RESUMEN
Leishmania poses a substantial threat to the human population all over the globe because of its visceral and cutaneous spread engendered by all 20 species. Unfortunately, the available drugs against leishmania are already hobbled with toxicity, prolonged treatment, and increasing instances of acquirement of resistance. Under these grave circumstances, the development of new drugs has become imperative to keep these harmful microbes at bay. To this end, a Groebke-Blackburn-Bienaymé multicomponent reaction-based library of different imidazo-fused heterocycles has been synthesized and screened against Leishmania amazonensis promastigotes and amastigotes. Among the library compounds, the imidazo-pyrimidine 24 has been found to be the most effective (inhibitory concentration of 50% (IC50) < 10 µM), with selective antileishmanial activity on amastigote forms, a stage of the parasite related to human disease. The compound 24 has exhibited an IC50 value of 6.63 µM, being â¼two times more active than miltefosine, a reference drug. Furthermore, this compound is >10 times more destructive to the intracellular parasites than host cells. The observed in vitro antileishmanial activity along with suitable in silico physicochemical and absorption, distribution, metabolism, excretion, and toxicity (ADMET) properties of compound 24 reinforce the imidazo-pyrimidine scaffold as a new antileishmanial pharmacophore and encourage further murine experimental leishmaniasis studies.
RESUMEN
A concise synthesis of molnupiravir in a one-pot two-step approach starting from uridine is described. Formally, herein, two sets of one-pot two-reaction steps introducing simplicity for purifications and using chemically available reagents are presented. In this context, molnupiravir was obtained in up to 68% overall yield and multigram-scale. In addition, HPLC analysis showed the molnupiravir purity above 99%.
RESUMEN
For the first time, compounds developed from the 1,2,3-triazole scaffold were evaluated as novel drugs to treat triple-negative breast cancer (TNBC). Four organic salts were idealized as nonclassical bioisosteres of miltefosine, which is used in the topical treatment for skin metastasizing breast carcinoma. Among them, derivative dhmtAc displayed better solubility and higher cytotoxicity against the human breast adenocarcinoma cell line and mouse 4T1 cell lines, which are representatives of TNBC. In vitro assays revealed that dhmtAc interferes with cell integrity, confirmed by lactate dehydogenase leakage. Due to its human peripheral blood mononuclear cell (PBMC) toxicity, dhmtAc in vivo studies were carried out with the drug incorporated in a long-circulating and pH-sensitive liposome (SpHL-dhmtAc), and the acute toxicity in BALB/c mice was determined. Free dhmtAc displayed cardiac and pulmonary toxicity after the systemic administration of 5 mg/kg doses. On the other hand, SpHL-dhmtAc displayed no toxicity at 20 mg/kg. The in vivo antitumor effect of SpHL-dhmtAc was investigated using the 4T1 heterotopic murine model. Intravenous administration of SpHL-dhmtAc reduced the tumor volume and weight, without interfering with the body weight, compared with the control group and the dhmtAc free form. The incorporation of the triazole compound in the liposome allowed the demonstration of its anticancer potential. These findings evidenced 1,3,4-trisubstituted-1,2,3-triazole as a promising scaffold for the development of novel drugs with applicability for the treatment of patients with TNBC.
Asunto(s)
Liposomas , Neoplasias de la Mama Triple Negativas , Animales , Línea Celular Tumoral , Humanos , Leucocitos Mononucleares , Ratones , Ratones Endogámicos BALB C , Relación Estructura-Actividad , Triazoles/farmacología , Neoplasias de la Mama Triple Negativas/tratamiento farmacológicoRESUMEN
OBJECTIVES: Evaluation of the anti-Leishmanial activity of imidazoquinoline-based TLR7/8 agonists. METHODS: TLR7/8-active imidazoquinolines (2 and 3) were synthesized and assessed for activity against Leishmania amazonensis-intracellular amastigotes using mouse peritoneal macrophages. The production of reactive oxygen species (ROS), nitric oxide (NO) and cytokines was determined in infected and non-infected macrophages. KEY FINDINGS: The imidazoquinolines, 2 and 3, were primarily agonists of TLR7 with compound 3 also showing modest TLR8 activity. Docking studies showed them to occupy the same binding pocket on TLR7 and 8 as the known agonists, imiquimod and resiquimod. Compounds 2 and 3 inhibited the growth of L. amazonensis-intracellular amastigotes with the most potent compound (3, IC50 = 5.93 µM) having an IC50 value close to miltefosine (IC50 = 4.05 µM), a known anti-Leishmanial drug. Compound 3 induced macrophages to produce ROS, NO and inflammatory cytokines that likely explain the anti-Leishmanial effects. CONCLUSIONS: This study shows that activating TLR7 using compounds 2 or 3 induces anti-Leishmanial activity associated with induction of free radicals and inflammatory cytokines able to kill the parasites. While 2 and 3 had a very narrow cytotoxicity window for macrophages, this identifies the possibility to further develop this chemical scaffold to less cytotoxic TLR7/8 agonist for potential use as anti-Leishmanial drug.
Asunto(s)
Antiprotozoarios/farmacología , Leishmania/efectos de los fármacos , Macrófagos Peritoneales/efectos de los fármacos , Receptor Toll-Like 7/agonistas , Receptor Toll-Like 8/agonistas , Animales , Antiprotozoarios/síntesis química , Citocinas/metabolismo , Femenino , Humanos , Imidazoles , Imiquimod , Inflamación/metabolismo , Leishmaniasis/parasitología , Macrófagos Peritoneales/parasitología , Ratones Endogámicos BALB C , Óxido Nítrico/metabolismo , Especies Reactivas de Oxígeno/metabolismoRESUMEN
In this work, we combined molecular modeling, computational docking and in vitro analysis to explore the antileishmanial effect of some resveratrol analogs (ResAn), focusing on their pro-oxidant effect. The molecular target was the trypanothione reductase of Leishmania braziliensis (LbTryR), an essential component of the antioxidant defenses in trypanosomatid parasites. Three-dimensional structures of LbTryR were modeled and molecular docking studies of ResAn1-5 compounds showed the following affinity: ResAn1 > ResAn2 > ResAn4 > ResAn5 > ResAn3. Positive correlation was observed between these compounds' affinity to the LbTryR and the IC50 values against Leishmania sp (ResAn1 < ResAn2 < ResAn4), which allows for TryR being considered an important target for them. As the compound ResAn1 showed the best antileishmanial activity, and docking studies showed its high affinity for NADP binding site (NS) of TryR, plus having been able to induce ROS production in L. braziliensis promastigotes treated, ResAn1 probably occupies NS interfering in the electron transfer processes responsible for the catalytic reaction. The in silico prediction of ADMET properties suggests that ResAn1 may be a promising drug candidate with properties to cross biological membranes and high gastrointestinal absorption, not violating Lipinski's rules. Ultimately, the antileishmanial effect of ResAn can be associated with a pro-oxidant effect which, in turn, can be exploited as an antimicrobial agent. Communicated by Ramaswamy H. Sarma.
Asunto(s)
Antiprotozoarios/farmacología , Regulación Enzimológica de la Expresión Génica/efectos de los fármacos , Leishmania braziliensis/efectos de los fármacos , Leishmania braziliensis/enzimología , Leishmaniasis/tratamiento farmacológico , NADH NADPH Oxidorreductasas/metabolismo , Resveratrol/química , Animales , Antioxidantes/química , Antioxidantes/farmacología , Antiprotozoarios/química , Sitios de Unión , Leishmaniasis/parasitología , Macrófagos/efectos de los fármacos , Macrófagos/enzimología , Macrófagos/parasitología , Ratones , Ratones Endogámicos BALB C , Modelos Moleculares , Simulación del Acoplamiento Molecular , Estructura Molecular , NADH NADPH Oxidorreductasas/química , Conformación Proteica , Proteínas Protozoarias/química , Proteínas Protozoarias/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Resveratrol/farmacología , Relación Estructura-ActividadRESUMEN
Ionic liquids (ILs) have been extensively studied and are considered green solvents capable of replacing traditional organic solvents. In this study, seven 1,2,3-triazolium derivative ILs have been synthesized. In order to study the effect of the cation nature on the ILs cytotoxicity, their structures were first identified by 1H, 13C NMR 1D, and 2D spectroscopy. DFT calculations have also been performed in a way to help to provide an insightful structural analysis from 13C NMR spectroscopy. The comparison made with the NMR experimental shifts was quite important to show that the 1,2,3-triazolium derivatives have the expected structure shown here. The in vitro cytotoxicity of ILs toward macrophages showed that among the compounds tested, five did not exhibit expressive cytotoxicity on mammalian cells. Besides the well-established relationship between the carbonic chain size of the cation and the cytotoxicity, the log P of the compounds predicts that the toxicity increases with the size of the carbon chain, demonstrating that the most cytotoxic compound is also the most lipophilic one. The low cytotoxicity effect of ILs on mammalian cells points to their potential application in large-scale by industry. Graphical abstract Seven triazolium ILs were synthesized and their in vitro cytotoxicity on murine macrophages showed a relationship with the carbonic chain size.
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Líquidos Iónicos/química , Espectroscopía de Resonancia Magnética , Triazoles/química , Animales , Supervivencia Celular/efectos de los fármacos , Macrófagos/efectos de los fármacos , Ratones , Modelos Moleculares , Estructura Molecular , Triazoles/síntesis química , Triazoles/farmacologíaRESUMEN
Fluorine configuration at C2' of the bis(2'-fluorothymidine) dinucleotide is demonstrated to drive intramolecular base stacking. 2'-ß F-Configuration drastically reduces stacking compared to the 2'-α series. Hence, base stacking emerges as being tunable by the C2'-F stereoconfiguration through dramatic puckering variations scrutinized by NMR and natural bond orbital analysis. Accordingly, 2'-ß F-isomer photoreactivity is significantly reduced compared to that of the 2'-α F-isomer.
RESUMEN
Nitrogenated heterocyclic compounds are present in both natural and synthetic drugs, and hexahydropyrimidine derivatives may prove to be efficient in treating dermatomycosis causing fungi. This study evaluated the antifungal activity of four hexahydropyrimidine derivatives against the dermatomycosis causing fungi. These derivatives were synthesized, characterized, and assessed in terms of their activity against Trichophyton mentagrophytes, Microsporum canis, Microsporum gypseum, Trichophyton rubrum, Fusarium oxysporum, and Epidermophyton floccosum between concentrations 7.8 and 1,000 µg mL-1. Scanning electron micrographs were assessed for the active derivatives and reference drugs, and these micrographs revealed that new agents cause morphological changes in fungi. The derivatives HHP1, HHP3, and HHP4 revealed poor activity against the four fungal strains (MICs range 500-1000 µg mL-1). Compound HHP3 was found to be the best potential antifungal agent among those tested and was the most effective among all the active derivatives that caused morphological changes in the susceptible strains.
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Antifúngicos/farmacología , Dermatomicosis/microbiología , Hongos/efectos de los fármacos , Pirimidinas/farmacología , Antifúngicos/síntesis química , Antifúngicos/química , Dermatomicosis/tratamiento farmacológico , Hongos/ultraestructura , Pruebas de Sensibilidad Microbiana , Estructura Molecular , Pirimidinas/síntesis química , Pirimidinas/químicaRESUMEN
In our previous work, we demonstrated the promising in vitro effect of VOSalophen, a vanadium complex with a stilbene derivative, against Leishmania amazonensis. Its antileishmanial activity has been associated with oxidative stress in L. amazonensis promastigotes and L. amazonensis-infected macrophages. In the present study, the mechanism involved in the death of parasites after treatment with VOSalophen, as well as in vivo effect in the murine model cutaneous leishmaniasis, has been investigated. Promastigotes of L. amazonensis treated with VOSalophen presented apoptotic cells features, such as cell volume decrease, phosphatidylserine externalization, and DNA fragmentation. An increase in autophagic vacuoles formation in treated promastigotes was also observed, showing that autophagy also may be involved in the death of these parasites. In intracellular amastigotes, DNA fragmentation was observed after treatment with VOSalophen, but this effect was not observed in host cells, highlighting the selective effect of this vanadium complex. In addition, VOSalophen showed activity in the murine model of cutaneous leishmaniasis, without hepatic and renal damages. The outcome described here points out that VOSalophen had promising antileishmanial properties and these data also contribute to the understanding of the mechanisms involved in the death of protozoa induced by metal complexes.
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Apoptosis/efectos de los fármacos , Autofagia/efectos de los fármacos , Leishmaniasis Cutánea/tratamiento farmacológico , Leishmaniasis Cutánea/patología , Compuestos Organometálicos/química , Compuestos Organometálicos/farmacología , Estilbenos/química , Vanadio/química , Animales , Fragmentación del ADN/efectos de los fármacos , Modelos Animales de Enfermedad , Femenino , Leishmaniasis Cutánea/genética , Ratones , Ratones Endogámicos BALB C , Compuestos Organometálicos/uso terapéuticoRESUMEN
Here, we report the effect of new non-classical bioisosteres of miltefosine on Leishmania amazonensis. Fifteen compounds were synthesized and the compound dhmtAc, containing an acetate anion, a side chain of 10 carbon atoms linked to N-1 and a methyl group linked to N-3, showed high and selective biological activity against L. amazonensis. On the intracellular amastigotes, stages of the parasite related to human disease, the IC50 values were near or similar to the 1.0µM (0.9, 0.8 and 1.0µM on L. amazonensis-WT, and two transgenic L. amazonensis expressing GFP and RFP, respectively), being more active than miltefosine. Furthermore, dhmtAc did not show toxic effects on human erythrocytes and macrophages (CC50=115.9µM) being more destructive to the intracellular parasites (selectivity index>115). Promastigotes and intramacrophage amastigotes treated with dhmtAc showed low capacity for reversion of the effect of the compound. A study of the mechanism of action of this compound showed some features of metazoan apoptosis, including cell volume decreases, loss of mitochondrial membrane potential, ROS production, an increase in the intracellular lipid bodies, in situ labeling of DNA fragments by TUNEL labeling and phosphatidylserine exposure to the outerleaflet of the plasma membrane. In addition, the plasma membrane disruption, revealed by PI labeling, suggests cell death by necrosis. No increase in autophagic vacuoles formation in treated promastigotes was observed. Taken together, the data indicate that the bioisostere of miltefosine, dhmtAc, has promising antileishmanial activity that is mediated via apoptosis and necrosis.
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Antiprotozoarios/química , Antiprotozoarios/farmacología , Leishmania mexicana/efectos de los fármacos , Fosforilcolina/análogos & derivados , Triazoles/química , Triazoles/farmacología , Animales , Apoptosis/efectos de los fármacos , Línea Celular , Eritrocitos/parasitología , Humanos , Leishmania mexicana/citología , Leishmania mexicana/fisiología , Leishmaniasis Cutánea/tratamiento farmacológico , Leishmaniasis Cutánea/parasitología , Macrófagos/parasitología , Ratones , Fosforilcolina/química , Fosforilcolina/farmacología , Especies Reactivas de Oxígeno/metabolismoRESUMEN
Leishmaniasis comprise a spectrum of diseases caused by protozoa parasites from the genus Leishmania, affecting millions of people worldwide, mainly in subtropical countries. Most antileishmanial drugs are highly toxic, present resistance issues or require long-term treatment. Consequently, new drugs are urgently needed. Quinoline-containing compounds have displayed an impressive array of biological properties over the years, including antileishmanial activity. In the present study, we report the synthesis and evaluation of novel quinoline derivatives (QuinDer) against Leishmania species and cytotoxic effect on mammalian cells. The ROS production and mitochondrial membrane potential analyses were also studied. The compound QuinDer1 showed activity on L. amazonensis and L. braziliensis promastigotes and this compound exhibited a strong inhibition of the proliferation of L. amazonensis amastigotes at nM concentration (IC50 of 0.0911 µM), being 139 times more active than miltefosine (IC50 of 12.7 µM), used as reference drug. This compound presents low cytotoxicity toward murine macrophages and human erythrocytes. In addition, promastigotes of L. amazonensis treated with the compound QuinDer1 present high generation of ROS levels with low alterations in mitochondrial membrane potential and maintenance of parasite membrane integrity. No substantial NO production in infected-macrophages treated with this compound was detected. These results suggest that the compound QuinDer 1 is a potent and selective antileishmanial agent by mitochondrial oxidative stress.
Asunto(s)
Leishmania/efectos de los fármacos , Mitocondrias/metabolismo , Estrés Oxidativo/efectos de los fármacos , Quinolinas/síntesis química , Quinolinas/farmacología , Animales , Antiprotozoarios/farmacología , Muerte Celular/efectos de los fármacos , Membrana Celular/efectos de los fármacos , Membrana Celular/metabolismo , Eritrocitos/efectos de los fármacos , Humanos , Macrófagos/efectos de los fármacos , Macrófagos/parasitología , Potencial de la Membrana Mitocondrial/efectos de los fármacos , Ratones , Mitocondrias/efectos de los fármacos , Quinolinas/química , Especies Reactivas de Oxígeno/metabolismoRESUMEN
The leishmanicidal activity of a series of 4-aminoquinoline (AMQ) derivatives was assayed against Leishmania amazonensis. This activity against the intracellular parasite was found stronger than for L. amazonensis promastigotes. Neither compound was cytotoxic against macrophages. The compound AMQ-j, which exhibited a strong activity against promastigotes and amastigotes of L. amazonensis (IC50 values of 5.9 and 2.4 µg/mL, respectively) and similar leishmanicidal activity to reference drugs, was chosen for studies regarding its possible mechanism of action toward parasite death. The results showed that the compound AMQ-j induced depolarization of the mitochondrial membrane potential in promastigotes and in L. amazonensis-infected macrophages, but not in uninfected macrophages. Furthermore, the depolarization of the mitochondrial membrane potential was dose dependent in infected macrophages. We have established that promastigotes and L. amazonensis-infected macrophages treated with AMQ-j were submitted to oxidative stress. This is in line with the increase in the level of reactive oxygen species (ROS). Leishmania amazonensis-infected macrophages treated with AMQ-j did not show a significant increase in the production of nitric oxide. Our results indicate the effective and selective action of AMQ-j against L. amazonensis, and its mechanism of action appears to be mediated by mitochondrial dysfunction associated with ROS production.
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Aminoquinolinas/química , Antiprotozoarios/química , Antiprotozoarios/farmacología , Leishmania mexicana/efectos de los fármacos , Animales , Muerte Celular/efectos de los fármacos , Membrana Celular/efectos de los fármacos , Células Cultivadas , Evaluación Preclínica de Medicamentos/métodos , Leishmania mexicana/citología , Leishmania mexicana/fisiología , Macrófagos/efectos de los fármacos , Macrófagos/metabolismo , Macrófagos/parasitología , Potencial de la Membrana Mitocondrial/efectos de los fármacos , Ratones Endogámicos BALB C/parasitología , Óxido Nítrico/metabolismo , Estrés Oxidativo/efectos de los fármacos , Especies Reactivas de Oxígeno/metabolismoRESUMEN
BACKGROUND: Given the threat of resistance of human malaria parasites, including to artemisinin derivatives, new agents are needed. Chloroquine (CQ) has been the most widely used anti-malarial, and new analogs (CQAns) presenting alkynes and side chain variations with high antiplasmodial activity were evaluated. METHODS: Six diaminealkyne and diaminedialkyne CQAns were evaluated against CQ-resistant (CQ-R) (W2) and CQ-sensitive (CQ-S) (3D7) Plasmodium falciparum parasites in culture. Drug cytotoxicity to a human hepatoma cell line (HepG2) evaluated, allowed to calculate the drug selectivity index (SI), a ratio of drug toxicity to activity in vitro. The CQAns were re-evaluated against CQ-resistant and -sensitive P. berghei parasites in mice using the suppressive test. Docking studies with the CQAns and the human (HssLDH) or plasmodial lactate dehydrogenase (PfLDH) enzymes, and, a ß-haematin formation assay were performed using a lipid as a catalyst to promote crystallization in vitro. RESULTS: All tested CQAns were highly active against CQ-R P. falciparum parasites, exhibiting half-maximal inhibitory concentration (IC(50)) values below 1 µΜ. CQAn33 and CQAn37 had the highest SIs. Docking studies revealed the best conformation of CQAn33 inside the binding pocket of PfLDH; specificity between the residues involved in H-bonds of the PfLDH with CQAn37. CQAn33 and CQAn37 were also shown to be weak inhibitors of PfLDH. CQAn33 and CQAn37 inhibited ß-haematin formation with either a similar or a 2-fold higher IC(50) value, respectively, compared with CQ. CQAn37 was active in mice with P. berghei, reducing parasitaemia by 100%. CQAn33, -39 and -45 also inhibited CQ-resistant P. berghei parasites in mice, whereas high doses of CQ were inactive. CONCLUSIONS: The presence of an alkyne group and the size of the side chain affected anti-P. falciparum activity in vitro. Docking studies suggested a mechanism of action other than PfLDH inhibition. The ß-haematin assay suggested the presence of an additional mechanism of action of CQAn33 and CQAn37. Tests with CQAn34, CQAn37, CQAn39 and CQAn45 confirmed previous results against P. berghei malaria in mice, and CQAn33, 39 and 45 were active against CQ-resistant parasites, but CQAn28 and CQAn34 were not. The result likely reflects structure-activity relationships related to the resistant phenotype.
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Antimaláricos/química , Antimaláricos/farmacología , Cloroquina/análogos & derivados , Cloroquina/farmacología , Resistencia a Medicamentos , Plasmodium falciparum/efectos de los fármacos , Antimaláricos/toxicidad , Supervivencia Celular/efectos de los fármacos , Cloroquina/toxicidad , Hepatocitos/efectos de los fármacos , Hepatocitos/fisiología , Concentración 50 Inhibidora , Simulación del Acoplamiento Molecular , Pruebas de Sensibilidad Parasitaria , Relación Estructura-ActividadRESUMEN
The title compound, C14H11NO4, exists in the solid phase in the zwitterionic form, 2-{[(4-carboxy-3-hydroxyphenyl)iminiumyl]methyl}phenolate, with the H atom from the phenol group on the 2-hydroxybenzylidene ring transferred to the imine N atom, resulting in a strong intramolecular N-HâââO hydrogen bond between the iminium H atom and the phenolate O atom, forming a six-membered hydrogen-bonded ring. In addition, there is an intramolecular O-HâââO hydrogen bond between the carboxylic acid group and the adjacent hydroxy group of the other ring, and an intermolecular C-HâââO contact involving the phenol group and the C-H group adjacent to the imine bond, connecting the molecules into a two-dimensional network in the (103) plane. π-π stacking interactions result in a three-dimensional network. This study is important because it provides crystallographic evidence, supported by IR data, for the iminium zwitterionic form of Schiff bases.
RESUMEN
Resveratrol has been extensively researched for its powerful antioxidant capacity and other biological effects. The number of patents involving this compound has been growing in recent years. However, the biggest problem associated with this molecule, a limited bioavailability due to its fast metabolism in the liver, has led to obtaining its analogues or derivatives. In this work, we selected patents which describe the application of the antioxidant activity of resveratrol and its analogues as food for the human segment.
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Antioxidantes/farmacología , Dieta , Suplementos Dietéticos , Patentes como Asunto , Extractos Vegetales/farmacología , Estilbenos/farmacología , Disponibilidad Biológica , Humanos , ResveratrolRESUMEN
In this work, we report the antileishmanial evaluation of twenty 7-chloro-4-quinolinyl hydrazone derivatives (1-20). Firstly, the compounds were tested against promastigotes of four different Leishmania species. After that, all derivatives were assayed against L. braziliensis amastigotes and murine macrophages. Furthermore, it was investigated whether the antiamastigote L. braziliensis effect of the compounds could be associated with nitric oxide production. Compounds 6 and 7 showed a strong leishmanicidal activity against intracellular parasite with IC50 in nanogram levels (30 and 20 ng/mL, respectively). Appreciable activity of three compounds tested can be considered an important finding for the rational design of new leads for antileishmanial compounds.
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Antiprotozoarios , Hidrazonas , Leishmania braziliensis/crecimiento & desarrollo , Leishmaniasis Cutánea/tratamiento farmacológico , Macrófagos Peritoneales/parasitología , Animales , Antiprotozoarios/síntesis química , Antiprotozoarios/química , Antiprotozoarios/farmacología , Humanos , Hidrazonas/síntesis química , Hidrazonas/química , Hidrazonas/farmacología , Leishmaniasis Cutánea/metabolismo , Leishmaniasis Cutánea/parasitología , Macrófagos Peritoneales/metabolismo , Ratones , Ratones Endogámicos BALB CRESUMEN
This paper describes the synthesis and in vitro biological activities of imidazolidine and hexahydropyrimidine derivatives against bacteria (Escherichia coli, Staphylococcus aureus and Mycobacterium tuberculosis) and Leishmania protozoa. Out of sixteen heterocyclic derivatives tested, none were cytotoxic against mammalian cells. The compounds showed significant bacterial effects and leishmanicidal activity. Compounds 4a and 4c were active against S. aureus and E. coli, respectively. Compounds 3a-3f, 4h and 4i presented promising results against M. tuberculosis, with MIC values ranging from 12.5 to 25.0 µg/mL, comparable to the "first and second line" drugs used to treat tuberculosis. Compounds 4a, 4c and 4e were active against L major. Three of them were structurally characterized by single-crystal X-ray diffraction.
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Antibacterianos/síntesis química , Antibacterianos/farmacología , Antiparasitarios , Bacterias/efectos de los fármacos , Imidazolidinas , Leishmania/efectos de los fármacos , Pirimidinas , Animales , Antibacterianos/química , Antiparasitarios/síntesis química , Antiparasitarios/química , Antiparasitarios/farmacología , Células Cultivadas , Cristalografía por Rayos X , Humanos , Imidazolidinas/síntesis química , Imidazolidinas/química , Imidazolidinas/farmacología , Ratones , Viabilidad Microbiana/efectos de los fármacos , Modelos Moleculares , Estructura Molecular , Mycobacterium tuberculosis/efectos de los fármacos , Pirimidinas/síntesis química , Pirimidinas/química , Pirimidinas/farmacologíaRESUMEN
The bioactivity guided fractionation of the dichloromethane extract of Mitracarpus frigidus afforded the pyranonaphthoquinone psychorubrin. This compound, hitherto unknown in the genus Mitracarpus, had its biological activity evaluated against one panel of bacteria and two fungi, three tumor cell lines (HL60, Jurkat and MCF-7) and four Leishmania species. Its identity was confirmed unambiguously by (1)H, (13)C, (1)H-COSY, IR and UV-Vis spectroscopy and mass spectrometry. Psychorubrin displayed a very promising antitumor with IC(50) of 4.5, 5.6 and 1.1 µM for HL60, Jurkat and MCF-7 cell lines, respectively. Antimicrobial activity, mainly against Cryptococcus neoformans (MIC of 87.3 µM) was observed. A pronounced antileishmanial potential was also verified with IC(50) varying from 1.7 to 2.7 µM for the Leishmania species tested. This is the first report of the presence of pyranonapthoquinones in the Mitracarpus genus, which may serve as a chemotaxonomical marker.
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Antibacterianos/farmacología , Antineoplásicos Fitogénicos/farmacología , Antiprotozoarios/farmacología , Naftoquinonas/farmacología , Rubiaceae/química , Antibacterianos/aislamiento & purificación , Antineoplásicos Fitogénicos/aislamiento & purificación , Antiprotozoarios/aislamiento & purificación , Línea Celular Tumoral , Bacterias Gramnegativas/efectos de los fármacos , Bacterias Grampositivas/efectos de los fármacos , Humanos , Concentración 50 Inhibidora , Leishmania/efectos de los fármacos , Pruebas de Sensibilidad Microbiana , Naftoquinonas/aislamiento & purificaciónRESUMEN
The Schiff base N,N'-bis(salicylidene)-o-phenylenediamine (salophen) was prepared by the condensation of salicylaldehyde with o-phenylenediamine in ethanol solution. The compound was characterized by elemental analysis, infrared (IR), (1)H, (13)C and (1)H(15)N HMBC nuclear magnetic resonance (NMR) spectroscopic measurements, and also by X-ray diffraction. The tautomerism of salophen was also studied by calculations using density functional theory (DFT). Two of the three tautomers were shown to coexist. A comparison of the DFT data of the three tautomers has shown that the most stable one is salophen 1, which is in accordance with experimental X-ray crystallographic data.