José G. Trujillo-Ferrara

Boron-containing compounds: chemico-biological properties and expanding medicinal potential in prevention, diagnosis and therapy

Introduction: Although the medicinal use of boron-containing compounds (BCCs) had long been limited to antiseptics, in the last few decades, these compounds have been used as antibiotics or chemotherapeutic agents. In the last few years, boron has been included in the moieties of many known drugs to improve their capacity in binding to their respective target receptors. Areas covered: The current review focuses on research and patent literature of the last decade related to the development of BCCs as preventive, diagnostic and therapeutic tools. It explores the possible mechanisms of action of these compounds as well as the advantageous features of their structure and chemico-pharmacological properties. Expert opinion: Although uncertainties exist about the mechanism of action of BCCs, increasing evidence about their toxicological profile strongly suggests that many can be safely administered to humans. Even stronger evidence exists regarding the capacity of BCCs to reach multiple targets that are involved in the treatment of common diseases. It seems fair to say that some BCCs will reach the market for medicinal use in the near future, not only for targeting microbial or neoplastic systems but also for acting on cell-signaling processes involved in many other disorders.

Synthesis, anticholinesterase activity and structure-activity relationships of m-Aminobenzoic acid derivatives.

The synthesis, acetylcholinesterase inhibitory capacity and structure-activity relationships of simple-structured m-Aminobenzoic acid derivatives are reported. Compound 1b was found to be more potent than galanthamine and tacrine in inhibiting acetylcholinesterase.

Boron-containing acids: preliminary evaluation of acute toxicity and access to the brain determined by Raman scattering spectroscopy.

Boron-containing compounds (BCCs), particularly boron containing acids (BCAs), have become attractive moieties or molecules in drug development. It has been suggested that when functional groups with boron atoms are added to well-known drugs, the latter are conferred with greater potency and efficacy in relation to their target receptors. However, the use of BCAs in drug development is limited due to the lack of a toxicological profile. Consequently, the aim of the present study was to evaluate the acute toxicity of boric and boronic acids. Thus, a determination was made of the lethal dose (LD50) of test compounds in male CD1 mice, as well as the effective dose required to negatively affect spontaneous motor activity and to produce notable behavioral abnormalities. After treatment of animals at different doses, macroscopic observations were made from a necropsy, and Raman scattering spectroscopic studies were carried out on brain tissue samples. In general, the results show that most of the tested BCAs have very low toxicity, evidenced by the high doses required to induce notable toxic effects (greater than 100 mg/kg of body weight for all compounds, except for 3-thyenilboronic acid). Such toxic effects, presumably mediated by action on the CNS, include eye damage, gastrointestinal effects (e.g., gastric-gut dilatation and fecal retention), sedation, hypnosis and/or trembling. This preliminary toxicological profile suggests that BCAs can be considered potential therapeutic agents or moieties to be added to other compounds in the development of new drugs. Future studies are required to explore possible chronic toxicity of BCCs.

Recent structural advances of β1 and β2 adrenoceptors yield keys for ligand recognition and drug design.

Because they represent attractive drug targets, adrenoceptors have been widely studied. Recent progress in structural data of β-adrenoceptors allows us to understand and predict key interactions in ligand recognition and receptor activation. Nevertheless, an important aspect of this process has only begun to be explored: the stabilization of a conformational state of these receptors upon contact with a ligand and the capacity of a ligand to influence receptor conformation through allosteric modulation, biased signaling, and selectivity. The aim of the present Perspective is to identify the well-defined orthosteric binding site and possible allosteric sites and to analyze the importance of the ligand-receptor interaction in the stabilization of certain receptor conformations. For this purpose, we have reviewed recent advances made through the use of X-ray data from ligand-β-adrenoceptor (including ADRB1 and ADRB2) crystal structures. Most importantly, implications in the medicinal chemistry field are explored in relation to drug design.

Reversible and irreversible inhibitory activity of succinic and maleic acid derivatives on acetylcholinesterase

Aryl succinic and maleic acid derivatives are potent inhibitors of bovine acetylcholinesterase in vitro. Succinic acid aminophenol derivatives 1b-e and 2b-d act as reversible inhibitors of acetylcholinesterase, while maleic acid aminophenol derivatives 3b-d and 4c-e act as choline subsite-directed irreversible inhibitors, detected by dialysis in the presence of edrophonium. Linear relationships between the logarithm of the velocity of hydrolysis of acetylcholine plotted against the time of incubation at several different inhibitor concentrations were determined. The K(i) for reversible competitive inhibitors was determined. For irreversible inhibitors the K(i) for the dissociation constant of the enzyme-inhibitor complex at the beginning of the recognition process was also determined as well as the inactivation constant of the enzyme-inhibitor adduct formation k(+2) and the bimolecular inhibition constant k(i) for the inhibition of acetylcholinesterase by aminophenol derivatives 3b-d and 4c-e. The conclusions of this study can be summarized as follows for both families: (a) the aromatic moiety played a critical role in the recognition of the active site; (b) in case of the reversible inhibitor, when the ester function took the place of the hydroxyl fragment, there was an important increase in the affinity; and (c) the distance between phenolic hydroxyl and nitrogen was critical because the inhibition is ortho<<meta

Exploration of the valproic acid binding site on histone deacetylase 8 using docking and molecular dynamic simulations

Epigenetic therapy is an important focus of research for drug development in the treatment of cancer. Valproic acid (VPA) is an HDAC inhibitor that has been evaluated in clinical studies. Despite its success in treating cancer, the mechanism of inhibition of VPA in HDAC is unknown. To this end, we have used docking and molecular dynamic simulations to investigate VPA binding to HDAC, employing both native and rebuilt 3-D structures. The results showed that VPA, via its carboxyl group, coordinates the Zn atom and other local residues (H141-142 and Y360) located at the catalytic site (CS) of HDAC. This causes electrostatic and hydrogen bonding interactions while having little interaction with the hydrophobic side chains, resulting in a low affinity. However, after several docking studies on different native HDAC 3-D structures and after using several snapshots from MD simulations, it became apparent that VPA bound with highest affinity at a site located at the acetyl-releasing channel, termed the hydrophobic active site channel (HASC). The affinity of VPA for HASC was due to its highly hydrophobic properties that allow VPA to take part in van der Waals interactions with Y18, I19, Y20, V25, R37, A38, V41, H42, I135 and W137, while VPA’s carboxylate group has several hydrogen bonding interactions with the backbones of S138, I19, N136 and W137. MD simulations showed that the HASC door continuously opened and closed, which affected the affinity of VPA to the HASC, but the affinity toward the HASC was consistently higher than that obtained for the CS, suggesting that the HASC could be involved in the mechanism of inhibition.

Synthesis, pharmacological and in silico evaluation of 1-(4-di-hydroxy-3,5-dioxa-4-borabicyclo[4.4.0]deca-7,9,11-trien-9-yl)-2-(tert-butylamino)ethanol, a compound designed to act as a β2 adrenoceptor agonist

In this study, 1-(4-di-hydroxy-3,5-dioxa-4-borabicyclo[4.4.0]deca-7,9,11-trien-9-yl)-2-(tert-butylamino)ethanol, (BR-AEA), was designed, synthesized, characterized and tested in docking studies and in vitro. Previous to its synthesis, a set of compounds, including well-known ligands and boron containing compounds, were studied under docking simulations. BR-AEA showed greater affinity than these well-known agonists and was found to be slightly closer than salbutamol to the residues in the TM5 and TM3 of the beta(2) adrenoceptor (beta(2)AR), making a greater number of interactions with them, including some that are apparently key to greater affinity and beta(2)AR activation. This study suggests that affinity is closely related to the interactions of the boron atom, as well as the capacity of boronic acid moieties to make a network of hydrogen bonds with the beta(2)AR. In vitro, the relaxing effects of BR-AEA on isolated guinea pig tracheal rings were compared with salbutamol. The EC(50) values for BR-AEA were at least five-fold lower than for salbutamol, showing the greater potency of the former. Additionally, propranolol and ICI 118,551 showed competitive antagonism in relation to the relaxing effect of the test compound (pA(2) 6.204+/-0.367 and 9.089+/-0.470, respectively).

Identification of the antiepileptic racetam binding site in the synaptic vesicle protein 2A by molecular dynamics and docking simulations

Synaptic vesicle protein 2A (SV2A) is an integral membrane protein necessary for the proper function of the central nervous system and is associated to the physiopathology of epilepsy. SV2A is the molecular target of the anti-epileptic drug levetiracetam and its racetam analogs. The racetam binding site in SV2A and the non-covalent interactions between racetams and SV2A are currently unknown; therefore, an in silico study was performed to explore these issues. Since SV2A has not been structurally characterized with X-ray crystallography or nuclear magnetic resonance, a three-dimensional (3D) model was built. The model was refined by performing a molecular dynamics simulation (MDS) and the interactions of SV2A with the racetams were determined by docking studies. A reliable 3D model of SV2A was obtained; it reached structural equilibrium during the last 15 ns of the MDS (50 ns) with remaining structural motions in the N-terminus and long cytoplasmic loop. The docking studies revealed that hydrophobic interactions and hydrogen bonds participate importantly in ligand recognition within the binding site. Residues T456, S665, W666, D670 and L689 were important for racetam binding within the trans-membrane hydrophilic core of SV2A. Identifying the racetam binding site within SV2A should facilitate the synthesis of suitable radio-ligands to study treatment response and possibly epilepsy progression.

Design, synthesis and in vitro evaluation of (R)-4-(2-(tert-butylamino)-1-hydroxyethyl)-2-(hydroxymethyl)phenyl hydrogen phenylboronate: A novel salbutamol derivative with high intrinsic efficacy on the β2 adrenoceptor

We tested a set of boron containing arylethanolamine derivatives on the human and guinea pig β(2) adrenoceptor (β(2)AR) 3-D structures by docking methodology. The compound with the highest affinity based on docking analysis, (R)-4-(2-(tert-butylamino)-1-hydroxyethyl)-2-(hydroxymethyl)phenyl hydrogen phenylboronate (boronterol) was synthesized, characterized and tested in guinea pig tracheal rings at basal tone and with histamine-induced contractions. Boronterol was at least eightfold more potent than salbutamol as a smooth muscle relaxant drug (judged by the EC(50) values) and showed a similar maximal relaxant effect as isoproterenol. ICI118,551 showed competitive antagonism on the relaxing effect of boronterol. These results suggest the β(2)AR agonist action of boronterol.

Inhibition of acetylcholinesterase by two arylderivatives: 3a-Acetoxy-5H-pyrrolo(1,2-a) (3,1)benzoxazin-1,5-(3aH)-dione and cis-N-p-Acetoxy-phenylisomaleimide

Two arylderivatives, 3a-Acetoxy-5H-pyrrolo(1,2-a) (3,1)benzoxazin-1,5-(3aH)-dione 3 and cis-N-p-Acetoxy-phenylisomaleimide 4, were synthesized from anthranilic acid and para-aminophenol, respectively. The inhibitory effects of these compounds on acetylcholinesterase (AChE) activity were evaluated in vitro as well as by docking simulations. Both compounds showed inhibition of AChE activity (Ki = 4.72 ± 2.3 μM for 3 and 3.6 ± 1.8 μM for 4) in in vitro studies. Moreover, they behaved as irreversible inhibitors and made π–π interaction with W84 and hydrogen bonded with S200 and Y337 according to experimental data and docking calculations. The docking calculations showed ΔG bind (kcal/mol) of − 9.22 for 3 and − 8.58 for 4. These two compounds that can be use as leads for a new family of anti-Alzheimer disease drugs.