avaliação Pré-Clínica de Medicamentos , Hemeproteínas/metabolismo , Malária/tratamento farmacológico , Malária/patologia , Malária/veterinária , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Plasmodium berghei/efeitos dos fármacos , Relação Estrutura-AtividadeRESUMO
A series of phenylsubstituted pyrazolo and pyrimido benzothiazine dioxide derivatives were synthesized and investigated for their abilities to inhibit beta-hematin formation, hemoglobin hydrolysis and in vivo for their antimalarial efficacy in rodent Plasmodium berghei. Compounds 3-amino-7-chloro-9-(2'-methylphenyl)-1,9-dihydro-pyrazolo-[4,3-b]benzothiazine 4,4-dioxide 2b and 2,4-diamino-8-chloro-10H-phenyl-pyrimido-[5,4-b]benzothiazine 5,5-dioxide 3a were the most promising as inhibitors of hemoglobin hydrolysis, however, their effect as inhibitors of beta-hematin formation was marginal, except for compound 3-amino-7-chloro-9-(3'-chlorophenyl)-1,9dihydro-pyrazolo-[4,3-b]benzothiazine 4,4-dioxide 2g. The most active compound to emerge from the in vitro and in vivo murine studies was 2b, suggesting an antimalarial activity via inhibition of hemoglobin hydrolysis, however, not as efficient as chloroquine.
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Antimaláricos/síntese química , Antimaláricos/farmacologia , Plasmodium berghei/efeitos dos fármacos , Tiazinas/síntese química , Tiazinas/farmacologia , Animais , Antimaláricos/química , Espectroscopia de Ressonância Magnética , Modelos Moleculares , Espectrofotometria Infravermelho , Tiazinas/químicaRESUMO
Brain dopaminergic system has a crucial role in the etiology of several neuropsychiatric disorders, including Parkinson's disease, depression, and schizophrenia. Several dopaminergic drugs are used to treat these pathologies, but many problems are attributed to these therapies. Within this context, the search for new more efficient dopaminergic agents with less adverse effects represents a vast research field. The aim of the present study was to synthesize N-[2-(4,5-dihydroxyphenyl)-methyl-ethyl]-4,5-dihydroxy-2-aminoindan hydrobromide (3), planned to be a dopamine ligand, and to evaluate its dopaminergic action profile. This compound was assayed as a diastereoisomeric mixture in two experimental models: stereotyped behavior (gnaw) and renal urinary response, after central administration. The pharmacological results showed that compound 3 significantly blocked the apomorphine-induced stereotypy and dopamine-induced diuresis and natriuresis in rats. Thus, compound 3 demonstrated an inhibitory effect on dopaminergic-induced behavior and renal action. N-[2-(-Methyl-ethyl)]-4,5-dihydroxy-2-aminoindan hydrobromide (4) was previously reported as an inotropic agent, and in the present work it was also re-evaluated as a diastereoisomeric mixture for its possible central action on the behavior parameters such as stereotypy and dopamine-induced diuresis and natriuresis in rats. Our results indicate that compound 4 produces an agonistic response, possibly through dopaminergic mechanisms. To better understand the experimental results we performed molecular dynamics simulations of two complexes: compound 3/D(2)DAR (dopamine receptor) and compound 4/D(2)DAR. The differential binding mode obtained for these complexes could explain the antagonist and agonist activity obtained for compounds 3 and 4, respectively.