Exploring the maximum Fukui function sites with the frontier-controlled soft-soft reactions using 1,3-dipolar cycloaddition reactions of nitrilium betaines.

According to P.K. Chattaraj. J Phys Chem A 2001, 105, 511-513 "the maximum Fukui function site is the best for the frontier-controlled soft-soft reactions whereas for the charge-controlled hard-hard interactions the preferred site is associated with the maximum net charge and not necessarily the minimum Fukui function". Taking into account these outcomes in this research is explored this reactivity scheme using in first case the reaction between fulminic acid with ethylene (reference reaction), after is varying the dipolarophile in the reaction between fulminic acid with acetylene, and finally is varying the dipole in the reaction between formonitrile imine with ethylene. These results allow study parameter such as charge transfer, polarizability, covalent character on bonding, among other; also shown the preference by the sf- / sf+ interactions in the transition state on the sf- / sf- interactions. On the other hand, these results also were justified using net electrophilicity which is defined as the electrophilic power of a system relative to its own nucleophilic power.

New insights of QTAIM and stress tensor to finding non-competitive/competitive torquoselectivity of cyclobutene.

This study aims to investigate the phenomenon of torquoselectivity through three thermal cyclobutene ring-opening reactions (N1-N3). This research focuses on the nature of the chemical bond, electronic reorganization, predicting non-competitive or competitive reactions, and torquoselectivity preference within Quantum Theory of Atoms in Molecules (QTAIM) and stress tensor frameworks. Various theoretical analyses for these reactions, such as metallicity ξ(rb), ellipticity ε, total local energy density H(rb), stress tensor polarizability ℙσ, stress tensor eigenvalue λ3σ, and bond-path length, display differently for non-competitive and competitive reactions as well as for the conrotatory preferences either it is the transition state outward conrotatory (TSout) or transition state inward conrotatory (TSin) directions by presenting degeneracy or non-degeneracy in their results. The ellipticity profile provides the motion of the bond critical point locations due to the different substituents of cyclobutene. In agreement with experimental results, examinations demonstrated that N1 is a competitive reaction and N2-N3 are non-competitive reactions with TSout and TSin preference directions, respectively. The concordant results of QTAIM and stress tensor scalar and vectors with experimental results provide a better understanding of reaction mechanisms.

Chemical characterization and evaluation of the neuroprotective potential of Indigofera sessiliflora through in-silico studies and behavioral tests in scopolamine-induced memory compromised rats.

In the current study, we investigated the phytochemical and neuropharmacological potential of Indigofera sessiliflora, an indigenous least characterized plant widely distributed in deserted areas of Pakistan. The crude extract of the whole plant Indigofera sessiliflora (IS.CR) was preliminary tested in-vitro for the existence of polyphenol content, antioxidant and anticholinesterase potential followed by detailed chemical characterization through UHPLC-MS. Rats administered with different doses of IS.CR (100-300 mg/kg) for the duration of 4-weeks were behaviorally tested for anxiety and cognition followed by biochemical evaluation of dissected brain. The in-silico studies were employed to predict the blood-brain barrier crossing tendencies of secondary metabolites with the elucidation of the target binding site. The in-vitro assays revealed ample phenols and flavonoids content in IS.CR with adequate anti-oxidant and anticholinesterase potential. The dose-dependent anxiolytic potential of IS.CR was demonstrated in open field (OFT), light/dark (L/D) and elevated plus maze (EPM) tests as animals spent more time in open, illuminated and elevated zones (P < 0.05). In the behavioral tests for learning/memory, the IS.CR reversed the scopolamine-induced cognitive deficits, as animals showed better (P < 0.05) spontaneous alternation and discrimination index in y-maze and novel object recognition (NOR) tests. Similarly, as compared to amnesic rats, the step-through latencies were increased (P < 0.05) and escape latencies were decreased (P < 0.05) in passive avoidance (PAT) and Morris water maze (MWM) tests, respectively. Biochemical analysis of rat brains showed significant reduction in malondialdehyde and acetylcholinesterase levels, alongwith preservation of glutathione peroxidase and superoxide dismutase activity. The docking studies further portrayed a possible interaction of detected phytoconstituents with acetylcholinesterase target. The results of the study show valuable therapeutic potential of phytoconstituents present in IS.CR to correct the neurological disarrays which might be through antioxidant activity or via modulation of GABAergic and cholinergic systems by artocommunol, 1,9-dideoxyforskolin and 6E,9E-octadecadienoic acid.

New insights about electronic mechanism of electrocyclic reactions: theoretical study about stereoselectivity in cyclobutenes.

This work presents the study of a series of electrocyclic reactions with the main aim of obtaining new insights into the reaction process along IRCs. The energy variation of the different reaction paths as well as the different transition states have been calculated. These trends are according to the experimental data. The natural bond orbitals have been obtained and the second order perturbational theory analysis has been carried out to determine the main charge transfers due to delocalization. Bond reactivity indexes have been used to describe the reactivity mechanism in a local way. These reactivity indexes are also based on NBOs and this has made it possible to connect the results of the indexes with the previous analysis. To determine quantitatively the bond structure, we used the quantum theory of atoms in molecules and we have hereby completed the information obtained from the NBO analysis. Finally, we used the Hirshfeld population analysis as an approximation to understand how the load density changes in the different reaction pathways, and we have connected these variations with the information obtained from the bond structure. The results has found that the reaction path with the lowest energy barrier Transition State Inward Conrotatory (TSIC) or Transition State Outward Conrotatory (TSOC) is determined by two magnitudes: the charge donations by delocalisation of the substituents (which we obtained from the Second Order Perturbational Theory Analysis of the NBOs) and in the case that these donations were very similar, the non-covalent interactions dominated (which we studied by means of the interaction energies of the Hirshfeld charges). Additionality, the most important factor influencing the lower energy reaction path was the interaction of lone pairs of the substituents with the σ∗(C-C) bond that is broken at the opening of the cycle. The alignment of these lone pairs with the C-C bond favours charge donation between them and, as can be seen in the discussion, this alignment varies depending on whether the structure is TSIC and TSOC.

Discerning the thermal cyclotrimerizations of fluoro- and chloroacetylenes through ELF, NBO descriptors and QTAIM analysis: pseudodiradical character.

In this study the thermal cyclotrimerization reactions of fluoro- and chloroacetylenes involving regioselectively stepwise {2 + 2} and stepwise {4 + 2} cycloadditions were studied using the topological analysis of the electron localization function (ELF), the quantum theory of atoms in molecules (QTAIM) and natural bond orbital (NBO) analyses. These methodologies have shown that the electronic reorganization in the regioselectively stepwise {2 + 2} and stepwise {4 + 2} cycloadditions may be considered as {2n+2n} and {2π+2n} pseudodiradical process, respectively. Finally, the last phase of this thermal reaction can be understood as an electronic migration process under the pseudodiradical character in the thermal ring-opening reaction, with the subsequent formation of reaction products. In this sense, new insights are reported on the electronic behavior in the bond formation in the thermal cyclotrimerization of fluoroacetylene.

Quantum mechanics and 3D-QSAR studies on thienopyridine analogues: inhibitors of IKKß.

Inhibitor of kappa B kinase subunit ß (IKKß) is a main regulator of nuclear factor kappa B (NF-κB) and has received considerable attention as an attractive therapeutic target for the treatment of lung cancer or other inflammatory disease. A group of diversified thienopyridine derivatives exhibited a wide range of biological activity was used to investigate its structural requirements by using DFT and 3D-Quantitative structure activity relationship. Comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) were established using the experimental activity of thienopyridine derivatives. The cross-validation coefficient (q2) values for CoMFA and CoMSIA are 0.671 and 0.647 respectively, were achieved, demonstrating high predictive capability of the model. The contour analysis indicate that presence of hydrophobic and electrostatic field is highly desirable for biological activity. The results indicate that substitution of hydrophobic group with electron withdrawing effect at R4 and R6 position have more possibility to increase the biological activity of thienopyridine derivatives. Subsequently molecular docking and DFT calculation were performed to assess the potency of the compounds.

Adenosine Derivates as Antioxidant Agents: Synthesis, Characterization, in Vitro Activity, and Theoretical Insights.

In this work, we present results about the synthesis and the antioxidant properties of seven adenosine derivatives. Four of these compounds were synthesized by substituting the N6-position of adenosine with aliphatic amines, and three were obtained by modification of the ribose ring. All compounds were obtained in pure form using column chromatography, and their structures were elucidated by infrared spectroscopy (IR) and Nuclear Magnetic Resonance (NMR). All adenosine derivatives were further evaluated in vitro as free radical scavengers. Our results show that compounds 1c, 3, and 5 display a potent antioxidant effect compared with the reference compound ascorbic acid. In addition, the absorption, distribution, metabolism and excretion (ADME) calculations show favorable pharmacokinetic parameters for the set of compounds analyzed, which guarantees their suitability as potential antioxidant drugs. Furthermore, theoretical analyses using Molecular Quantum Similarity and reactivity indices were performed in order to discriminate the different reactive sites involved in oxidative processes.

Efficient synthesis and antioxidant activity of novel N-propargyl tetrahydroquinoline derivatives through the cationic Povarov reaction.

New N-propargyl tetrahydroquinolines 6a-g have been synthesized efficiently through the cationic Povarov reaction (a domino Mannich/Friedel-Crafts reaction), catalyzed by Indium (III) chloride (InCl3), from the corresponding N-propargylanilines preformed, formaldehyde and N-vinylformamide, with good to moderate yields. All tetrahydroquinoline derivatives obtained were evaluated in vitro as free radical scavengers. Results showed that compound 6c presents a potent antioxidant effect compared with ascorbic acid, used as a reference compound. ADME predictions also revealed favorable pharmacokinetic parameters for the synthesized compounds, which warrant their suitability as potentials antioxidant. Additionally, a theoretical study using Molecular Quantum Similarity and reactivity indices were developed to discriminate different reactive sites in the new molecules in which the oxidative process occurs.

Ultrasound-assisted synthesis of novel chalcone, heterochalcone and bis-chalcone derivatives and the evaluation of their antioxidant properties and as acetylcholinesterase inhibitors.

The chalcone and bis-chalcone derivatives have been synthesized under sonication conditions via Claisen-Schmidt condensation with KOH in ethanol at room temperature (20-89%). The structures were established on the basis of NMR, IR, Single-crystal XRD, and MS. The best compound 3u had inhibitory activity (IC50 = 7.50 µM). The synthesis, the antioxidative properties, chemical reactivity descriptors supported in Density Functional Theory (DFT), acetylcholinesterase (AChE) inhibition and their potential binding modes, and affinity were predicted by molecular docking of a number of morpholine-chalcones and quinoline-chalcone. A series of bis-chalcones are also reported. Molecular docking and an enzyme kinetic study on compound 3u suggested that it simultaneously binds to the catalytic active site (CAS) and peripheral anionic site (PAS) of AChE. Moreover, the pharmacokinetic profile of these compounds was investigated using a computational method.

Mycobacterium tuberculosis serine/threonine protein kinases: structural information for the design of their specific ATP-competitive inhibitors.

In the last decades, human protein kinases (PKs) have been relevant as targets in the development of novel therapies against many diseases, but the study of Mycobacterium tuberculosis PKs (MTPKs) involved in tuberculosis pathogenesis began much later and has not yet reached an advanced stage of development. To increase knowledge of these enzymes, in this work we studied the structural features of MTPKs, with focus on their ATP-binding sites and their interactions with inhibitors. PknA, PknB, and PknG are the most studied MTPKs, which were previously crystallized; ATP-competitive inhibitors have been designed against them in the last decade. In the current work, reported PknA, PknB, and PknG inhibitors were extracted from literature and their orientations inside the ATP-binding site were proposed by using docking method. With this information, interaction fingerprints were elaborated, which reveal the more relevant residues for establishing chemical interactions with inhibitors. The non-crystallized MTPKs PknD, PknF, PknH, PknJ, PknK, and PknL were also studied; their three-dimensional structural models were developed by using homology modeling. The main characteristics of MTPK ATP-binding sites (the non-crystallized and crystallized MTPKs, including PknE and PknI) were accounted; schemes of the main polar and nonpolar groups inside their ATP-binding sites were constructed, which are suitable for a major understanding of these proteins as antituberculotic targets. These schemes could be used for establishing comparisons between MTPKs and human PKs in order to increase selectivity of MTPK inhibitors. As a key tool for guiding medicinal chemists interested in the design of novel MTPK inhibitors, our work provides a map of the structural elements relevant for the design of more selective ATP-competitive MTPK inhibitors.

Molecular Quantum Similarity, Chemical Reactivity and Database Screening of 3D Pharmacophores of the Protein Kinases A, B and G from Mycobacterium tuberculosis.

Mycobacterium tuberculosis remains one of the world's most devastating pathogens. For this reason, we developed a study involving 3D pharmacophore searching, selectivity analysis and database screening for a series of anti-tuberculosis compounds, associated with the protein kinases A, B, and G. This theoretical study is expected to shed some light onto some molecular aspects that could contribute to the knowledge of the molecular mechanics behind interactions of these compounds, with anti-tuberculosis activity. Using the Molecular Quantum Similarity field and reactivity descriptors supported in the Density Functional Theory, it was possible to measure the quantification of the steric and electrostatic effects through the Overlap and Coulomb quantitative convergence (alpha and beta) scales. In addition, an analysis of reactivity indices using global and local descriptors was developed, identifying the binding sites and selectivity on these anti-tuberculosis compounds in the active sites. Finally, the reported pharmacophores to PKn A, B and G, were used to carry out database screening, using a database with anti-tuberculosis drugs from the Kelly Chibale research group (http://www.kellychibaleresearch.uct.ac.za/), to find the compounds with affinity for the specific protein targets associated with PKn A, B and G. In this regard, this hybrid methodology (Molecular Mechanic/Quantum Chemistry) shows new insights into drug design that may be useful in the tuberculosis treatment today.

Distinguishing and quantifying the torquoselectivity in competitive ring-opening reactions using the stress tensor and QTAIM.

Currently the theories to explain and predict the classification of the electronic reorganization due to the torquoselectivity of a ring-opening reaction cannot accommodate the directional character of the reaction pathway; the torquoselectivity is a type of stereoselectivity and therefore is dependent on the pathway. Therefore, in this investigation we introduced new measures from quantum theory of atoms in molecules and the stress tensor to clearly distinguish and quantify the transition states of the inward (TSIC) and outward (TSOC) conrotations of competitive ring-opening reactions of 3-(trifluoromethyl)cyclobut-1-ene and 1-cyano-1-methylcyclobutene. We find the metallicity ξ(rb ) of the ring-opening bond does not occur exactly at the transition state in agreement with transition state theory. The vector-based stress tensor response ßσ was used to distinguish the effect of the CN, CH3 , and CF3 groups on the TSIC and TSOC paths that was consistent with the ellipticity ε, the total local energy density H(rb ) and the stress tensor stiffness Sσ . We determine the directional properties of the TSIC and TSOC ring-opening reactions by constructing a stress tensor UσTS space with trajectories TσTS (s) with length l in real space, longer l correlated with the lowest density functional theory-evaluated total energy barrier and hence will be more thermodynamically favored. © 2016 Wiley Periodicals, Inc.

Analyzing the substitution effect on the CoMFA results within the framework of density functional theory (DFT).

Though QSAR was originally developed in the context of physical organic chemistry, it has been applied very extensively to chemicals (drugs) which act on biological systems, in this idea one of the most important QSAR methods is the 3D QSAR model. However, due to the complexity of understanding the results it is necessary to postulate new methodologies to highlight their physical-chemical meaning. In this sense, this work postulates new insights to understand the CoMFA results using molecular quantum similarity and chemical reactivity descriptors within the framework of density functional theory. To obtain these insights a simple theoretical scheme involving quantum similarity (overlap, coulomb operators, their euclidean distances) and chemical reactivity descriptors such as chemical potential (µ), hardness (ɳ), softness (S), electrophilicity (ω), and the Fukui functions, was used to understand the substitution effect. In this sense, this methodology can be applied to analyze the biological activity and the stabilization process in the non-covalent interactions on a particular molecular set taking a reference compound.

Analyzing torquoselectivity in electrocyclic ring opening reactions of trans-3,4-dimethylcyclobutene and 3-formylcyclobutene through electronic structure principles.

The validity of maximum hardness, minimum electrophilicity and minimum polarizability principles is assessed to explain the phenomenon of torquoselectivity (inward and outward preference) in the conrotatory ring opening reactions of trans-3,4-dimethylcyclobutene into Z,Z- and E,E-butadienes and 3-formylcyclobutene into E- and Z-2,4-pentadienals. The hardness, average polarizability and electrophilicity profiles are computed along the intrinsic reaction coordinate and divided into three relevant stages. The transition states involved in the unfavorable inward conrotation of trans-3,4-dimethylcyclobutene and in the unfavorable outward conrotation of 3-formylcyclobutene are found to be higher in energy, softer, more electrophilic and more polarizable than the transition states corresponding to the torquoselective outward and inward conrotations, respectively. These observations are in conformity with the maximum hardness, minimum electrophilicity and minimum polarizability principles. The sharp changes in the local reactivity descriptors are also observed around the transition states in their respective profiles.

Understanding the comparative molecular field analysis (CoMFA) in terms of molecular quantum similarity and DFT-based reactivity descriptors.

The three-dimensional quantitative structure-activity relationship (3D QSAR) models have many applications, although the inherent complexity to understand the results coming from 3D-QSAR arises the necessity of new insights in the interpretation of them. Hence, the quantum similarity field as well as reactivity descriptors based on the density functional theory were used in this work as a consistent approach to better understand the 3D-QSAR studies in drug design. For this purpose, the quantification of steric and electrostatic effects on a series of bicycle [4.1.0] heptane derivatives as melanin-concentrating hormone receptor 1 antagonists were performed on the basis of molecular quantum similarity measures. The maximum similarity superposition and the topo-geometrical superposition algorithms were used as molecular alignment methods to deal with the problem of relative molecular orientation in quantum similarity. In addition, a chemical reactivity analysis using global and local descriptors such as chemical hardness, softness, electrophilicity, and Fukui functions, was developed. Overall, our results suggest that the application of this methodology in drug design can be useful when the receptor is known or even unknown.

New insights into steric and electronic effects in a series of phosphine ligands from the perspective of local quantum similarity using the Fukui function.

The field of molecular quantum similarity (MQS) was introduced by Carbó-Dorca 30 years ago. MQS currently suffers from numerous bottlenecks, for example when studying similarities in chemical reactivity, because there is no clear guidance on the best methodology to follow. For this reason, we have revisited this topic here. Today's search tools and methodologies have made an important contribution to studying steric and electronic effects in phosphine ligands (PR3). In this contribution, we propose a hybrid methodology joining (MQS) and chemical reactivity. Additionally, a chemical reactivity study using global and local reactivity descriptors was performed in the context of density functional theory (DFT). Phosphines are σ-donor and π-acceptor ligands, therefore reactivity descriptors allow us quantify the retrodonor process in terms of quantum similarity (QS). In this regard, new ways to characterize steric and electronic effects in phosphine ligands and their chemical bonds are presented in the QS context.

Three-dimensional quantitative structure-activity relationship CoMSIA/CoMFA and LeapFrog studies on novel series of bicyclo [4.1.0] heptanes derivatives as melanin-concentrating hormone receptor R1 antagonists.

Comparative molecular similarity indices analysis (CoMSIA) and comparative molecular field analysis (CoMFA) were performed on a series of bicyclo [4.1.0] heptanes derivatives as melanin-concentrating hormone receptor R1 antagonists (MCHR1 antagonists). Molecular superimposition of antagonists on the template structure was performed by database alignment method. The statistically significant model was established on sixty five molecules, which were validated by a test set of ten molecules. The CoMSIA model yielded the best predictive model with a q(2) = 0.639, non cross-validated R(2) of 0.953, F value of 92.802, bootstrapped R(2) of 0.971, standard error of prediction = 0.402, and standard error of estimate = 0.146 while the CoMFA model yielded a q(2) = 0.680, non cross-validated R(2) of 0.922, F value of 114.351, bootstrapped R(2) of 0.925, standard error of prediction = 0.364, and standard error of estimate = 0.180. CoMFA analysis maps were employed for generating a pseudo cavity for LeapFrog calculation. The contour maps obtained from 3D-QSAR studies were appraised for activity trends for the molecules analyzed. The results show the variability of steric and electrostatic contributions that determine the activity of the MCHR1 antagonist, with these results we proposed new antagonists that may be more potent than previously reported, these novel antagonists were designed from the addition of highly electronegative groups in the substituent di(i-C(3)H(7))N- of the bicycle [4.1.0] heptanes, using the model CoMFA which also was used for the molecular design using the technique LeapFrog. The data generated from the present study will further help to design novel, potent, and selective MCHR1 antagonists.