Luísa C. R. Carvalho

Developments Towards Regioselective Synthesis of 1,2‐Disubstituted Benzimidazoles

1,2-Disubstituted benzimidazoles play an important role in several areas and particularly as drug discovery targets. Herein, several methods to assemble these structures are reviewed, from the classical approaches to the more recently developed metal-catalyzed intramolecular amination process, the cascade arylamination/condensation reaction and polymer-supported benzimidazole assembly under microwave conditions.

Stereoselective glycosylation of glucosamine: the role of the N-protecting group.

Oligosaccharides and glycoconjugates play an important role in biological processes. The use of these complex polymers as biocompatible materials for medicinal applications as well as therapeutic agents for the treatment of several diseases has attracted considerable interest. However, these investigations require large and pure amounts of glycostructures. Glucosamine is one of the major building blocks of these highly important glycoconjugates. Recently, considerable synthetic efforts have been devoted to improving stereoselective glycosylation. In this Focus review, the role of the amine protecting group in the outcome of the glucosamine glycosylation reaction is highlighted.

Antioxidant activity of unexplored indole derivatives: synthesis and screening.

The present study envisaged the development of novel antioxidant candidates using the indole scaffold. Several tryptophan and tryptamine derivatives were synthesized, in particular prenylated indole compounds, and their scavenging activity for reactive oxygen species (ROS) and reactive nitrogen species (RNS) was investigated. The library substitution pattern included several alkyl chains at positions N-1, C-2 of the indole nucleus, including prenyl and isopentyl chain, as well as different groups at the side chain (C-3) that allowed the investigation of a possible radical stabilization. The results obtained showed that tryptophan (8), tryptamine (9), N-phthaloyl tryptamine (5) and N-prenyl tryptophan (13) were the most active against peroxyl radical (ROO(•)) with activities higher than Trolox, which was used as control. The scavenging of hypochlorous acid (HOCl) was also evaluated and tryptophan (8) and tryptamine (9) showed IC(50) of 3.50 ± 0.4 and 6.00 ± 0.60 μM, respectively. Significant activity was also found for the N-prenyl tryptophan (13) with an IC(50) of 4.13 ± 0.17 μM and C-2 prenylated derivative (14), with 4.56 ± 0.48 μM. The studies were extended to RNS and best results were obtained against peroxynitrite anion (ONOO(-)) in the presence of NaHCO(3). N-alkylated tryptophan (18) showed a high activity with an IC(50) of 14.0 ± 6.8 μM. The results show that the tested compounds are effective scavengers of ROS and RNS, and suggest that the radical stabilization is strongly dependent on the type of substituents on the indolic moiety and on their relative positions. In addition, the radical dissipation inside the indolic system is mandatory for the observed antioxidant activity.

Indole based cyclooxygenase inhibitors: synthesis, biological evaluation, docking and NMR screening.

The close structural similarity between the two cyclooxygenase (COXs) isoforms and the absence of selective inhibitors without side effects continues to stimulate the development of novel approaches towards selective anti-inflammatory drugs. In the present study a small library of new indolic compounds involving two different substitutions patterns at the indole scaffold was synthesized. In order to establish a relation between the spatial distribution of known functional groups related with inhibitory activity, two substitution patterns were explored: one with substituents at N-1, C-3, C-5 positions and another at C-2, C-3 and C5 positions. Accordingly, indole positions C-5, C-3 and N-1 were substituted with: sulfonamide or methylsulfone at C-5, p-halo-benzyl group at C-3, and an alkyl chain with a trifluoromethyl group at N-1. Alternatively, a p-halo-benzyl group was introduced at C-2, leaving the indolic nitrogen free. Inhibitory studies were performed and the activity results obtained against both COXs isoforms were rationalized based on docking and NMR studies. Docking studies show that dialkyation at C-2 and C-3 favors a binding with an orientation similar to that of the known selective inhibitor SC-558. From the tested compounds, this substitution pattern is correlated with the highest inhibitory activity and selectivity: 70% COX-2 inhibition at 50 μM, and low COX-1 inhibition (18 ± 9%). Additionally, Saturation Transfer Difference NMR experiments reveal different interaction patterns with both COXs isoforms that may be related with different orientations of the sulfonamide group in the binding pocket. Despite the moderated inhibitory activities found, this study represents an innovative approach towards COXs inhibitory activity rationalization and to the design of anti-inflammatory drugs.

Synthesis and evaluation of new benzimidazole- based COX inhibitors: a naproxen-like interaction detected by STD-NMR†

Non-steroidal anti-inflammatory drugs exert their pharmacological activity through inhibition of cyclooxygenase 1 and 2 (COX-1 and COX-2). Recent research suggests that a balanced inhibition of both COX-1 and COX-2 is the key to reduce the side-effects exhibited by COX inhibitors. We developed new benzimidazole-based compounds that showed a balanced COX inhibition, supported by molecular docking screening. The human whole blood assays demonstrated that the ester derivatives were potent inhibitors. Competitive saturation transfer difference (STD)-NMR experiments, in the presence of COX-2, using naproxen and diclofenac demonstrated that ester derivatives do not compete with diclofenac for the same binding site, but compete with the allosteric inhibitor naproxen. Combination of NMR spectroscopy with molecular docking has permitted us to detect a new naproxen-like inhibitor, which could be used for future drug development.

Selective Modification of Chitin and Chitosan: En Route to Tailored Oligosaccharides

Chitin and chitosan are attractive biopolymers with enormous structural possibilities for chemical modification, creating platforms for new chemical entities with a broad scope of applications, ranging from material science to medicine. During the last few years, incredible efforts have been dedicated to the regioselective modification of these biopolymers paving the way for improved properties and tailored activities. Herein, the most recent advances in chitin/chitosan regioselective modification, reaction conditions, selectivity, and the impact on its applications are highlighted. Moreover, the recent focus on chitooligosaccharides, their regioselective and chemoselective functionalization, as well as their role in biological studies, including molecular recognition with several biological targets are also covered.

A new insight on the hypochlorous acid scavenging mechanism of tryptamine and tryptophan derivatives.

The reaction mechanisms of hypochlorous acid (HOCl) with several tryptophan and tryptamine derivatives, previously reported to scavenge this powerful oxidant, was investigated to determine whether ionic or radical pathways were involved. For this purpose, the reaction of tryptamine and tryptophan derivatives with HOCl was optimized and some compounds were isolated by HPLC and their structures assigned. In order to prevent possible radical reaction pathway, experiments have been carried in the presence of the radical trap TEMPO (2,2,6,6-tetramethylpiperidine-1-oxyl). The obtained results show that the reaction mechanisms are influenced by the type of structure and that a complex pathway is involved, in which both ionic and radical mechanisms can occur.

Pd-catalysed amination on a soluble polymer support: arylation of anilines with PEG-supported aryl halides

PEG supported aryl halides were found to serve as substrates for the Pd-catalysed N-arylation of several substituted anilines and alkyl amines under solventless conditions. Moreover, the Pd2dba3/XPhos catalyst system enabled the coupling reactions to take place smoothly with excellent yields under a low catalyst loading (1 mol% Pd and 3 mol% ligand).