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.

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.

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.

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).

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.