The role of non-covalent interactions in 4-hydroxybenzylamine macrocyclisation: computational and synthetic evidence.

4-hydroxybenzylamine's intermolecular interactions and their possible influence on the course of 4-hydroxybenzylamine's reaction with formaldehyde are analysed in this article. Computational calculations established that 4-hydroxybenzylamine forms dimers in solution by O-H⋯N hydrogen bonds; such dimers are stabilised by π-stacking interactions. These cyclic dimers' formation led to obtaining a 12-atom azacyclophane through 4-hydroxybenzylamine's reaction with formaldehyde.

Pincer Ligands as Multifunctional Agents for Alzheimer's Copper Dysregulation and Oxidative Stress: A Computational Evaluation.

Alzheimer's disease (AD) is the most common form of dementia worldwide, affecting millions of people around the globe. AD is characterized by different pathologies being beta-amyloid (Aß) plaque formation, metal ion dysregulation, and oxidative stress (OS) central topics under investigation. Copper-Aß complexes have been shown to induce catalytic hydrogen peroxide formation and increase OS in the brain leading to neuronal death. Pincer-type compounds are tridentate ligands that coordinate metals in a planar fashion whose properties can be tuned via group substitutions, giving rise to many possibilities in catalysis and drug discovery. In this work we evaluated the potential pharmaceutical activity of 26 pincer compounds in AD's copper ion-related oxidative stress framework. In this sense, four key aspects were considered: 1) Lipinski's rule of five, 2) blood-brain barrier permeation, 3) standard reduction potential (SRP) of the formed copper complexes, and 4) the ligand's affinity towards copper cations. The evaluation of these criteria was performed by means of bioinformatic tools and electronic structure calculations at the DFT level of theory. Our results suggest that two compounds from this set are potential antioxidant agents, whereas five of them are promissory distributor-like compounds in the context of AD.

Computational Evaluation of the Potential Pharmacological Activity of Salen-Type Ligands in Alzheimer's Disease.

BACKGROUND: Alzheimer's disease (AD) is the most common form of dementia representing from 60% to 70% of the cases globally. It is a multifactorial disease that, among its many pathological characteristics, has been found to provoke the metal ion dysregulation in the brain, along with an increase in the oxidative stress. There is proof that metallic complexes formed by the amyloid-ß peptide (Aß) and extraneuronal copper can catalyze the production of reactive oxygen species, leading to an increase in oxidative stress, promoting neuronal death. Due to this interaction, bioavailable copper has become an important redox active target to consider within the search protocols of multifunctional agents for AD's treatment. OBJECTIVE: In this study, we examined by using bioinformatics and electronic structure calculations the potential application of 44 salen-type copper chelating ligands and 12 further proposed molecules as possible multifunctional agents in the context of AD. METHODS: The candidates were evaluated by combining bioinformatic tools and electronic structure calculations, which allowed us to classify the molecules as potential antioxidants, redistributor-like compounds, and the newly proposed suppressor mechanism. RESULTS: This evaluation demonstrate that salen-type ligands exhibit properties suitable for interfering in the chain of copper-induced oxidative stress reactions present in AD and potential redistributor and suppressor activity for copper ions. Finally, a novel set of plausible candidates is proposed and evaluated. CONCLUSION: According to the evaluated criteria, a subset of 13 salen-type candidates was found to exhibit promissory pharmacological properties in the AD framework and were classified according to three plausible action mechanisms.

Exploring the Non-Covalent Bonding in Water Clusters.

QTAIM and source function analysis were used to explore the non-covalent bonding in twelve different water clusters (H2O)n obtained by considering n = 2-7 and various geometrical arrangements. A total of seventy-seven O-H⋯O hydrogen bonds (HBs) were identified in the systems under consideration, and the examination of the electron density at the bond critical point (BCP) of these HBs revealed the existence of a great diversity of O-H⋯O interactions. Furthermore, the analysis of quantities, such as |V(r)|/G(r) and H(r), allowed a further description of the nature of analogous O-H⋯O interactions within each cluster. In the case of 2-D cyclic clusters, the HBs are nearly equivalent between them. However, significant differences among the O-H⋯O interactions were observed in 3-D clusters. The assessment of the source function (SF) confirmed these findings. Finally, the ability of SF to decompose the electron density (ρ) into atomic contributions allowed the evaluation of the localized or delocalized character of these contributions to ρ at the BCP associated to the different HBs, revealing that weak O-H⋯O interactions have a significant spread of the atomic contributions, whereas strong interactions have more localized atomic contributions. These observations suggest that the nature of the O-H⋯O hydrogen bond in water clusters is determined by the inductive effects originated by the different spatial arrangements of the water molecules in the studied clusters.

Role of Metal Cations of Copper, Iron, and Aluminum and Multifunctional Ligands in Alzheimer's Disease: Experimental and Computational Insights.

Alzheimer's disease (AD) is the most common form of dementia, affecting millions of people around the world. Even though the causes of AD are not completely understood due to its multifactorial nature, some neuropathological hallmarks of its development have been related to the high concentration of some metal cations. These roles include the participation of these metal cations in the production of reactive oxygen species, which have been involved in neuronal damage. In order to avoid the increment in the oxidative stress, multifunctional ligands used to coordinate these metal cations have been proposed as a possible treatment to AD. In this review, we present the recent advances in experimental and computational works aiming to understand the role of two redox active and essential transition-metal cations (Cu and Fe) and one nonbiological metal (Al) and the recent proposals on the development of multifunctional ligands to stop or revert the damaging effects promoted by these metal cations.

Facile, Single-Step Synthesis of a Series of D-Ring Ethisterones Substituted with 1,4-1,2,3-Triazoles: Preliminary Evaluation of Cytotoxic Activities.

A series of new D-ring ethisterones substituted with 1,4-1,2,3-triazoles were obtained in a facile manner via click chemistry reactions. The new compounds were characterized by multinuclear NMR spectroscopy, mass spectrometry, IR and unequivocally by single crystal X-ray diffraction studies for compound 1. The cytotoxic activity of these derivatives was tested against a series of human cancer cell lines including human glioblastoma (U-251), human prostatic adenocarcinoma (PC-3), human colorectal adenocarcinoma (HCT-15), human mammary adenocarcinoma (MCF-7), human chronic myelogenous leukemia (K562), and human lung adenocarcinoma (SKLU-1). Derivatives (3, X=Cl) and (5, X=I) showed promising cytotoxicity activities for leukemia adenocarcinoma (K562) and lung adenocarcinoma (SKLU). CI50% of K562: 11.72±0.9 µM (3) and 24.50±1.0 µM (5). CI50% of SKLU: 14.9±0.8 µM (3) and 46.0±2.8 µM (5). In addition, DNA docking simulations showed that all compounds interact with DNA through crosslink instrastrand p-alkyl-like interactions.

A Theoretical Study of the C-X Bond Cleavage Mediated by Cob(II)Aloxime.

The C-X bond cleavage in different methyl halides (CH3X; X = Cl, Br, I) mediated by 5,6-dimethylbenzimidazole-bis(dimethylglyoximate)cobalt(II) (CoIICbx) was theoretically investigated in the present work. An SN2-like mechanism was considered to simulate the chemical process where the cobalt atom acts as the nucleophile and the halogen as the leaving group. The reaction path was computed by means of the intrinsic reaction coordinate method and analyzed in detail through the reaction force formalism, the quantum theory of atoms in molecules (QTAIM), and the calculation of one-electron density derived quantities, such as the source function (SF) and the spin density. A thorough comparison of the results with those obtained in the same reaction occurring in presence of 5,6-dimethylbenzimidazole-bis(dimethylglyoximate)cobalt(I) (CoICbx) was conducted to reveal the main differences between the two cases. The reactions mediated by CoIICbx were observed to be endothermic and possess higher activation energies in contrast to the reactions where the CoICbx complex is present. The latter was supported by the reaction force results, which suggest a relationship between the activation energy and the ionization potentials of the different nucleophiles present in the cleavage reaction. Moreover, the SF results indicates that the lower axial ligand (i.e., 5,6-dimethylbenzimidazole) exclusively participates on the first stage of the reaction mediated by the CoIICbx complex, while for the CoICbx case, it appears to have an important role along the whole process. Finally, the QTAIM charge analysis indicates that oxidation of the cobalt atom occurs in both cases; at the same time, it suggests the formation of an uncommon two-center one-electron bond in the CoIICbx case. The latter was confirmed by means of electron localization calculations, which resulted in a larger electron count at the Co-C interatomic region for the CoICbx case upon comparison with its CoIICbx counterpart.

A computational protocol for the calculation of the standard reduction potential of iron complexes: application to Fe2+/3+-Aß model systems relevant to Alzheimer's disease.

Iron complexes play a key role in several biological processes, and they are also related to the development of neurological disorders, such as Alzheimer's and Parkinson's diseases. One of the main properties involved in these processes is the standard reduction potential (SRP) of iron complexes. However, the calculation of this property is challenging, mainly due to problems in the electronic structure description, solvent effects and the thermodynamic cycles used for its calculation. In this work, we proposed a computational protocol for the calculation of SRPs of iron complexes by evaluating a wide range of density functionals for the electronic structure description, two implicit solvent models with varying radii and two thermodynamic cycles. Results show that the M06L density functional in combination with the SMD solvation model and the isodesmic method provides good results compared with SRP experimental values for a set of iron complexes. Finally, this protocol was applied to three Fe2+/3+-Aß model systems involved in the development of Alzheimer's disease and the obtained SRP values are in good agreement with those reported previously by means of MP2 calculations.

Synthesis, Characterization, and Preliminary In Vitro Cytotoxic Evaluation of a Series of 2-Substituted Benzo [d] [1,3] Azoles.

A series of benzo [d] [1,3] azoles 2-substituted with benzyl- and allyl-sulfanyl groups were synthesized, and their cytotoxic activities were in vitro evaluated against a panel of six human cancer cell lines. The results showed that compounds BTA-1 and BMZ-2 have the best inhibitory effects, compound BMZ-2 being comparable in some cases with the reference drug tamoxifen and exhibiting a low cytotoxic effect against healthy cells. In silico molecular coupling studies at the tamoxifen binding site of ERα and GPER receptors revealed affinity and the possible mode of interaction of both compounds BTA-1 and BMZ-2.

Computational Design of Copper Ligands with Controlled Metal Chelating, Pharmacokinetics, and Redox Properties for Alzheimer's Disease.

BACKGROUND: Redox active metal cations, such as Cu2 +, have been related to induce amyloid plaques formation and oxidative stress, which are two of the key events in the development of Alzheimer's disease (AD) and others metal promoted neurodegenerative diseases. In these oxidative events, standard reduction potential (SRP) is an important property especially relevant in the reactive oxygen species formation. OBJECTIVE: The SRP is not usually considered for the selection of drug candidates in anti-AD treatments. In this work, we present a computational protocol for the selection of multifunctional ligands with suitable metal chelating, pharmacokinetics, and redox properties. METHODS: The filtering process is based on quantum chemical calculations and the use of in silico tools. Calculations of SRP were performed by using the M06-2X density functional and the isodesmic approach. Then, a virtual screening technique (VS) was used for similar structure search. RESULTS: Protocol application allowed the assessment of chelating, drug likeness, and redox properties of copper ligands. Those molecules showing the best features were selected as molecular scaffolds for a VS procedure in order to obtain related compounds. After applying this process, we present a list of candidates with suitable properties to prevent the redox reactions mediated by copper(II) ion. CONCLUSION: The protocol incorporates SRP in the filtering stage and can be effectively used to obtain a set of potential drug candidates for AD treatments.

Computational Evaluation of Interaction Between Curcumin Derivatives and Amyloid-ß Monomers and Fibrils: Relevance to Alzheimer's Disease.

BACKGROUND: The most important hallmark in the neuropathology of Alzheimer's disease (AD) is the formation of amyloid-ß (Aß) fibrils due to the misfolding/aggregation of the Aß peptide. Preventing or reverting the aggregation process has been an active area of research. Naturally occurring products are a potential source of molecules that may be able to inhibit Aß42 peptide aggregation. Recently, we and others reported the anti-aggregating properties of curcumin and some of its derivatives in vitro, presenting an important therapeutic avenue by enhancing these properties. OBJECTIVE: To computationally assess the interaction between Aß peptide and a set of curcumin derivatives previously explored in experimental assays. METHODS: The interactions of ten ligands with Aß monomers were studied by combining molecular dynamics and molecular docking simulations. We present the in silico evaluation of the interaction between these derivatives and the Aß42 peptide, both in the monomeric and fibril forms. RESULTS: The results show that a single substitution in curcumin could significantly enhance the interaction between the derivatives and the Aß42 monomers when compared to a double substitution. In addition, the molecular docking simulations showed that the interaction between the curcumin derivatives and the Aß42 monomers occur in a region critical for peptide aggregation. CONCLUSION: Results showed that a single substitution in curcumin improved the interaction of the ligands with the Aß monomer more so than a double substitution. Our molecular docking studies thus provide important insights for further developing/validating novel curcumin-derived molecules with high therapeutic potential for AD.

Synthesis of Pt(II) complexes of the type [Pt(1,10-phenanthroline)(SArFn)2] (SArFn = SC6H3-3,4-F2; SC6F4-4-H; SC6F5). Preliminary evaluation of their in vitro anticancer activity.

A series of Pt(II) complexes of the type [Pt(1,10-phenanthroline)(SArFn)2] (SArFn = SC6H3-3,4-F2(1); SC6F4-4-H (2); SC6F5(3)) were synthesized from [Pt(1,10-phenanthroline)(Cl)2] and [Pb(SArFn)2] via metathesis reactions. The complexes were fully characterized including the unambiguous determination of their molecular structures by single-crystal X-ray diffraction techniques, showing the metal centers to be into a slightly distorted square-planar environments. The in vitro cytotoxic activity of the complexes was evaluated on six cancerous cell lines, i.e: glial cells of nervous central system (U-251), prostate (PC-3), leukemia (K-562), colon (HCT-15), breast (MCF-7) and lung (SKLU-1); we also included a healthy cell line of COS-7 (African green monkey kidney) for comparative purposes. We found that complex 2 was selective for PC-3. In addition, the IC50 values for the series of complexes were determined using the U-251, HCT-15 and SKLU-1 cancerous cell lines, as well as in the healthy cell line (COS-7), where complex 1 exhibited the best activity, with IC50 values going from 4.56 to 4.78 µM. These studies where further complemented with DNA docking theoretical calculations and DNA affinity experiments.

The role of LasR active site amino acids in the interaction with the Acyl Homoserine Lactones (AHLs) analogues: A computational study.

The present work combines molecular docking calculations, 3D-QSAR, molecular dynamics simulations and free binding energy calculations (MM/PBSA and MM/GBSA) in a set of 28 structural analogues of acyl homoserine lactones with Quorum Sensing antagonist activity. The aim of this work is to understand how ligand binds and is affected by the molecular microenvironment in the active site of the LasR receptor for pseudomonas aeruginosa. We also study the stability of the interaction to find key structural characteristics that explain the antagonist activities of this set of ligands. This information is relevant for the rational modification or design of molecules and their identification as powerful LasR modulators. The analysis of molecular docking simulations shows that the 28 analogues have a similar binding mode compared to the native ligand. The carbonyl groups belonging to the lactone ring and the amide group of the acyl chain are oriented towards the amino acids forming hydrogen bond like interactions. The difference in antagonist activity is due to location and orientation of the LasR side chains within the hydrophobic pocket in its binding site. Additionally, we carried out molecular dynamics simulations to understand the conformational changes in the ligand-receptor interaction and the stability of each complex. Results show a direct relationship among the interaction energies of the ligands and the activities as an antagonist of the LasR receptor.

Assessment of the isodesmic method in the calculation of standard reduction potential of copper complexes.

Molecular phenomena involving electron transfer and reduction/oxidation processes are of the utmost importance in chemistry. However, accurate computational calculations of standard reduction potentials (SRPs) for transition metal complexes are still challenging. For this reason, some computational strategies have been proposed in order to overcome the main limitations in SRP calculations for copper complexes. However, these strategies are limited to particular coordination spheres and do not represent a general methodology. In this work, we present standard reduction potential calculations for copper complexes in aqueous solution covering a wide range of coordination spheres. These calculations were performed using the M06-2X density functional, and by employing the direct and isodesmic approaches. Result analysis reveals that values obtained with the use of the isodesmic method are in better agreement with experimental values than those obtained from the direct method (mean unsigned error 0.39 V with the direct and 0.08 V with the isodesmic method). This approach provides values with errors comparable to the experimental uncertainty due to the proper cancellation of computational errors. These results strongly suggest the isodesmic approach as an adequate methodology for the calculation of SRPs for copper complexes with diverse coordination spheres. Graphical Abstract Comparison between direct and isodesmic methods in the calculation of standard reduction potentials for copper complexes using DFT methods.

Fast and accurate prediction of proton affinities: revisiting the extended Koopmans' theorem for protons.

In this work we propose schemes based on the extended Koopmans' theorem for quantum nuclei (eKT), in the framework of the any particle molecular orbital approach (APMO/KT), for the quantitative prediction of gas phase proton affinities (PAs). The performance of these schemes has been tested on a set of 300 organic molecules containing diverse functional groups. The APMO/KT scheme scaled by functional group (APMO/KT-SC-FG) displays an overall mean absolute error of 1.1 kcal mol-1 with respect to experimental data. Its performance in PA calculations is similar to that of post-Hartree-Fock composite methods or that of the APMO second order proton propagator (APMO/PP2) approach. The APMO/KT-SC-FG scheme is also employed to predict PAs of polyfunctional molecules such as the Nerve Agent VX and the 20 common α-amino acids, finding excellent agreement with available theoretical and/or experimental data. The accuracy of the predictions demonstrates that the APMO/KT-SC-FG scheme is a low-cost alternative to adiabatic methods for the calculation of accurate PAs. One of the most appealing features of the APMO/KT-SC-FG scheme, is that PAs can be derived from one single-point APMO Hartree-Fock calculation.

Prediction of proton affinities of organic molecules using the any-particle molecular-orbital second-order proton propagator approach.

We assess the performance of the recently developed any-particle molecular-orbital second-order proton propagator (APMO/PP2) scheme [M. Díaz-Tinoco, J. Romero, J. V. Ortiz, A. Reyes and R. Flores-Moreno, J. Chem. Phys., 2013, 138, 194108] on the calculation of gas phase proton affinities (PAs) of a set of 150 organic molecules comprising several functional groups: amines, alcohols, aldehydes, amides, ketones, esters, ethers, carboxylic acids and carboxylate anions. APMO/PP2 PAs display an overall mean absolute error of 0.68 kcal mol-1 with respect to experimental data. These results suggest that the APMO/PP2 method is an alternative approach for the quantitative prediction of gas phase proton affinities. One novel feature of the method is that a PA can be obtained from a single calculation of the optimized protonated molecule.

Dioxygen activation in the Cu-amyloid ß complex.

We investigate, by means of density-functional theory, the binding of dioxygen to Cu(I)-amyloid ß (Aß), one of the first steps in the oxidation of ascorbate by dioxygen. Cu, Aß, ascorbate and dioxygen are all present in the synapse during neurodegeneration, when the above species can trigger an irreversible oxidative stress inducing the eventual death of neurons. The binding of dioxygen to Cu(I) is possible and its role in dioxygen activation of Cu ligands and of residues in the first coordination sphere is described in atomic detail. Dioxygen is activated when a micro-environment suitable for a square-planar Cu(2+) coordination is present and a negatively charged group like Asp 1 carboxylate takes part in the Cu coordination anti to O2.

Coordination properties of a metal chelator clioquinol to Zn(2+) studied by static DFT and ab initio molecular dynamics.

Several lines of evidence supporting the role of metal ions in amyloid aggregation, one of the hallmarks of Alzheimer's disease (AD), have turned metal ion chelation into a promising therapeutic treatment. The design of efficient chelating ligands requires proper knowledge of the electronic and molecular structure of the complexes formed, including their hydration properties. Among various potential chelators, clioquinol (5-chloro-7-iodo-8-hydroxyquinoline, CQH) has been evaluated with relative success in in vitro experiments and even in phase 2 clinical trials. Clioquinol interacts with Zn(ii) to lead to a binary metal/ligand 1 : 2 stoichiometric complex in which the phenolic group of CQH is deprotonated, resulting in Zn(CQ)2 neutral complexes, to which additional water molecules may coordinate. In the present work, the coordinative properties of clioquinol in aqueous solution have been analyzed by means of static, minimal cluster based DFT calculations and explicit solvent ab initio molecular dynamics simulations. Results from static calculations accounting for solvent effects by means of polarized continuum models suggest that the preferred metal coordination environment is tetrahedral Zn(CQ)2, whereas ab initio molecular dynamics simulations point to quasi degenerate penta Zn(CQ)2(H2O) and hexa Zn(CQ)2(H2O)2 coordinated complexes. The possible reasons for these discrepant results are discussed.

3D structures and redox potentials of Cu2+-Aß(1-16) complexes at different pH: a computational study.

Oxidative stress induced by redox-active metal cations such as Cu(2+) is a key event in the development of Alzheimer's disease. A detailed knowledge of the structure of Cu(2+)-Aß complex is thus important to get a better understanding of this critical process. In the present study, we use a computational approach that combines homology modeling with quantum-mechanics-based methods to determine plausible 3D structures of Cu(2+)-Aß(1-16) complexes that enclose the different metal coordination spheres proposed experimentally at different pH values. With these models in hand, we determine their standard reduction potential (SRP) with the aim of getting new insights into the relation between the structure of these complexes and their redox behavior. Results show that in all cases copper reduction induces CObackbone decoordination, which, for distorted square planar structures in the oxidized state (Ia_δδ, IIa_εδε, IIa_εεε, and IIc_ε), leads to tricoordinated species. For the pentacoordinated structural candidate Ib_δε with Glu11 at the apical position, the reduction leads to a distorted tetrahedral structure. The present results highlight the importance of the nature of the ligands on the SRP. The computed values (with respect to the standard hydrogen electrode) for complexes enclosing negatively charged ligands in the coordination sphere (from -0.81 to -0.12 V) are significantly lower than those computed for models involving neutral ligands (from 0.19 to 0.28 V). Major geometry changes induced by reduction, on both the metal site and the peptide configuration, are discussed as well as their possible influence in the formation of reactive oxygen species.

Capping amyloid ß-sheets of the tau-amyloid structure VQIVYK with hexapeptides designed to arrest growth. An ONIOM and density functional theory study.

We present ONIOM calculations using density functional theory (DFT) as the high and AM1 as the medium level that explore the abilities of different hexapeptide sequences to terminate the growth of a model for the tau-amyloid implicated in Alzheimer's disease. We delineate and explore several design principles (H-bonding in the side chains, using antiparallel interactions on the growing edge of a parallel sheet, using all-d residues to form rippled interactions at the edge of the sheet, and replacing the H-bond donor N-H's that inhibit further growth) that can be used individually and in combination to design such peptides that will have a greater affinity for binding to the parallel ß-sheet of acetyl-VQIVYK-NHCH3 than the natural sequence and will prevent another strand from binding to the sheet, thus providing a cap to the growing sheet that arrests further growth. We found peptides in which the Q is replaced by an acetyllysine (aK) residue to be particularly promising candidates, particularly if the reverse sequence (KYVIaKV) is used to form an antiparallel interaction with the sheet.