RESUMEN

The endocannabinoid system (ECS) constitutes a broad-spectrum modulator of homeostasis in mammals, providing therapeutic opportunities for several pathologies. Its two main receptors, cannabinoid type 1 (CB1) and type 2 (CB2) receptors, mediate anti-inflammatory responses; however, their differing patterns of expression make the development of CB2-selective ligands therapeutically more attractive. The benzo[d]imidazole ring is considered to be a privileged scaffold in drug discovery and has demonstrated its versatility in the development of molecules with varied pharmacologic properties. On the other hand, the main psychoactive component of Cannabis sativa, delta-9-tetrahydrocannabinol (THC), can be structurally described as an aliphatic terpenoid motif fused to an aromatic polyphenolic (resorcinol) structure. Inspired by the structure of this phytocannabinoid, we combined different natural product motifs with a benzo[d]imidazole scaffold to obtain a new library of compounds targeting the CB2 receptor. Here, we synthesized 26 new compounds, out of which 15 presented CB2 binding and 3 showed potent agonist activity. SAR analysis indicated that the presence of bulky aliphatic or aromatic natural product motifs at position 2 of the benzo[d]imidazoles ring linked by an electronegative atom is essential for receptor recognition, while substituents with moderate bulkiness at position 1 of the heterocyclic core also participate in receptor recognition. Compounds 5, 6, and 16 were further characterized through in vitro cAMP functional assay, showing potent EC50 values between 20 and 3 nM, and compound 6 presented a significant difference between the EC50 of pharmacologic activity (3.36 nM) and IC50 of toxicity (30-38 µM).

Asunto(s)

Productos Biológicos , Cannabinoides , Animales , Agonistas de Receptores de Cannabinoides/farmacología , Productos Biológicos/farmacología , Cannabinoides/farmacología , Cannabinoides/química , Imidazoles , Receptor Cannabinoide CB2 , Receptor Cannabinoide CB1 , Relación Estructura-Actividad , Mamíferos

RESUMEN

Resistance to antibacterial agents is a growing global public health problem that reduces the efficacy of available antibacterial agents, leading to increased patient mortality and morbidity. Unfortunately, only 16 antibacterial drugs have been approved by the FDA in the last 10 years, so it is necessary to develop new agents with novel chemical structures and/or mechanisms of action. In response to this, our group takes up the challenge of designing a new family of pyrimidoisoquinolinquinones displaying antimicrobial activities against multidrug-resistant Gram-positive bacteria. Accordingly, the objective of this study was to establish the necessary structural requirements to obtain compounds with high antibacterial activity, along with the parameters controlling antibacterial activity. To achieve this goal, we designed a family of compounds using different strategies for drug design. Forty structural candidates were synthesized and characterized, and antibacterial assays were carried out against high-priority bacterial pathogens. A variety of structural properties were modified, such as hydrophobicity and chain length of functional groups attached to specific carbon positions of the quinone core. All the synthesized compounds inhibited Gram-positive pathogens in concentrations ranging from 0.5 to 64 µg/mL. Two derivatives exhibited minimum inhibitory concentrations of 64 µg/mL against Klebsiella pneumoniae, while compound 28 demonstrated higher potency against MRSA than vancomycin.

RESUMEN

The activation of the human cannabinoid receptor type II (CB2R) is known to mediate analgesic and anti-inflammatory processes without the central adverse effects related to cannabinoid receptor type I (CB1R). In this work we describe the synthesis and evaluation of a novel series of N-aryl-2-pyridone-3-carboxamide derivatives tested as human cannabinoid receptor type II (CB2R) agonists. Different cycloalkanes linked to the N-aryl pyridone by an amide group displayed CB2R agonist activity as determined by intracellular [cAMP] levels. The most promising compound 8d exhibited a non-toxic profile and similar potency (EC50 = 112 nM) to endogenous agonists Anandamide (AEA) and 2-Arachidonoylglycerol (2-AG) providing new information for the development of small molecules activating CB2R. Molecular docking studies showed a binding pose consistent with two structurally different agonists WIN-55212-2 and AM12033 and suggested structural requirements on the pyridone substituents that can satisfy the orthosteric pocket and induce an agonist response. Our results provide additional evidence to support the 2-pyridone ring as a suitable scaffold for the design of CB2R agonists and represent a starting point for further optimization and development of novel compounds for the treatment of pain and inflammation.

Asunto(s)

Agonistas de Receptores de Cannabinoides/química , Agonistas de Receptores de Cannabinoides/farmacología , Piridonas/química , Receptor Cannabinoide CB2/agonistas , Animales , Ácidos Araquidónicos/química , Ácidos Araquidónicos/farmacología , Benzoxazinas/química , Benzoxazinas/farmacología , Sitios de Unión , Células CHO , Agonistas de Receptores de Cannabinoides/síntesis química , Supervivencia Celular/efectos de los fármacos , Cricetulus , AMP Cíclico/metabolismo , Evaluación Preclínica de Medicamentos , Endocannabinoides/química , Endocannabinoides/farmacología , Glicéridos/química , Glicéridos/farmacología , Células HL-60 , Células Hep G2 , Humanos , Simulación del Acoplamiento Molecular , Morfolinas/química , Morfolinas/farmacología , Naftalenos/química , Naftalenos/farmacología , Alcamidas Poliinsaturadas/química , Alcamidas Poliinsaturadas/farmacología , Piridonas/farmacología , Receptor Cannabinoide CB2/química , Receptor Cannabinoide CB2/genética , Receptor Cannabinoide CB2/metabolismo , Relación Estructura-Actividad

RESUMEN

Platelets are the smallest blood cells, and their activation (platelet cohesion or aggregation) at sites of vascular injury is essential for thrombus formation. Since the use of antiplatelet therapy is an unsolved problem, there are now focused and innovative efforts to develop novel antiplatelet compounds. In this context, we assessed the antiplatelet effect of an acylhydroquinone series, synthesized by Fries rearrangement under microwave irradiation, evaluating the effect of diverse acyl chain lengths, their chlorinated derivatives, and their dimethylated derivatives both in the aromatic ring and also the effect of the introduction of a bromine atom at the terminus of the acyl chain. Findings from a primary screening of cytotoxic activity on platelets by lactate dehydrogenase assay identified 19 non-toxic compounds from the 27 acylhydroquinones evaluated. A large number of them showed IC50 values less than 10 µM acting against specific pathways of platelet aggregation. The highest activity was obtained with compound 38, it exhibited sub-micromolar IC50 of 0.98 ± 0.40, 1.10 ± 0.26, 3.98 ± 0.46, 6.79 ± 3.02 and 42.01 ± 3.48 µM against convulxin-, collagen-, TRAP-6-, PMA- and arachidonic acid-induced platelet aggregation, respectively. It also inhibited P-selectin and granulophysin expression. We demonstrated that the antiplatelet mechanism of compound 38 was through a decrease in a central target in human platelet activation as in mitochondrial function, and this could modulate a lower response of platelets to activating agonists. The results of this study show that the chemical space around ortho-carbonyl hydroquinone moiety is a rich source of biologically active compounds, signaling that the acylhydroquinone scaffold has a promising role in antiplatelet drug research.

Asunto(s)

Plaquetas/efectos de los fármacos , Hidroquinonas/química , Hidroquinonas/farmacología , Inhibidores de Agregación Plaquetaria/química , Inhibidores de Agregación Plaquetaria/farmacología , Plaquetas/fisiología , Humanos , Agregación Plaquetaria/efectos de los fármacos , Agregación Plaquetaria/fisiología , Relación Estructura-Actividad

RESUMEN

A series of 27 compounds of general structure 2,3-dihydro-benzo[1,4]oxazin-4-yl)-2-{4-[3-(1H-3indolyl)-propyl]-1-piperazinyl}-ethanamides, Series I: 7(a-o) and (2-{4-[3-(1H-3-indolyl)-propyl]-1-piperazinyl}-acetylamine)-N-(2-morfolin-4-yl-ethyl)-fluorinated benzamides Series II: 13(a-l) were synthesized and evaluated as novel multitarget ligands towards dopamine D2 receptor, serotonin transporter (SERT), and monoamine oxidase-A (MAO-A) directed to the management of major depressive disorder (MDD). All the assayed compounds showed affinity for SERT in the nanomolar range, with five of them displaying Ki values from 5 to 10 nM. Compounds 7k, Ki = 5.63 ± 0.82 nM, and 13c, Ki = 6.85 ± 0.19 nM, showed the highest potencies. The affinities for D2 ranged from micro to nanomolar, while MAO-A inhibition was more discrete. Nevertheless, compounds 7m and 7n showed affinities for the D2 receptor in the nanomolar range (7n: Ki = 307 ± 6 nM and 7m: Ki = 593 ± 62 nM). Compound 7n was the only derivative displaying comparable affinities for SERT and D2 receptor (D2/SERT ratio = 3.6) and could be considered as a multitarget lead for further optimization. In addition, docking studies aimed to rationalize the molecular interactions and binding modes of the designed compounds in the most relevant protein targets were carried out. Furthermore, in order to obtain information on the structure-activity relationship of the synthesized series, a 3-D-QSAR CoMFA and CoMSIA study was conducted and validated internally and externally (q2 = 0.625, 0.523 for CoMFA and CoMSIA and r2ncv = 0.967, 0.959 for CoMFA and CoMSIA, respectively).

Asunto(s)

Bioensayo/métodos , Receptores de Dopamina D2/metabolismo , Proteínas de Transporte de Serotonina en la Membrana Plasmática/metabolismo , Simulación del Acoplamiento Molecular , Relación Estructura-Actividad Cuantitativa , Receptores de Dopamina D2/genética , Proteínas de Transporte de Serotonina en la Membrana Plasmática/genética , Relación Estructura-Actividad

RESUMEN

During the last decade, the one drug-one target strategy has resulted to be inefficient in facing diseases with complex ethiology like Alzheimer's disease and many others. In this context, the multitarget paradigm has emerged as a promising strategy. Based on this consideration, we aim to develop novel molecules as promiscuous ligands acting in two or more targets at the same time. For such purpose, a new series of indolylpropyl-piperazinyl oxoethyl-benzamido piperazines were synthesized and evaluated as multitarget-directed drugs for the serotonin transporter (SERT) and acetylcholinesterase (AChE). The ability to decrease ß-amyloid levels as well as cell toxicity of all compounds were also measured. In vitro results showed that at least four compounds displayed promising activity against SERT and AChE. Compounds 18 and 19 (IC50 = 3.4 and 3.6 µM respectively) exhibited AChE inhibition profile in the same order of magnitude as donepezil (DPZ, IC50 = 2.17 µM), also displaying nanomolar affinity in SERT. Moreover, compounds 17 and 24 displayed high SERT affinities (IC50 = 9.2 and 1.9 nM respectively) similar to the antidepressant citalopram, and significant micromolar AChE activity at the same time. All the bioactive compounds showed a low toxicity profile in the range of concentrations studied. Molecular docking allowed us to rationalize the binding mode of the synthesized compounds in both targets. In addition, we also show that compounds 11 and 25 exhibit significant ß-amyloid lowering activity in a cell-based assay, 11 (50% inhibition, 10 µM) and 25 (35% inhibition, 10 µM). These results suggest that indolylpropyl benzamidopiperazines based compounds constitute promising leads for a multitargeted approach for Alzheimer's disease.

Asunto(s)

Acetilcolinesterasa/metabolismo , Enfermedad de Alzheimer/tratamiento farmacológico , Antidepresivos/síntesis química , Inhibidores de la Colinesterasa/síntesis química , Piperazinas/síntesis química , Inhibidores Selectivos de la Recaptación de Serotonina/síntesis química , Proteínas de Transporte de Serotonina en la Membrana Plasmática/metabolismo , Péptidos beta-Amiloides/metabolismo , Animales , Antidepresivos/farmacología , Línea Celular , Inhibidores de la Colinesterasa/farmacología , Donepezilo/química , Diseño de Fármacos , Humanos , Ratones , Simulación del Acoplamiento Molecular , Neuroblastoma , Piperazinas/farmacología , Conformación Proteica , Inhibidores Selectivos de la Recaptación de Serotonina/farmacología , Relación Estructura-Actividad

RESUMEN

Nicotinic acetylcholine receptors (nAChRs), serotonin transporters (SERT) and dopamine transporters (DAT) represent targets for the development of novel nicotinic derivatives acting as multiligands associated with different health conditions, such as depressive, anxiety and addiction disorders. In the present work, a series of functionalized esters structurally related to acetylcholine and nicotine were synthesized and pharmacologically assayed with respect to these targets. The synthesized compounds were studied in radioligand binding assays at α4ß2 nAChR, h-SERT and h-DAT. SERT experiments showed not radioligand [3H]-paroxetine displacement, but rather an increase in the radioligand binding percentage at the central binding site was observed. Compound 20 showed Ki values of 1.008 ± 0.230 µM for h-DAT and 0.031 ± 0.006 µM for α4ß2 nAChR, and [3H]-paroxetine binding of 191.50% in h-SERT displacement studies, being the only compound displaying triple affinity. Compound 21 displayed Ki values of 0.113 ± 0.037 µM for α4ß2 nAChR and 0.075 ± 0.009 µM for h-DAT acting as a dual ligand. Molecular docking studies on homology models of α4ß2 nAChR, h-DAT and h-SERT suggested potential interactions among the compounds and agonist binding site at the α4/ß2 subunit interfaces of α4ß2 nAChR, central binding site of h-DAT and allosteric modulator effect in h-SERT.

Asunto(s)

Acetilcolina/análogos & derivados , Proteínas de Transporte de Dopamina a través de la Membrana Plasmática/química , Nicotina/análogos & derivados , Receptores Nicotínicos/química , Proteínas de Transporte de Serotonina en la Membrana Plasmática/química , Acetilcolina/agonistas , Acetilcolina/síntesis química , Acetilcolina/química , Regulación Alostérica , Sitios de Unión , Dopamina/química , Agonistas de Dopamina/química , Proteínas de Transporte de Dopamina a través de la Membrana Plasmática/agonistas , Ésteres/química , Células HEK293 , Humanos , Ligandos , Simulación del Acoplamiento Molecular , Nicotina/agonistas , Nicotina/síntesis química , Nicotina/química , Agonistas Nicotínicos/química , Pirrolidinas/química , Ensayo de Unión Radioligante , Proteínas de Transporte de Serotonina en la Membrana Plasmática/agonistas , Relación Estructura-Actividad

RESUMEN

Neuronal α4ß2 nicotinic acetylcholine receptors (nAChRs) are ligand-gated ion channels (LGIC) that have been implicated in nicotine addiction, reward, cognition, pain disorders, anxiety, and depression. Nicotine has been widely used as a template for the synthesis of ligands that prefer α4ß2 nAChRs subtypes. The most important therapeutic use for α4ß2 nAChRs is as replacement therapy for smoking cessation and withdrawal and the most successful therapeutic ligands are partial agonists. In this case, we use the N-methylpyrrolidine moiety of nicotine to design and synthesize new α4ß2 nicotinic derivatives, coupling the pyrrolidine moiety to an aromatic group by introducing an ether-bonded functionality. Meta-substituted phenolic derivatives were used for these goals. Radioligand binding assays were performed on clonal cell lines of hα4ß2 nAChR and two electrode voltage-clamp experiments were used for functional assays. Molecular docking was performed in the open state of the nAChR in order to rationalize the agonist activity shown by our compounds.

Asunto(s)

Nicotina/química , Nicotina/farmacología , Agonistas Nicotínicos/química , Agonistas Nicotínicos/farmacología , Receptores Nicotínicos/química , Unión Competitiva , Relación Dosis-Respuesta a Droga , Humanos , Cinética , Conformación Molecular , Simulación del Acoplamiento Molecular , Simulación de Dinámica Molecular , Estructura Molecular , Nicotina/análogos & derivados , Unión Proteica , Relación Estructura-Actividad

RESUMEN

Highly malignant triple-negative breast cancer (TNBC) cells rely mostly on glycolysis to maintain cellular homeostasis; however, mitochondria are still required for migration and metastasis. Taking advantage of the metabolic flexibility of TNBC MDA-MB-231 cells to generate subpopulations with glycolytic or oxidative phenotypes, we screened phenolic compounds containing an ortho-carbonyl group with mitochondrial activity and identified a bromoalkyl-ester of hydroquinone named FR58P1a, as a mitochondrial metabolism-affecting compound that uncouples OXPHOS through a protonophoric mechanism. In contrast to well-known protonophore uncoupler FCCP, FR58P1a does not depolarize the plasma membrane and its effect on the mitochondrial membrane potential and bioenergetics is moderate suggesting a mild uncoupling of OXPHOS. FR58P1a activates AMPK in a Sirt1-dependent fashion. Although the activation of Sirt1/AMPK axis by FR58P1a has a cyto-protective role, selectively inhibits fibronectin-dependent adhesion and migration in TNBC cells but not in non-tumoral MCF10A cells by decreasing ß1-integrin at the cell surface. Prolonged exposure to FR58P1a triggers a metabolic reprograming in TNBC cells characterized by down-regulation of OXPHOS-related genes that promote cell survival but comprise their ability to migrate. Taken together, our results show that TNBC cell migration is susceptible to mitochondrial alterations induced by small molecules as FR58P1a, which may have therapeutic implications.

Asunto(s)

Antineoplásicos/farmacología , Movimiento Celular/efectos de los fármacos , Hidroquinonas/farmacología , Fosforilación Oxidativa/efectos de los fármacos , Transducción de Señal/efectos de los fármacos , Neoplasias de la Mama Triple Negativas/tratamiento farmacológico , Proteínas Quinasas Activadas por AMP/metabolismo , Animales , Línea Celular Tumoral , Metabolismo Energético/efectos de los fármacos , Femenino , Humanos , Hidroquinonas/química , Integrina beta1/metabolismo , Sirtuina 1/metabolismo , Neoplasias de la Mama Triple Negativas/metabolismo

RESUMEN

With the purpose of expanding the structural variety of chemical compounds available as pharmacological tools for the treatment of Alzheimer's disease, we synthesized and evaluated a novel series of indole-benzoxazinones (Family I) and benzoxazine-arylpiperazine derivatives (Family II) for potential human acetylcholinesterase (hAChE) inhibitory properties. The most active compounds 7a and 7d demonstrated effective inhibitory profiles with Ki values of 20.3 ± 0.9 µM and 20.2 ± 0.9 µM, respectively. Kinetic inhibition assays showed non-competitive inhibition of AChE by the tested compounds. According to our docking studies, the most active compounds from both series (Families I and II) showed a binding mode similar to donepezil and interact with the same residues.

Asunto(s)

Acetilcolinesterasa/efectos de los fármacos , Benzoxazinas/farmacología , Inhibidores de la Colinesterasa/farmacología , Piperazinas/farmacología , Acetilcolinesterasa/metabolismo , Enfermedad de Alzheimer/tratamiento farmacológico , Benzoxazinas/síntesis química , Benzoxazinas/química , Inhibidores de la Colinesterasa/síntesis química , Inhibidores de la Colinesterasa/química , Donepezilo , Diseño de Fármacos , Humanos , Indanos/farmacología , Simulación del Acoplamiento Molecular , Piperazinas/síntesis química , Piperazinas/química , Piperidinas/farmacología , Unión Proteica , Relación Estructura-Actividad

RESUMEN

A series of novel 3-indolylpropyl derivatives was synthesized and evaluated for their binding affinities at the serotonin-1A receptor subtype (5-HT1A R) and the 5-HT transporter (SERT). Compounds 11b and 14b exhibited the highest affinities at the 5-HT1A R (Ki = 43 and 56 nM), whereas compounds 11c and 14a were the most potent analogs at the SERT (Ki = 34 and 17 nM). On the other hand, compounds 14b and 11d showed potent activity at both targets, displaying a profile that makes them promising leads for the search for novel potent ligands with a dual mechanism of action. Molecular docking studies in all the compounds unveiled relevant drug-target interactions, which allowed rationalizing the observed affinities.

Asunto(s)

Indoles/síntesis química , Indoles/farmacología , Simulación del Acoplamiento Molecular , Receptor de Serotonina 5-HT1A/metabolismo , Serotoninérgicos/síntesis química , Serotoninérgicos/farmacología , Proteínas de Transporte de Serotonina en la Membrana Plasmática/metabolismo , Antidepresivos/síntesis química , Antidepresivos/farmacología , Relación Dosis-Respuesta a Droga , Humanos , Indoles/química , Estructura Molecular , Serotoninérgicos/química , Relación Estructura-Actividad

RESUMEN

Herein we report the design, synthesis, bioinformatic and biological studies of benzimidazole and benzothiophene derivatives as new cannabinoid receptor ligands. To test the hypothesis that the lack of a hydrogen bond interaction between benzimidazole and benzothiophene derivatives with Lys192 reduces their affinity for CB1 receptors (as we previously reported) and leads to CB2 selectivity, most of the tested compounds do not exhibit hydrogen bond acceptors. All compounds displayed mostly CB2 selectivity, although this was more pronounced in the benzimidazoles derivatives. Furthermore, docking assays revealed a ∏-cation interaction with Lys109 which could play a key role for the CB2 selectivity index. The series displayed low toxicity on five different cell lines. Derivative 8f presented the best binding profile (Ki = 0.08 µM), high selectivity index (KiCB1/KiCB2) and a low citoxicity. Interestingly, in cell viability experiments, using HL-60 cells (expressing exclusively CB2 receptors), all synthesised compounds were shown to be cytotoxic, suggesting that a CB2 agonist response may be involved.

Asunto(s)

Bencimidazoles/metabolismo , Bencimidazoles/farmacología , Simulación del Acoplamiento Molecular , Receptor Cannabinoide CB2/metabolismo , Tiofenos/metabolismo , Tiofenos/farmacología , Antineoplásicos/síntesis química , Antineoplásicos/química , Antineoplásicos/metabolismo , Antineoplásicos/farmacología , Bencimidazoles/síntesis química , Bencimidazoles/química , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Técnicas de Química Sintética , Diseño de Fármacos , Humanos , Unión Proteica , Conformación Proteica , Receptor Cannabinoide CB2/química , Tiofenos/síntesis química , Tiofenos/química

RESUMEN

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/química

RESUMEN

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 , Transfección

RESUMEN

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 Cuantitativa

RESUMEN

Tumor cells present a known metabolic reprogramming, which makes them more susceptible for a selective cellular death by modifying its mitochondrial bioenergetics. Anticancer action of the antioxidant 9,10-dihydroxy-4,4-dimethyl-5,8-dihydroanthracen-1(4H)-one (HQ) on mouse mammary adenocarcinoma TA3, and its multiresistant variant TA3-MTXR, were evaluated. HQ decreased the viability of both tumor cells, affecting slightly mammary epithelial cells. This hydroquinone blocked the electron flow through the NADH dehydrogenase (Complex I), leading to ADP-stimulated oxygen consumption inhibition, transmembrane potential dissipation and cellular ATP level decrease, without increasing ROS production. Duroquinol, an electron donor at CoQ level, reversed the decrease of cell viability induced by HQ. Additionally, HQ selectively induced G2/M-phase arrest. Taken together, our results suggest that the bioenergetic dysfunction provoked by HQ is implicated in its anticancer action.

Asunto(s)

Adenocarcinoma/tratamiento farmacológico , Antineoplásicos/farmacología , Metabolismo Energético/efectos de los fármacos , Puntos de Control de la Fase G2 del Ciclo Celular/efectos de los fármacos , Hidroquinonas/farmacología , Neoplasias Mamarias Animales/tratamiento farmacológico , Mitocondrias/efectos de los fármacos , Adenocarcinoma/metabolismo , Adenocarcinoma/patología , Animales , Antineoplásicos/química , Antineoplásicos/uso terapéutico , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Supervivencia Celular/fisiología , Metabolismo Energético/fisiología , Puntos de Control de la Fase G2 del Ciclo Celular/fisiología , Hidroquinonas/química , Hidroquinonas/uso terapéutico , Masculino , Neoplasias Mamarias Animales/metabolismo , Neoplasias Mamarias Animales/patología , Ratones , Mitocondrias/fisiología

RESUMEN

A series of 3-[3-(4-aryl-1-piperazinyl)-propyl]-1H-indole derivatives (12a-h) was synthesized and evaluated for binding affinity at the human 5-hydroxytryptamine(1A) receptor (5-HT(1A)R) compounds (12b) and (12h) showed the highest 5-HT(1A) receptor affinity (IC(50)=15 nM). Molecular docking studies with all the compounds in a homology model of 5-HT(1A) showed that the main interaction anchoring the ligand in the receptor was a charge-reinforced bond between the protonated nitrogen atom (N-4) of the piperazine ring and Aspartate(3.32).

Asunto(s)

Indoles/química , Piperazinas/química , Receptor de Serotonina 5-HT1A/química , Ácido Aspártico/química , Sitios de Unión , Simulación por Computador , Humanos , Indoles/síntesis química , Piperazina , Estructura Terciaria de Proteína , Receptor de Serotonina 5-HT1A/metabolismo , Relación Estructura-Actividad

RESUMEN

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 Electrospray

RESUMEN

This study describes the effect of novel 6-Arylbenzimidazo[1,2-c]quinazoline derivatives as tumor necrosis factor alpha (TNF-alpha) production inhibitors. The newly synthesized compounds were tested for their in vitro ability to inhibit the lipolysaccharide (LPS) induced TNF-alpha secretion in the human promyelocytic cell line HL-60. The compound 6-Phenyl-benzimidazo[1,2-c]quinazoline, coded as Gl, resulted as the most potent inhibitor and with no significant cytotoxic activity. Thus, 6-Arylbenzimidazo[1,2-c]quinazoline derivatives may have a potential as anti-inflammatory agents.

Asunto(s)

Antiinflamatorios/farmacología , Quinazolinas/farmacología , Factor de Necrosis Tumoral alfa/antagonistas & inhibidores , Antiinflamatorios/química , Células HL-60 , Humanos , Lipopolisacáridos/farmacología , Quinazolinas/química , ARN Mensajero/efectos de los fármacos , ARN Mensajero/metabolismo , Acetato de Tetradecanoilforbol/análogos & derivados , Acetato de Tetradecanoilforbol/farmacología , Factor de Necrosis Tumoral alfa/biosíntesis

RESUMEN

This study describes the effect of novel 6-Arylbenzimidazo [1,2-c] quinazoline derivatives as tumor necrosis factor alpha (TNF-á) production inhibitors. The newly synthesized compounds were tested for their in vitro ability to inhibit the lipolysaccharide (LPS) induced TNF-á secretion in the human promyelocytic cell line HL-60. The compound 6-Phenyl-benzimidazo [1,2-c] quinazoline, coded as Gl, resulted as the most potent inhibitor and with no significant cytotoxic activity. Thus, 6-Arylbenzimidazo [1,2-c] quinazoline derivatives may have a potential as anti-inflammatory agents.

Asunto(s)

Humanos , Antiinflamatorios/farmacología , Quinazolinas/farmacología , Factor de Necrosis Tumoral alfa/antagonistas & inhibidores , Antiinflamatorios/química , Lipopolisacáridos/farmacología , Quinazolinas/química , ARN Mensajero/efectos de los fármacos , ARN Mensajero/metabolismo , Acetato de Tetradecanoilforbol/análogos & derivados , Acetato de Tetradecanoilforbol/farmacología , Factor de Necrosis Tumoral alfa/biosíntesis