RESUMEN
Herein we report an expeditive C-3 vinylation of unprotected 3-iodoindazoles under microwave irradiation. Ten C-5 substituted 3-vinylindazole derivatives, nine of them novel, were synthesized through this method, which proceeds in moderate to excellent yields starting from C-5 substituted 3-iodoindazole derivatives. In all cases, the C-3 vinylated derivative was the only isolated product. This methodology allows access to 3-vinylated indazoles selectively and directly without the need of N-protection. 3-Vinylindazoles could be interesting synthetic intermediates allowing access to biologically active molecules.
Asunto(s)
Ácidos Borónicos/química , Indazoles/química , Yodo/química , Microondas , Compuestos de Vinilo/química , Catálisis , Glicoles/química , Estructura Molecular , Oxidación-ReducciónRESUMEN
The wide tissue distribution of the adrenergic ß3 receptor makes it a potential target for the treatment of multiple pathologies such as diabetes, obesity, depression, overactive bladder (OAB), and cancer. Currently, there is only one drug on the market, mirabegron, approved for the treatment of OAB. In the present study, we have carried out an extensive structure-activity relationship analysis of a series of 41 aryloxypropanolamine compounds based on three-dimensional quantitative structure-activity relationship (3D-QSAR) techniques. This is the first combined comparative molecular field analysis (CoMFA) and comparative molecular similarity index analysis (CoMSIA) study in a series of selective aryloxypropanolamines displaying anti-diabetes and anti-obesity pharmacological profiles. The best CoMFA and CoMSIA models presented values of r²ncv = 0.993 and 0.984 and values of r²test = 0.865 and 0.918, respectively. The results obtained were subjected to extensive external validation (q², r², r²m, etc.) and a final series of compounds was designed and their biological activity was predicted (best pEC50 = 8.561).
Asunto(s)
Agonistas de Receptores Adrenérgicos beta 3/química , Fármacos Antiobesidad/química , Hipoglucemiantes/química , Propanolaminas/química , Agonistas de Receptores Adrenérgicos beta 3/farmacología , Fármacos Antiobesidad/farmacología , Sitios de Unión , Diseño de Fármacos , Humanos , Hipoglucemiantes/farmacología , Modelos Moleculares , Estructura Molecular , Propanolaminas/farmacología , Relación Estructura-Actividad Cuantitativa , Electricidad EstáticaRESUMEN
A rapid emergence of resistant bacteria is occurring worldwide, endangering the efficacy of antibiotics and reducing the therapeutic arsenal available for treatment of infectious diseases. In the present study, we developed a new class of compounds with antibacterial activity obtained by a simple, two step synthesis and screened the products for in vitro antibacterial activity against ATCC® strains using the broth microdilution method. The compounds exhibited minimum inhibitory concentrations (MIC) of 1â»32 µg/mL against Gram-positive ATCC® strains. The structureâ»activity relationship indicated that the thiophenol ring is essential for antibacterial activity and the substituents on the thiophenol ring module, for antibacterial activity. The most promising compounds detected by screening were tested against methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant Enterococcus faecium (VREF) clinical isolates. We found remarkable activity against VREF for compounds 7 and 16, were the MIC50/90 were 2/4 µg/mL and 4/4 µg/mL, respectively, while for vancomycin the MIC50/90 was 256/512 µg/mL. Neither compound affected cell viability in any of the mammalian cell lines at any of the concentrations tested. These in vitro data show that compounds 7 and 16 have an interesting potential to be developed as new antibacterial drugs against infections caused by VREF.
Asunto(s)
Antibacterianos/química , Antibacterianos/farmacología , Farmacorresistencia Bacteriana Múltiple/efectos de los fármacos , Enterococcus faecium/efectos de los fármacos , Staphylococcus aureus/efectos de los fármacos , Antibacterianos/síntesis química , Fenómenos Químicos , Humanos , Pruebas de Sensibilidad Microbiana , Modelos Moleculares , Estructura Molecular , Relación Estructura-Actividad , Difracción de Rayos XRESUMEN
Several bacteria use the plant hormone indole-3-acetic acid (IAA) as a sole carbon and energy source. A cluster of genes (named iac) encoding IAA degradation has been reported in Pseudomonas putida 1290, but the functions of these genes are not completely understood. The plant-growth-promoting rhizobacterium Paraburkholderia phytofirmans PsJN harbors iac gene homologues in its genome, but with a different gene organization and context than those of P. putida 1290. The iac gene functions enable P. phytofirmans to use IAA as a sole carbon and energy source. Employing a heterologous expression system approach, P. phytofirmans iac genes with previously undescribed functions were associated with specific biochemical steps. In addition, two uncharacterized genes, previously unreported in P. putida and found to be related to major facilitator and tautomerase superfamilies, are involved in removal of an IAA metabolite called dioxindole-3-acetate. Similar to the case in strain 1290, IAA degradation proceeds through catechol as intermediate, which is subsequently degraded by ortho-ring cleavage. A putative two-component regulatory system and a LysR-type regulator, which apparently respond to IAA and dioxindole-3-acetate, respectively, are involved in iac gene regulation in P. phytofirmans These results provide new insights about unknown gene functions and complex regulatory mechanisms in IAA bacterial catabolism. IMPORTANCE: This study describes indole-3-acetic acid (auxin phytohormone) degradation in the well-known betaproteobacterium P. phytofirmans PsJN and comprises a complete description of genes, some of them with previously unreported functions, and the general basis of their gene regulation. This work contributes to the understanding of how beneficial bacteria interact with plants, helping them to grow and/or to resist environmental stresses, through a complex set of molecular signals, in this case through degradation of a highly relevant plant hormone.
Asunto(s)
Proteínas Bacterianas/genética , Burkholderiaceae/genética , Burkholderiaceae/metabolismo , Regulación Bacteriana de la Expresión Génica , Ácidos Indolacéticos/metabolismo , Reguladores del Crecimiento de las Plantas/metabolismo , Proteínas Bacterianas/metabolismo , Burkholderiaceae/fisiología , Genes Bacterianos , Desarrollo de la Planta , Reguladores del Crecimiento de las Plantas/química , Pseudomonas putida/genética , Pseudomonas putida/metabolismo , Estrés Fisiológico/genéticaRESUMEN
Based on a known pharmacophore model for 5-HT6 receptor antagonists, a series of novel extended derivatives of the N-arylsulfonyindole scaffold were designed and identified as a new class of 5-HT6 receptor modulators. Eight of the compounds exhibited moderate to high binding affinities and displayed antagonist profile in 5-HT6 receptor functional assays. Compounds 2-(4-(2-methoxyphenyl)piperazin-1-yl)-1-(1-tosyl-1H-indol-3-yl)ethanol (4b), 1-(1-(4-iodophenylsulfonyl)-1H-indol-3-yl)-2-(4-(2-methoxyphenyl)piperazin-1-yl)ethanol (4g) and 2-(4-(2-methoxyphenyl)piperazin-1-yl)-1-(1-(naphthalen-1-ylsulfonyl)-1H-indol-3-yl)ethanol (4j) showed the best binding affinity (4b pKi = 7.87; 4g pKi = 7.73; 4j pKi = 7.83). Additionally, compound 4j was identified as a highly potent antagonist (IC50 = 32 nM) in calcium mobilisation functional assay.
Asunto(s)
Arilsulfonatos/química , Indoles/síntesis química , Receptores de Serotonina/metabolismo , Antagonistas de la Serotonina/síntesis química , Sitios de Unión , Humanos , Indoles/química , Indoles/farmacología , Modelos Moleculares , Estructura Molecular , Unión Proteica , Receptores de Serotonina/química , Antagonistas de la Serotonina/química , Antagonistas de la Serotonina/farmacología , Relación Estructura-ActividadRESUMEN
A series of N-acyl-2,5-dimethoxyphenyl-1H-benzimidazoles were designed based on a CoMFA model for cannabinoid receptor type 1 (CB1) ligands. Compounds were synthesized and radioligand binding affinity assays were performed. Eight novel benzimidazoles exhibited affinity for the CB1 receptor in the nanomolar range, and the most promising derivative compound 5 displayed a K(i) value of 1.2 nM when compared to CP55,940. These results confirm our previously reported QSAR model on benzimidazole derivatives, providing new information for the development of small molecules with high CB1 affinity.
Asunto(s)
Bencimidazoles/síntesis química , Bencimidazoles/metabolismo , Agonistas de Receptores de Cannabinoides/síntesis química , Agonistas de Receptores de Cannabinoides/metabolismo , Diseño de Fármacos , Receptor Cannabinoide CB1/metabolismo , Bencimidazoles/farmacología , Sitios de Unión , Unión Competitiva , Agonistas de Receptores de Cannabinoides/farmacología , Diseño Asistido por Computadora , Ciclohexanoles/metabolismo , Ligandos , Simulación del Acoplamiento Molecular , Estructura Molecular , Unión Proteica , Conformación Proteica , Relación Estructura-Actividad Cuantitativa , Receptor Cannabinoide CB1/agonistas , Receptor Cannabinoide CB1/químicaRESUMEN
A series of functionalized indolylalkylarenes 3-16(a and b) were synthesized and their affinities for the serotonin transporter were investigated in vitro. Compounds 3-12(a and b) were obtained by nucleophilic substitution of 3-(1H-indol-3-yl)propyl-4-methylbenzenesulfonates 2(a and b) with a series of azaheterocycles. Compounds 14-16(a and b) were prepared in a two-step sequence by reaction of 3-(1H-indol-3-yl)-2-methylpropanal with substituted 1,2-phenylenediamines. Compounds 3b, 4b, and 5b showed good binding affinities (K(i) = 33.0, 48.0, and 17 nM, respectively). The other synthesized compounds showed moderate or no affinity in the binding studies.
Asunto(s)
Indoles/síntesis química , Indoles/metabolismo , Inhibidores Selectivos de la Recaptación de Serotonina/síntesis química , Inhibidores Selectivos de la Recaptación de Serotonina/metabolismo , Proteínas de Transporte de Serotonina en la Membrana Plasmática/metabolismo , Células HEK293 , Humanos , Indoles/farmacología , Estructura Molecular , Proteínas de Transporte de Serotonina en la Membrana Plasmática/efectos de los fármacos , Proteínas de Transporte de Serotonina en la Membrana Plasmática/genética , Inhibidores Selectivos de la Recaptación de Serotonina/farmacología , Relación Estructura-Actividad , TransfecciónRESUMEN
A series of novel 2-pyridylbenzimidazole derivatives was rationally designed and synthesized based on our previous studies on benzimidazole 14, a CB1 agonist used as a template for optimization. In the present series, 21 compounds displayed high affinities with Ki values in the nanomolar range. JM-39 (compound 39) was the most active of the series (KiCB1 = 0.53 nM), while compounds 31 and 44 exhibited similar affinities to WIN 55212-2. CoMFA analysis was performed based on the biological data obtained and resulted in a statistically significant CoMFA model with high predictive value (q2 = 0.710, r2 = 0.998, r2pred = 0.823).
Asunto(s)
Bencimidazoles/síntesis química , Bencimidazoles/farmacología , Cannabinoides/química , Receptor Cannabinoide CB1/metabolismo , Benzoxazinas/química , Humanos , Ligandos , Modelos Biológicos , Morfolinas/química , Naftalenos/química , Conformación Proteica , Relación Estructura-Actividad CuantitativaRESUMEN
A series of novel benzo[b]thiophen-2-yl-3-(4-arylpiperazin-1-yl)-propan-1-one derivatives 6a-f, 7a-f and their corresponding alcohols 8a-f were synthesized and evaluated for their affinity towards 5-HT(1A) receptors. The influence of arylpiperazine moiety and benzo[b]thiophene ring substitutions on binding affinity was studied. The most promising analogue, 1-(benzo[b]thiophen-2-yl)-3-(4-(pyridin-2-yl)piperazin-1-yl)propan-1-one (7e) displayed micromolar affinity (K(i) = 2.30 µM) toward 5-HT(1A) sites. Docking studies shed light on the relevant electrostatic interactions which could explain the observed affinity for this compound.
Asunto(s)
Piperazinas/síntesis química , Piperazinas/farmacología , Receptor de Serotonina 5-HT1A/efectos de los fármacos , Espectroscopía de Resonancia Magnética , Modelos Moleculares , Piperazinas/química , Espectrometría de Masa por Ionización de ElectrosprayRESUMEN
A new series of twenty-two C-5 substituted N-arylsulfonylindoles was prepared with the aim of exploring the influence of C-5 substitution on 5-HT6 receptor affinity. Eleven compounds showed moderate to high affinity at the receptor (Ki = 58-403 nM), with compound 4d being identified as the most potent ligand. However, regarding C-5 substitution, both methoxy and fluorine were detrimental for receptor affinity compared to our previously published unsubstituted compounds. In order to shed light on these observations, we performed docking and molecular dynamics simulations with the most potent compounds of each series (4d and 4l) and PUC-10, a highly active ligand previously reported by our group. The comparison brings about deeper insight about the influence of the C-5 substitution on the binding mode of the ligands, suggesting that these replacements are detrimental to the affinity due to precluding a ligand from reaching deeper inside the binding site. Additionally, CoMFA/CoMSIA studies were performed to systematize the information of the main structural and physicochemical characteristics of the ligands, which are responsible for their biological activity. The CoMFA and CoMSIA models presented high values of q2 (0.653; 0.692) and r2 (0.879; 0.970), respectively. Although the biological activity of the ligands can be explained in terms of the steric and electronic properties, it depends mainly on the electronic nature.
RESUMEN
Bradyrhizobium japonicum E109 is a bacterium widely used for inoculants production in Argentina. It is known for its ability to produce several phytohormones and degrade indole-3-acetic acid (IAA). The genome sequence of B. japonicum E109 was recently analyzed and it showed the presence of genes related to the synthesis of IAA by indole-3-acetonitrile, indole-3-acetamide and tryptamine pathways. Nevertheless, B. japonicum E109 is not able to produce IAA and instead has the ability to degrade this hormone under saprophytic culture conditions. This work aimed to study the molecular and physiological features of IAA degradation and identify the genes responsible of this activity. In B. japonicum E109 we identified two sequences coding for a putative 3-phenylpropionate dioxygenase (subunits α and ß) responsible for the IAA degradation that were homologous to the canonical cluster of iacC and iacD of Pseudomonas putida 1290. These genes form a separate cluster together with three additional genes with unknown functions. The degradation activity was found to be constitutively expressed in B. japonicum E109. As products of IAA degradation, we identified two compounds, 3-indoleacetic acid 2,3-oxide and 2-(2-hydroperoxy-3-hydroxyindolin-3-yl) acetic acid. Our report proposes, for the first time, a model for IAA degradation in Bradyrhizobium.
Asunto(s)
Bradyrhizobium/genética , Bradyrhizobium/metabolismo , Ácidos Indolacéticos/metabolismo , Redes y Vías Metabólicas/genética , Indoles/metabolismo , Triptaminas/metabolismoRESUMEN
Opioids are arguably one of the most important pharmacologic classes, mainly due to their rich history, their useful and potent analgesic effects, and also, just as importantly, their "Dark Side", constituted by their reinforcing properties that have led countless of users to a spiral of addiction, biological dependence, tolerance, withdrawal syndromes, and death. Among the most significant abused and addictive known opioids are heroin and desomorphine, both synthetic derivatives of morphine that belong to the 4,5-epoxymorphinan structural chemical group of the opioid family drugs. These agents share not only structural, pharmacological, and epidemiological features but also a common geographical distribution. A drop in Afghan heroin production and its "exports" to Russia gave rise to widespread consumption of desomorphine in ex-Soviet republics during the first decade of the 21st century, representing an economical and accessible alternative for misusers to this sort of derivative. Herein we review the state of the art of history, chemistry and synthesis, pharmacology, and impact on society of these "cursed cousins".