Carlos David Pessoa-Mahana

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. On the other hand, no effect of micelles was observed for orange juice and pulp fruit extracts. The ORAC (Oxygen Radical Absorbance Capacity) index was evaluated in the absence (ORAC-PGR) and presence of Triton X-100 micelles (ORAC-PGRMIC). Triton X-100 micelles affect ORAC-PGR values of antioxidants in a lipophilicity-dependent way. From the obtained results, we conclude that ORAC-PGR and ORAC-PGRMIC assays could be considered as an alternative to estimate the antioxidant ability (ORAC-PGR) and to infer the association to Triton X-100 micelles (ORAC-PGR/ORAC-PGRMIC) of pure antioxidants and their complex mixtures.

Docking and Quantitative Structure–Activity Relationship Studies for the Bisphenylbenzimidazole Family of Non-Nucleoside Inhibitors of HIV-1 Reverse Transcriptase

Molecular docking studies on a set of bisphenylbenzimidazole derivatives were conducted to identify the compounds binding orientations within the HIV‐1 reverse transcriptase non‐nucleoside binding pocket. A good correlation between the calculated binding free energies and the experimental inhibitory activities suggests that the identified binding conformations of these inhibitors are reliable. Based on obtained bisphenylbenzimidazoles binding conformations, a predictive quantitative structure–activity relationship model based on radial distribution function descriptors was developed. The obtained quantitative structure–activity relationship model was predictive according to internal and external validation experiments and might provide guidelines for the design of novel non‐nucleoside HIV‐1 reverse transcriptase inhibitors based on the 1‐benzyl‐2‐arylbenzimidazole scaffold.

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. Thus, 6-Arylbenzimidazo[1,2-c]quinazoline derivatives may have a potential as anti-inflammatory agents.

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 = 0.53 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).

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 = 7.87; 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.

Synthesis of 2‐Benzothienyl Carbonyl 4‐Arylpiperazines as Novel Delavirdine Analogs

Abstract A novel series of 2‐benzothienyl carbonyl arylpiperazines (6a–f) was synthesized as potential HIV nonnucleoside reverse transcriptase inhibitors (NNRTIs). Preparation of the derivatives was performed by reacting benzo[b]thiophene carbonyl chloride (5) with a series of substituted 4‐arylpiperazines.

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. However, the FDA (Food and Drug Administration) in USA and the MHRA (Medicines and Healthcare products Regulatory Agency) in UK have made reports of potentially life-threatening side effects associated with the administration of Mirabegron, casting doubts on the continuity of this compound. Therefore, it is of utmost importance to gather information for the rational design and synthesis of new β3 adrenergic ligands. Herein, we present the first combined 2D-QSAR (two-dimensional Quantitative Structure-Activity Relationship) and 3D-QSAR/CoMSIA (three-dimensional Quantitative Structure-Activity Relationship/Comparative Molecular Similarity Index Analysis) study on a series of potent β3 adrenergic agonists of indole-alkylamine structure. We found a series of changes that can be made in the steric, hydrogen-bond donor and acceptor, lipophilicity and molar refractivity properties of the compounds to generate new promising molecules. Finally, based on our analysis, a summary and a regiospecific description of the requirements for improving β3 adrenergic activity is given.

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. Compounds 3b, 4b, and 5b showed good binding affinities (Ki = 33.0, 48.0, and 17 nM, respectively). The other synthesized compounds showed moderate or no affinity in the binding studies.

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. On the basis of the results obtained, it was determined that the absorption of 2-pyridin-3-yl-1H-benzimidazole is better in solutions than in microemulsions. This is attributed to the system of microemulsions used (myristic isopropyl ester/water/Tween 80: Span 80: 1.2 Octanediol 3:1:1.2 v/v/v), which does not provide an adequate thermodynamic activity for this molecule. In contrast, the absorption of 2-pyridin-3-yl-1-(3,4,5-trimethoxybenzoyl)-1H-benzimidazole is independent of the vehicle in which it is in, a fact attributable to the limitation of absorption due to parameters proper to this molecule, such as the value of its Log Poct, its molecular weight, or its low solubility in water. In addition, it was possible to implement a methodology based on HPLC to determine the Log P of these compounds. In this way, it was determined that the inclusion of 3,4,5-trimethoxybenzoyl moiety to the molecule 2-pyridin-3-yl-1H-benzimidazole, despite increasing the Log Poct value of this molecule up to a value considered optimal for absorption through membranes, did not produce an increase in transdermal absorption. In fact, its molar absorption diminished by more than 50%, which is attributable to the increase of molecular weight and the decrease of affinity for water that the inclusion of this group causes.