Motifs in Natural Products as Useful Scaffolds to Obtain Novel Benzo[]imidazole-Based Cannabinoid Type 2 (CB2) Receptor Agonists.

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[]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.

Synthesis, Docking, 3-D-Qsar, and Biological Assays of Novel Indole Derivatives Targeting Serotonin Transporter, Dopamine D2 Receptor, and Mao-A Enzyme: In the Pursuit for Potential Multitarget Directed Ligands.

A series of 27 compounds of general structure 2,3-dihydro-benzo[1,4]oxazin-4-yl)-2-{4-[3-(1-3indolyl)-propyl]-1-piperazinyl}-ethanamides, Series I: (-) and (2-{4-[3-(1-3-indolyl)-propyl]-1-piperazinyl}-acetylamine)--(2-morfolin-4-yl-ethyl)-fluorinated benzamides Series II: (-) were synthesized and evaluated as novel multitarget ligands towards dopamine D 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 i values from 5 to 10 nM. Compounds , i = 5.

Nitrofuran drugs beyond redox cycling: Evidence of Nitroreduction-independent cytotoxicity mechanism.

Nitrofurans (5-nitro-2-hydrazonylfuran as pharmacophore) are a group of widely used antimicrobial drugs but also associated to a variety of side effects. The molecular mechanisms that underlie the cytotoxic effects of nitrofuran drugs are not yet clearly understood. One-electron reduction of 5-nitro group by host enzymes and ROS production via redox cycling have been attributed as mechanisms of cell toxicity.

Synthesis, in vitro evaluation and molecular docking of a new class of indolylpropyl benzamidopiperazines as dual AChE and SERT ligands for Alzheimer's disease.

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.

Cannabidiol binding and negative allosteric modulation at the cannabinoid type 1 receptor in the presence of delta-9-tetrahydrocannabinol: An In Silico study.

Recent evidence has raised in discussion the possibility that cannabidiol can act as a negative allosteric modulator of the cannabinoid type 1 receptor. Here we have used computational methods to study the modulation exerted by cannabidiol on the effects of delta-9-tetrahydrocannabinol in the cannabinoid receptor type 1 and the possibility of direct receptor blockade. We propose a putative allosteric binding site that is located in the N-terminal region of receptor, partially overlapping the orthosteric binding site.

Three-Dimensional Quantitative Structure-Activity Relationships (3D-QSAR) on a Series of Piperazine-Carboxamides Fatty Acid Amide Hydrolase (FAAH) Inhibitors as a Useful Tool for the Design of New Cannabinoid Ligands.

Fatty Acid Amide Hydrolase (FAAH) is one of the main enzymes responsible for endocannabinoid metabolism. Inhibition of FAAH increases endogenous levels of fatty acid ethanolamides such as anandamide (AEA) and thus consitutes an indirect strategy that can be used to modulate endocannabinoid tone. In the present work, we present a three-dimensional quantitative structure-activity relationships/comparative molecular similarity indices analysis (3D-QSAR/CoMSIA) study on a series of 90 reported irreversible inhibitors of FAAH sharing a piperazine-carboxamide scaffold.

Synthesis and biological evaluation of potential acetylcholinesterase inhibitors based on a benzoxazine core.

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 K values of 20.3 ± 0.

2D-QSAR and 3D-QSAR/CoMSIA Studies on a Series of (R)-2-((2-(1H-Indol-2-yl)ethyl)amino)-1-Phenylethan-1-ol with Human β₃-Adrenergic Activity.

The β₃ adrenergic receptor is raising as an important drug target for the treatment of pathologies such as diabetes, obesity, depression, and cardiac diseases among others. Several attempts to obtain selective and high affinity ligands have been made. Currently, Mirabegron is the only available drug on the market that targets this receptor approved for the treatment of overactive bladder.

Effect of alpha lipoic acid on leukotriene A hydrolase.

Leukotriene A hydrolase is a soluble enzyme with epoxide hydrolase and aminopeptidase activities catalysing the conversion of leukotriene A to leukotriene B and the hydrolysis of the peptide proline-glycine-proline. Imbalances in leukotriene B synthesis are related to several pathologic conditions. Currently there are no available drugs capable to modulate the synthesis of leukotriene B or to block its receptors.

Synthesis and Docking of Novel 3-Indolylpropyl Derivatives as New Polypharmacological Agents Displaying Affinity for 5-HT R/SERT.

A series of novel 3-indolylpropyl derivatives was synthesized and evaluated for their binding affinities at the serotonin-1A receptor subtype (5-HT R) and the 5-HT transporter (SERT). Compounds 11b and 14b exhibited the highest affinities at the 5-HT R (K  = 43 and 56 nM), whereas compounds 11c and 14a were the most potent analogs at the SERT (K  = 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.

Synthesis, binding assays, cytotoxic activity and docking studies of benzimidazole and benzothiophene derivatives with selective affinity for the CB2 cannabinoid receptor.

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.

Extended N-Arylsulfonylindoles as 5-HT₆ Receptor Antagonists: Design, Synthesis & Biological Evaluation.

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.

Design, synthesis, biological evaluation and binding mode modeling of benzimidazole derivatives targeting the cannabinoid receptor type 1.

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.

Synthesis and biological screening of novel indolalkyl arenes targeting the serotonine transporter.

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.

Synthesis, docking and pharmacological evaluation of novel homo- and hetero-bis 3-piperazinylpropylindole derivatives at SERT and 5-HT1A receptor.

A series of 3-(3-(4-(3-(1H-indol-3-yl)propyl)piperazin-1-yl)propyl)-1H-indole derivatives (3a-d and 5a-f) as homo- and hetero-bis-ligands, were synthesized and evaluated for in vitro affinity at the serotonin transporter (SERT) and the 5-HT1A receptor. Compounds 5b and 5f showed nanomolar affinities for both targets. The experimental data were rationalized according to results obtained from docking experiments.

Design, synthesis, binding and docking-based 3D-QSAR studies of 2-pyridylbenzimidazoles--a new family of high affinity CB1 cannabinoid ligands.

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.

Synthesis, 5-hydroxytryptamine1A receptor affinity and docking studies of 3-[3-(4-aryl-1-piperazinyl)-propyl]-1H-indole derivatives.

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).

Synthesis, docking studies and biological evaluation of benzo[b]thiophen-2-yl-3-(4-arylpiperazin-1-yl)-propan-1-one derivatives on 5-HT1A serotonin receptors.

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.

Antioxidant capacity of pure compounds and complex mixtures evaluated by the ORAC-pyrogallol red assay in the presence of Triton X-100 micelles.

The protective effect of different antioxidants and complex mixtures on the consumption of pyrogallol red (PGR) induced by peroxyl radicals was studied in the absence and presence of Triton X-100 micelles. The presence of micelles decreased significantly the protection of PGR afforded by lipophilic antioxidants (β-carotene, octyl gallate), while no effect of micelles was observed for hydrophilic antioxidants such as Trolox, caffeic acid, gallic acid, and ascorbic acid. In the presence of complex mixtures a clear effect of Triton X-100 micelles was also observed in the protection afforded by wines, tea infusions, and seed extracts of Eugenia jambolana and Myrciaria cauliflora.

Biological evaluation of novel 6-Arylbenzimidazo[1,2-c]quinazoline derivatives as inhibitors of LPS-induced TNF-alpha secretion.

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.

Influence of lipophilia and of the vehicle used in the transdermal absorption of novel benzimidazole compounds with possible anti-HIV activity.

The molecules 2-pyridin-3-yl-1H-benzimidazole and 2-pyridin-3-yl-1-(3,4,5-trimethoxybenzoyl)-1H-benzimidazole are compounds that have been synthesized with the aim of finding new inhibitors of the reverse transcriptase enzyme, which is key in the process of cellular contagion of HIV. Because of the possible biological activity of these molecules, it is important to determine if some factors exist that condition their absorption across membranes. In this article, we studied the transdermal absorption of both molecules when included in solutions and microemulsions; the latter of these systems is known for their capacity to promote absorption.

Computational modeling study of functional microdomains in cannabinoid receptor type 1.

The seven transmembrane helices (TMH) G-protein-coupled receptors (GPCRs) constitute one of the largest superfamily of signaling proteins found in mammals. Some of its members, in which the cannabinoid (CB) receptors are included, stand out because their functional states can be modulated by a broad spectrum of effector molecules. The relative ligand promiscuity exhibited by these receptors could be related with particular attributes conferred by their molecular architecture and represents a motivating issue to be explored.