Synthesis, Molecular Electron Density Theory Study, Molecular Docking, and Pharmacological Evaluation of New Coumarin-Sulfonamide-Nitroindazolyl-Triazole Hybrids as Monoamine Oxidase Inhibitors.

Inhibitors of monoamine oxidases (MAOs) are of interest for the treatment of neurodegenerative disorders and other human pathologies. In this frame, the present work describes different synthetic strategies to obtain MAO inhibitors via the coupling of the aminocoumarin core with arylsulfonyl chlorides followed by copper azide-alkyne cycloaddition, leading to coumarin-sulfonamide-nitroindazolyl-triazole hybrids. The nitration position on the coumarin moiety was confirmed through nuclear magnetic resonance spectroscopy and molecular electron density theory in order to elucidate the molecular mechanism and selectivity of the electrophilic aromatic substitution reaction. The coumarin derivatives were evaluated for their inhibitory potency against monoamine oxidases and cholinesterases. Molecular docking calculations provided a rational binding mode of the best compounds in the series with MAO A and B. The work identified hybrids 14a-c as novel MAO inhibitors, with a selective action against isoform B, of potential interest to combat neurological diseases.

Revealing the Critical Role of Global Electron Density Transfer in the Reaction Rate of Polar Organic Reactions within Molecular Electron Density Theory.

The critical role of global electron density transfer (GEDT) in increasing the reaction rate of polar organic reactions has been studied within the framework of Molecular Electron Density Theory (MEDT). To this end, the series of the polar Diels-Alder (P-DA) reactions of cyclopentadiene with cyanoethylene derivatives, for which experimental kinetic data are available, have been chosen. A complete linear correlation between the computed activation Gibbs free energies and the GEDT taking place at the polar transition state structures (TSs) is found; the higher the GEDT at the TS, the lower the activation Gibbs free energy. An interacting quantum atoms energy partitioning analysis allows for establishing a complete linear correlation between the electronic stabilization of the electrophilic ethylene frameworks and the GEDT taking place at the polar TSs. This finding supports Parr's proposal for the definition of the electrophilicity ω index. The present MEDT study establishes the critical role of the GEDT in the acceleration of polar reactions, since the electronic stabilization of the electrophilic framework with the electron density gain is greater than the destabilization of the nucleophilic one, making a net favorable electronic contribution to the decrease in the activation energy.

A combined BET and IQA-REG study of the activation energy of non-polar zw-type [3+2] cycloaddition reactions.

A combined Bonding Evolution Theory (BET) and Interacting Quantum Atoms-Relative Energy Gradient (IQA-REG) study is carried out on a non-polar zw-type [3+2] cycloaddition (32CA) reaction. BET is the joint use of Catastrophe Theory and the topology of the Electron Localization Function (ELF) to characterise molecular mechanisms, while IQA is a quantum topological energy partitioning method and REG is a method to compute chemical insight at atomistic level, usually in connection with energy. This 32CA reaction involves the simplest nitrone with ethylene and has been studied here at B3LYP/6-311G(d,p) level within the context of Molecular Electron Density Theory (MEDT), which is based on the idea that changes in electron density, and not molecular orbital interactions, are responsible for chemical reactivity. We aim to determine the origin of the high activation energy of 32CA reactions involving zwitterionic three-atom-components. The BET study and IQA-REG method are applied to the overall activation energy path. While BET suggests that the barrier is mainly associated with the rupture of the nitrone CN double bond, IQA-REG indicates that it is mainly related to the rupture of the ethylene CC double bond. The present study shows that activation energies can be accurately and easily described by IQA-REG, and its complementary use with BET helps achieving a more detailed description of molecular mechanisms.

New spiro-indeno[1,2-b]quinoxalines clubbed with benzimidazole scaffold as CDK2 inhibitors for halting non-small cell lung cancer; stereoselective synthesis, molecular dynamics and structural insights.

Despite the crucial role of CDK2 in tumorigenesis, few inhibitors reached clinical trials for managing lung cancer, the leading cause of cancer death. Herein, we report combinatorial stereoselective synthesis of rationally designed spiroindeno[1,2-b]quinoxaline-based CDK2 inhibitors for NSCLC therapy. The design relied on merging pharmacophoric motifs and biomimetic scaffold hopping into this privileged skeleton via cost-effective one-pot multicomponent [3 + 2] cycloaddition reaction. Absolute configuration was assigned by single crystal x-ray diffraction analysis and reaction mechanism was studied by Molecular Electron Density Theory. Initial MTT screening of the series against A549 cells and normal lung fibroblasts Wi-38 elected 6b as the study hit regarding potency (IC50 = 54 nM) and safety (SI = 6.64). In vitro CDK2 inhibition assay revealed that 6b (IC50 = 177 nM) was comparable to roscovitine (IC50 = 141 nM). Docking and molecular dynamic simulations suggested that 6b was stabilised into CDK2 cavity by hydrophobic interactions with key aminoacids.

A Molecular Electron Density Theory Study of the Domino Reaction of N-Phenyl Iminoboranes with Benzaldehyde Yielding Fused Bicyclic Compounds.

The reaction of N-phenyl iminoborane with benzaldehyde yielding a fused aromatic compound, recently reported by Liu et al., has been studied within the Molecular Electron Density Theory (MEDT). Formation of the fused aromatic compound is a domino process that comprises three consecutive reactions: (i) formation of a weak molecular complex between the reagents; (ii) an intramolecular electrophilic attack of the activated carbonyl carbon of benzaldehyde on the ortho position of the N-phenyl substituent of iminoborane; and (iii) a formal 1,3-hydrogen shift yielding the final fused aromatic compound. The two last steps correspond to a Friedel-Crafts acylation reaction, the product of the second reaction being the tetrahedral intermediate of an electrophilic aromatic substitution reaction. However, the presence of the imino group adjacent to the aromatic ring strongly stabilizes the corresponding intermediate, being the reaction product when the ortho positions are occupied by t-butyl substituents. This domino reaction shows a great similitude with the Brønsted acid catalyzed Povarov reaction. Although N-phenyl iminoborane can experience a formal [2+2] cycloaddition reaction with benzaldehyde, its higher activation Gibbs free energy compared to the intramolecular electrophilic attack of the activated carbonyl carbon of benzaldehyde on the ortho position of the N-phenyl substituent, 6.6 kcal·mol-1, prevents the formation of the formal [2+2] cycloadduct. The present MEDT study provides a different vision of the molecular mechanism of these reactions based on the electron density.

Unveiling the high reactivity of experimental pseudodiradical azomethine ylides within molecular electron density theory.

The [3+2] cycloaddition (32CA) reactions of N-methyl azomethine ylide (AY) with styrene, benzaldehyde and methyl 2-formyl-benzoate (MFB) were studied within molecular electron density theory (MEDT), at the ωB97X-D/6-311G(d) computational level, in order to characterize the reactivity of an experimental pseudodiradical TAC for the first time. ELF topological analysis indicates that AY presents a pseudodiradical structure. Analysis of CDFT reactivity indices allows classifying AY as a supernucleophile; while styrene is classified as a moderate electrophile, benzaldehyde and MFB are classified as strong electrophiles. The 32CA reaction with MFB is the most favorable one with a relatively low activation Gibbs free energy of 6.9 kcal mol-1, being irreversible and completely endo stereo- and chemo-selective towards the carbonyl group, a behavior predicted by the analysis of the Parr functions. The bonding evolution theory (BET) study indicates that while the 32CA reaction of AY with styrene is characterized as a pdr-type 32CA reaction, the one involving benzaldehyde follows a pmr-type mechanism prompted by the presence of the carbonyl group. The present MEDT study describes in detail the tunable high reactivity of one of the few experimentally available pseudodiradical TACs, showing that the mechanism of 32CA reactions can be modified not only by changing the electronic structure of TACs through proper substitution but also by the nature of their opposing ethylene derivative.

Design, Synthesis and In Vitro Evaluation of Spirooxindole-Based Phenylsulfonyl Moiety as a Candidate Anti-SAR-CoV-2 and MERS-CoV-2 with the Implementation of Combination Studies.

The search for an effective anti-viral to inhibit COVID-19 is a challenge for the specialized scientific research community. This work investigated the anti-coronavirus activity for spirooxindole-based phenylsulfone cycloadducts in a single and combination protocols. The newly designed anti-SARS-CoV-2 therapeutics spirooxindoles synthesized by [3 + 2] cycloaddition reactions represent an efficient approach. One-pot multicomponent reactions between phenyl vinyl sulfone, substituted isatins, and amines afforded highly stereoselective anti-SARS-CoV-2 therapeutics spirooxindoles with three stereogenic centers. Herein, the newly synthesized spirooxindoles were assessed individually against the highly pathogenic human coronaviruses and proved to be highly potent and safer. Interestingly, the synergistic effect by combining the potent, tested spirooxindoles resulted in an improved antiviral activity as well as better host-cell safety. Compounds 4i and 4d represented the most potent activity against MERS-CoV with IC50 values of 11 and 23 µM, respectively. Both compounds 4c and 4e showed equipotent activity with the best IC50 against SARS-CoV-2 with values of 17 and 18 µM, respectively, then compounds 4d and 4k with IC50 values of 24 and 27 µM, respectively. Then, our attention oriented to perform a combination protocol as anti-SARS-CoV-2 for the best compounds with a different binding mode and accompanied with different pharmacophores. Combination of compound 4k with 4c and combination of compounds 4k with 4i proved to be more active and safer. Compounds 4k with 4i displayed IC50 = 3.275 µM and half maximal cytotoxic-concentration CC50 = 11832 µM. MD simulation of the most potential compounds as well as in silico ADMET properties were investigated. This study highlights the potential drug-like properties of spirooxindoles as a cocktail anti-coronavirus protocol.

A Molecular Electron Density Theory Study of the [3+2] Cycloaddition Reaction of an Azomethine Ylide with an Electrophilic Ethylene Linked to Triazole and Ferrocene Units.

The [3+2] cycloaddition (32CA) reaction of an azomethine ylide (AY) with an electrophilic ethylene linked to triazole and ferrocene units has been studied within the Molecular Electron Density Theory (MEDT) at the ωB97X-D/6-311G(d,p) level. The topology of the electron localization function (ELF) of this AY allows classifying it as a pseudo(mono)radical species characterized by the presence of two monosynaptic basins, integrating a total of 0.76 e, at the C1 carbon. While the ferrocene ethylene has a strong electrophilic character, the AY is a supernucleophile, suggesting that the corresponding 32CA reaction has a high polar character and a low activation energy. The most favorable ortho/endo reaction path presents an activation enthalpy of 8.7 kcal·mol-1, with the 32CA reaction being exergonic by -42.1 kcal·mol-1. This reaction presents a total endo stereoselectivity and a total ortho regioselectivity. Analysis of the global electron density transfer (GEDT) at the most favorable TS-on (0.23 e) accounts for the high polar character of this 32CA reaction, classified as forward electron density flux (FEDF). The formation of two intermolecular hydrogen bonds between the two interacting frameworks at the most favorable TS-on accounts for the unexpected ortho regioselectivity experimentally observed.

Understanding the Participation of Fluorinated Azomethine Ylides in Carbenoid-Type [3 + 2] Cycloaddition Reactions with Ynal Systems: A Molecular Electron Density Theory Study.

The carbenoid-type (cb-type) 32CA reaction of 1,1-difluoroated azomethine ylide (DFAY) with phenylpropynal has been studied using the molecular electron density theory (MEDT). Electron localization function (ELF) characterizes DFAY as a carbenoid species participating in cb-type 32CA reactions. The supernucleophilic character of DFAY and the strong electrophilic character of the ynal cause this polar 32CA reaction to have an unappreciable barrier; the reaction, which is highly exothermic, presents total chemo- and regioselectivity. ELF topological analysis of the bonding changes along the reaction establishes its non-concerted two-stage one-step mechanism, in which the nucleophilic attack of the carbenoid carbon of DFAY on the electrophilic carbonyl carbon of the ynal characterizes the cb-type reactivity of this three-atom component (TAC). The presence of two fluorines at DFAY modifies the pseudodiradical structure and reactivity of the simplest azomethine ylide to that of a carbenoid TAC participating in cb-type 32CA reactions toward electrophilic ethylenes.

The catalytic effects of a thiazolium salt in the oxa-Diels-Alder reaction between benzaldehyde and Danishefsky's diene: a molecular electron density theory study.

The oxa-Diels-Alder (ODA) reaction of benzaldehyde with Danishefsky's diene in the presence of a [thiazolium][Cl] salt, as a model of an ionic liquid, has been studied within Molecular Electron Density Theory (MEDT) at the M06-2X/6-311G(d,p) computational level. The formation of two hydrogen bonds (HBs) between the thiazolium cation and the carbonyl oxygen of benzaldehyde modifies neither the electrophilic character of benzaldehyde nor its electronic structure substantially but accelerates the reaction considerably. This ODA reaction presents an activation energy of 4.5 kcal mol-1; the formation of the only observed dihydropyranone is strongly exothermic by -28.8 kcal mol-1. The presence of the [thiazolium][Cl] salt decreases the Gibbs free energy of activation of the ODA reaction between benzaldehyde and Danishefsky's diene by 5.9 kcal mol-1. This ODA reaction presents total para regioselectivity and high endo stereoselectivity. This ODA reaction takes place through a highly asynchronous polar transition state structure (TS) associated with a non-concerted two-stage one-step mechanism. ELF analysis of para/endo TSs associated with the ODA reactions in the absence and presence of the [thiazolium][Cl] salt shows that the formation of the HBs at the TSs does not modify their electronic structure substantially. This MEDT study makes it possible to conclude that the acceleration found in the ODA reaction of benzaldehyde with Danishefsky's diene in ILs is a consequence of an increase of the global electron density transfer at TS3-pn, resulting from HB formation, and the greater strength of the HBs at the polar TS3-pn compared to that at the benzaldehyde : [thiazolium][Cl] complex, and that the strength in the HB formed is more relevant that than an increase of the electrophilic character of the interaction between reagent.

Closer Investigation of the Kinetics and Mechanism of Spirovinylcyclopropyl Oxindole Reaction with 3Σ-g-O2 by Topological Approaches and Unraveling the Role of the I2 Catalyst.

In this investigation at the MN15L/Def2-TZVP level of theory, we present computational evidence indicating that the reaction of 3Σ-g-O2 with spirovinylcyclopropyl oxindole (2) leads to a product called spiro-1,2-dioxolane (2) in its singlet state; this reaction occurs via a stepwise mechanism and its rate-determining step is catalyzed by iodine radicals, which promotes opening of the three-membered ring under dark conditions. The conversion of 2 to 1-benzylindoline-2,3-dione (3) and 2-vinyloxirane (4) takes place via a concerted and slightly asynchronous reaction. Both electron localization function and AIM topological analysis reveal that the step associated with the attack of the 3Σ-g-O2 molecule on the intermediate 3MC characterizes the formation of the only new O2-C3 single bond, which occurs in a stepwise mechanism, in contrast to the Δg-O2 reaction with 15 species.

Unveiling the Ionic Diels-Alder Reactions within the Molecular Electron Density Theory.

The ionic Diels-Alder (I-DA) reactions of a series of six iminium cations with cyclopentadiene have been studied within the Molecular Electron Density Theory (MEDT). The superelectrophilic character of iminium cations, ω > 8.20 eV, accounts for the high reactivity of these species participating in I-DA reactions. The activation energies are found to be between 13 and 20 kcal·mol-1 lower in energy than those associated with the corresponding Diels-Alder (DA) reactions of neutral imines. These reactions are low endo selective as a consequence of the cationic character of the TSs, but highly regioselective. Solvents have poor effects on the relative energies, and an unappreciable effect on the geometries. In acetonitrile, the activation energies increase slightly as a consequence of the better solvation of the iminium cations than the cationic TSs. Electron localization function (ELF) topological analysis of the bonding changes along the I-DA reactions shows that they are very similar to those in polar DA reactions. The present MEDT study establishes that the global electron density transfer (GEDT) taking place at the TSs of I-DA reactions, and not steric (Pauli) repulsions such as have been recently proposed, are responsible for the features of these types of DA reactions.

Straightforward Regio- and Diastereoselective Synthesis, Molecular Structure, Intermolecular Interactions and Mechanistic Study of Spirooxindole-Engrafted Rhodanine Analogs.

Straightforward regio- and diastereoselective synthesis of bi-spirooxindole-engrafted rhodanine analogs 5a-d were achieved by one-pot multicomponent [3 + 2] cycloaddition (32CA) reaction of stabilized azomethine ylide (AYs 3a-d) generated in situ by condensation of L-thioproline and 6-chloro-isatin with (E)-2-(5-(4-chlorobenzylidene)-2,4-dioxothiazolidin-3-yl)-N-(2-morpholinoethyl)acetamide. The bi-spirooxindole-engrafted rhodanine analogs were constructed with excellent diastereo- and regioselectivity along with high chemical yield. X-ray crystallographic investigations for hybrid 5a revealed the presence of four contiguous stereocenters related to C11, C12, C19 and C22 of the spiro structure. Hirshfeld calculations indicated the presence of many short intermolecular contacts such as Cl...C, S...S, S...H, O...H, N...H, H...C, C...C and H...H interactions. These contacts played a very important role in the crystal stability. The polar nature of the 32CA reaction was studied by analysis of the conceptual DFT reactivity indices. Theoretical study of this 32CA reaction indicated that it takes place through a non-concerted two-stage one-step mechanism associated with the nucleophilic attack of AY 3a to the electrophilic ethylene derivative.

Lithium Cation-Catalyzed Benzene Diels-Alder Reaction: Insights on the Molecular Mechanism Within the Molecular Electron Density Theory.

The lithium cation Li+-catalyzed Diels-Alder (DA) reactions of benzene toward a series of acetylenes of improved nucleophilicity can be described within the context of the molecular electron density theory (MEDT) at the ωB97XD/6-311G(d,p) level. Conceptual density functional theory indices characterize the crown ether solvated complex benzene-lithium Bz-Li-Cro as a superelectrophile. Coordination of a lithium cation to benzene does not change substantially the electron localization function electronic structure of benzene. The DA reaction of Bz-Li-Cro with acetylene shows a reduction of the energy of activation of 6.9 kcal·mol-1, which is not sufficient for the reaction to take place, thus demanding the participation of strong nucleophilic acetylenes. DA reactions of complexes Bz-M-Cro (M = Li, Na, and K) are decelerated with the decrease of the ionization potential of the alkali metal. The one-step mechanism of these lithium cation Li+-catalyzed DA reactions changes to a two-step one for the reaction with dimethyl propynamine. The present MEDT study proves that analysis of the electrophilicity and nucleophilicity indices is an excellent tool for experimental organic chemists to understand, even to predict, the chemical organic reactivity.

A Close Look to the Oxaphosphetane Formation along the Wittig Reaction: A [2+2] Cycloaddition?

The Wittig reaction between triphenylphosphine methylide and benzaldehyde has been studied both from conceptual and computational approaches. The supernucleophilic character of ylide accounts for the feasibility of the initial nucleophilic attack. The nature of bonding driving the formation of the first oxaphosphetane (OPA) intermediate in such a domino reaction is examined within a topological-based bonding evolution theory perspective. The sequence of the electronic flow associated to the changes in electron density supports a rationalization via two main electronic stages characterizing the single kinetic step: first, the C-C bond formation, which takes place via donation of electron density of the ylide carbon to the carbonyl carbon of benzaldehyde at a C-C distance of 2.02 Å, is formally associated to the transition state region; then, the P-O bond formation via the donation of electron density of the nonbonding region of the carbonyl oxygen to phosphorus at a P-O distance of 2.06 Å is located at the end of the reaction path. The detailed picture of bonding patterns suggests that the OPA formation in the Wittig mechanism can be better understood in terms of a two-stage one-step mechanism beyond molecular orbital considerations behind the traditionally accepted [2+2] cycloaddition proposal.

A molecular electron density theory study of the enhanced reactivity of aza aromatic compounds participating in Diels-Alder reactions.

The enhanced reactivity of a series of four aza aromatic compounds (AACs) participating in the Diels-Alder (DA) reactions with ethylene has been studied using Molecular Electron Density Theory (MEDT). The analysis of the electronic structure of these AACs allows establishing that the substitution of the C-H unity by the isoelectronic N: unity linearly decreases the ring electron density (RED) of these compounds and concomitantly decreases their aromatic character and increases their electrophilic character. These behaviours not only decrease drastically the activation energies of these DA reactions, but also increase the reaction energies when they are compared with the very unfavourable DA reaction between benzene and ethylene. Very good correlations between the NICS(0) values and the electrophilicity ω indices of these AACs with the RED values are found. The present MEDT study makes it possible to establish two empirical electron density unity (EDU) indices accounting for the contribution of the C and N unities, 2.77 and 2.19 e, respectively, for the RED, which is mainly responsible for the reactivity of these AACs. Comprehensive chemical concepts such as electron density, aromaticity and electrophilicity make it possible to explain the chemical reactivity of these AACs participating in DA reactions towards ethylene.

Unveiling the Lewis Acid Catalyzed Diels-Alder Reactions Through the Molecular Electron Density Theory.

The effects of metal-based Lewis acid (LA) catalysts on the reaction rate and regioselectivity in polar Diels-Alder (P-DA) reactions has been analyzed within the molecular electron density theory (MEDT). A clear linear correlation between the reduction of the activation energies and the increase of the polar character of the reactions measured by analysis of the global electron density transfer at the corresponding transition state structures (TS) is found, a behavior easily predictable by analysis of the electrophilicity ω and nucleophilicity N indices of the reagents. The presence of a strong electron-releasing group in the diene changes the mechanism of these P-DA reactions from a two-stage one-step to a two-step one via formation of a zwitterionic intermediate. However, this change in the reaction mechanism does not have any chemical relevance. This MEDT study makes it possible to establish that the more favorable nucleophilic/electrophilic interactions taking place at the TSs of LA catalyzed P-DA reactions are responsible for the high acceleration and complete regioselectivity experimentally observed.

Unveiling the Different Chemical Reactivity of Diphenyl Nitrilimine and Phenyl Nitrile Oxide in [3+2] Cycloaddition Reactions with (R)-Carvone through the Molecular Electron Density Theory.

The [3+2] cycloaddition (32CA) reactions of diphenyl nitrilimine and phenyl nitrile oxide with (R)-carvone have been studied within the Molecular Electron Density Theory (MEDT). Electron localisation function (ELF) analysis of these three-atom-components (TACs) permits its characterisation as carbenoid and zwitterionic TACs, thus having a different reactivity. The analysis of the conceptual Density Functional Theory ( DFT) indices accounts for the very low polar character of these 32CA reactions, while analysis of the DFT energies accounts for the opposite chemoselectivity experimentally observed. Topological analysis of the ELF along the single bond formation makes it possible to characterise the mechanisms of these 32CA reactions as cb- and zw-type. The present MEDT study supports the proposed classification of 32CA reactions into pdr-, pmr-, cb- and zw-type, thus asserting MEDT as the theory able to explain chemical reactivity in Organic Chemistry.

On the nature of organic electron density transfer complexes within molecular electron density theory.

The structural features of a series of organic molecular complexes formed between the strong electrophilic tetracyanoethylene and twelve benzene derivatives with increased nucleophilic character, herein called Electron Density Transfer Complexes (EDTCs), have been studied using Molecular Electron Density Theory. The favourable nucleophilic/electrophilic interactions, which favour the global electron density transfer (GEDT) towards the electrophile, are responsible for the formation of these species. Molecular complexes presenting a GEDT above 0.05e are classified as EDTCs. Analysis of the Parr functions of the separated reagents and the topological analysis of the electron density of the EDTCs allow the understanding of the subtle changes in the electronic structure of this significant class of molecular complexes, and consequently, their physical properties.

Are one-step aromatic nucleophilic substitutions of non-activated benzenes concerted processes?

Aromatic nucleophilic substitution (SNAr) reactions of non-electrophilically activated benzenes have been studied within the Molecular Electron Density Theory (MEDT) at the B3LYP/6-311+G(d) computational level. These reactions, taking place through a one-step mechanism, present a high activation Gibbs free energy, ΔG≠ = 31.0 kcal mol-1, which decreases to 22.1 kcal mol-1 in the intramolecular process. A topological analysis of the electron localisation function along the reaction paths permits establishing the non-concerted nature of these SNAr reactions. A series of unstable structures, with similar electronic structures to those of Meisenheimer intermediates, are characterised. The present MEDT study makes it possible to establish that even these one-step SNAr reactions involving only two single bonds are non-concerted processes.