Density functional theory and enzyme studies support interactions between angiotensin receptor blockers and angiotensin converting enzyme-2: Relevance to coronavirus 2019.

The binding affinities and interactions between eight drug candidates, both commercially available (candesartan; losartan; losartan carboxylic acid; nirmatrelvir; telmisartan) and newly synthesized benzimidazole-N-biphenyltetrazole (ACC519T), benzimidazole bis-N,N'-biphenyltetrazole (ACC519T(2) and 4-butyl-N,N-bis([2-(2H-tetrazol-5-yl)biphenyl-4-yl]) methyl (BV6), and the active site of angiotensin-converting enzyme-2 (ACE2) were evaluated for their potential as inhibitors against SARS-CoV-2 and regulators of ACE2 function through Density Functional Theory methodology and enzyme activity assays, respectively. Notably, telmisartan and ACC519T(2) exhibited pronounced binding affinities, forming strong interactions with ACE2's active center, favorably accepting proton from the guanidinium group of arginine273. The ordering of candidates by binding affinity and reactivity descriptors, emerged as telmisartan > ACC519T(2) > candesartan > ACC519T > losartan carboxylic acid > BV6 > losartan > nirmatrelvir. Proton transfers among the active center amino acids revealed their interconnectedness, highlighting a chain-like proton transfer involving tyrosine, phenylalanine, and histidine. Furthermore, these candidates revealed their potential antiviral abilities by influencing proton transfer within the ACE2 active site. Furthermore, through an in vitro pharmacological assays we determined that candesartan and the BV6 derivative, 4-butyl-N,N0-bis[20-2Htetrazol-5-yl)bipheyl-4-yl]methyl)imidazolium bromide (BV6(K+)2) also contain the capacity to increase ACE2 functional activity. This comprehensive analysis collectively underscores the promise of these compounds as potential therapeutic agents against SARS-CoV-2 by targeting crucial protein interactions.

Quadruple bonds in MoC: Accurate calculations and precise measurement of the dissociation energy of low-lying states of MoC.

In the present work, the electronic structure and chemical bonding of the MoC X3Σ- ground state and the six lowest excited states, A3Δ, a1Γ, b5Σ-, c1Δ, d1Σ+, and e5Π, have been investigated in detail using multireference configuration interaction methods and basis sets, including relativistic effective core potentials. In addition, scalar relativistic effects have been considered in the second order Douglas-Kroll-Hess approximation, while spin-orbit coupling has also been calculated. Five of the investigated states, X3Σ-, A3Δ, a1Γ, c1Δ, and d1Σ+, present quadruple σ2σ2π2π2 bonds. Experimentally, the predissociation threshold of MoC was measured using resonant two-photon ionization spectroscopy, allowing for a precise measurement of the dissociation energy of the ground state. Theoretically, the complete basis set limit of the calculated dissociation energy with respect to the atomic ground state products, including corrections for scalar relativistic effects, De(D0), is computed as 5.13(5.06) eV, in excellent agreement with our measured value of D0(MoC) of 5.136(5) eV. Furthermore, the calculated dissociation energies of the states having quadruple bonds with respect to their adiabatic atomic products range from 6.22 to 7.23 eV. The excited electronic states A3Δ2 and c1Δ2 are calculated to lie at 3899 and 8057 cm-1, also in excellent agreement with the experimental values of DaBell et al., 4002.5 and 7834 cm-1, respectively.

Synthesis of Thiazolidin-4-Ones Derivatives, Evaluation of Conformation in Solution, Theoretical Isomerization Reaction Paths and Discovery of Potential Biological Targets.

Thiazolin-4-ones and their derivatives represent important heterocyclic scaffolds with various applications in medicinal chemistry. For that reason, the synthesis of two 5-substituted thiazolidin-4-one derivatives was performed. Their structure assignment was conducted by NMR experiments (2D-COSY, 2D-NOESY, 2D-HSQC and 2D-HMBC) and conformational analysis was conducted through Density Functional Theory calculations and 2D-NOESY. Conformational analysis showed that these two molecules adopt exo conformation. Their global minimum structures have two double bonds (C=N, C=C) in Z conformation and the third double (C=N) in E. Our DFT results are in agreement with the 2D-NMR measurements. Furthermore, the reaction isomerization paths were studied via DFT to check the stability of the conformers. Finally, some potential targets were found through the SwissADME platform and docking experiments were performed. Both compounds bind strongly to five macromolecules (triazoloquinazolines, mglur3, Jak3, Danio rerio HDAC6 CD2, acetylcholinesterase) and via SwissADME it was found that these two molecules obey Lipinski's Rule of Five.

Computational and Spectroscopic Studies on the Formation of Halogen-Bonded Complexes Between Tertiary Amines and CBr4 and Application in the Light-Mediated Amino Acid Coupling.

In recent years, halogen-bonded complexes (XBCs), in solution, have played a pivotal role in inducing photochemical organic reactions. In this work, we explore the ability of various tertiary amines to act as XB acceptors in the presence of the XB donor CBr4 by computational and spectroscopic studies. DFT studies clearly showcase the formation of XBCs between the studied tertiary amines and CBr4. Simultaneously, computational and experimental UV-Vis studies display intense red shifts that are consistent with charge transfer observed from tertiary amines to CBr4. A detailed NMR study revealed a clear chemical shift of the carbon carrying the bromine atoms upon mixing the XB acceptor with the donor, suggesting that this spectroscopic technique is indeed an experimental tool to identify the generation of XBCs. An application of the ability of such XBCs to activate a carboxylic acid under UVA irradiation or sunlight is presented for amino acid coupling. Among the various tertiary amines studied, the pair DABCO-CBr4 was found to work well for the photochemical amide bond formation. Direct infusion-HRMS studies allowed us to propose a general mechanism for the photochemical amino acid coupling in the presence of a tertiary amine and CBr4, initiated by the photoactivation of an XBC.

Electronic Structure and Chemical Bonding of the First-, Second-, and Third-Row-Transition-Metal Monoborides: The Formation of Quadruple Bonds in RhB, RuB, and TcB.

Boron presents an important role in chemistry, biology, and materials science. Diatomic transition-metal borides (MBs) are the building blocks of many complexes and materials, and they present unique electronic structures with interesting and peculiar properties and a variety of bonding schemes which are analyzed here. In the first part of this paper, we present a review on the available experimental and theoretical studies on the first-row-transition-metal borides, i.e., ScB, TiB, VB, CrB, MnB, FeB, CoB, NiB, CuB, and ZnB; the second-row-transition-metal borides, i.e., YB, ZrB, NbB, MoB, TcB, RuB, RhB, PdB, AgB, and CdB; and the third-row-transition-metal borides, i.e., LaB, HfB, TaB, WB, ReB, OsB, IrB, PtB, AuB, and HgB. Consequently, in the second part, the second- and third-row MBs are studied via DFT calculations using the B3LYP, TPSSh, and MN15 functionals and, in some cases, via multi-reference methods, MRCISD+Q, in conjunction with the aug-cc-pVQZ-PPM/aug-cc-pVQZB basis sets. Specifically, bond distances, dissociation energies, frequencies, dipole moments, and natural NPA charges are reported. Comparisons between MB molecules along the three rows are presented, and their differences and similarities are analyzed. The bonding of the diatomic borides is also described; it is found that, apart from RhB(X1Σ+), which was just recently found to form quadruple bonds, RuB(X2Δ) and TcB(X3Σ-) also form quadruple σ2σ2π2π2 bonds in their X states. Moreover, to fill the gap existing in the current literature, here, we calculate the TcB molecule.

Electronic Structure of the Low-Lying States of the Triatomic MoS2 Molecule: The Building Block of 2D MoS2.

Molybdenum disulfide (MoS2 ) is the building component of 1D-monolayer, 2D-layered nanosheets and nanotubes having many applications in industry, and it is detected in various molecular systems observed in nature. Here, the electronic structure and the chemical bonding of sixteen low-lying states of the triatomic MoS2 molecule are investigated, while the connection of the chemical bonding of the isolated MoS2 molecule to the relevant 2D-MoS2 , is emphasized. The MoS2 molecule is studied via DFT and multireference methodologies, i. e., MRCISD(+Q)/aug-cc-pVQZ(-PP)Mo . The ground state, X ˜ ${\tilde{X}}$ 3 B1 , is bent (Mo-S=2.133 Šand ϕ(SMoS)=115.9°) with a dissociation energy to atomic products of 194.7 kcal/mol at MRCISD+Q. In the ground and in the first excited state a double bond is formed between Mo and each S atom, i. e., a 1 2 a 1 2 b 2 2 a 2 2 ${{{\rm a}}_{1}^{2}{{\rm a}}_{1}^{2}{{\rm b}}_{2}^{2}{{\rm a}}_{2}^{2}}$ . These two states differ in which d electrons of Mo are unpaired. The Mo-S bond distances of the calculated states range from 2.108 to 2.505 Å, the SMoS angles range from 104.1 to 180.0°, and the Mo-S bonds are single or double. Potential energy curves and surfaces have been plotted for the X ˜ ${\tilde{X}}$ 3 B1 , 5 A1 and 5 B1 states. Finally, the low-lying septet states of the triatomic molecule are involved in the material as a building block, explaining the variety of its morphologies.

Photoswitchable Molecular Units with Tunable Nonlinear Optical Activity: A Theoretical Investigation.

The first-, second-, and third-order molecular nonlinear optical properties, including two-photon absorption of a series of derivatives, involving two dithienylethene (DTE) groups connected by several molecular linkers (bis(ethylene-1,2-dithiolato)Ni- (NiBDT), naphthalene, quasilinear oligothiophene chains), are investigated by employing density functional theory (DFT). These properties can be efficiently controlled by DTE switches, in connection with light of appropriate frequency. NiBDT, as a linker, is associated with a greater contrast, in comparison to naphthalene, between the first and second hyperpolarizabilities of the "open-open" and the "closed-closed" isomers. This is explained by invoking the low-lying excited states of NiBDT. It is shown that the second hyperpolarizability can be used as an index, which follows the structural changes induced by photochromism. Assuming a Förster type transfer mechanism, the intramolecular excited-state energy transfer (EET) mechanism is studied. Two important parameters related to this are computed: the electronic coupling (VDA) between the donor and acceptor fragments as well as the overlap between the absorption and emission spectra of the donor and acceptor groups. NiBDT as a linker is associated with a low electronic coupling, VDA, value. We found that VDA is affected by molecular geometry. Our results predict that the linker strongly influences the communication between the open-closed DTE groups. The sensitivity of the molecular nonlinear optical properties could assist with identification of molecular isomers.

Microwave-Assisted, Copper-Catalyzed Domino O-H/C-H Arylation Reaction toward the Synthesis of Oxygen-Doped Polyaromatic Molecules.

Benzoxanthenes and their analogues are a very important class of compounds mainly due to their wide range of biological and technological applications. The development of a new methodology for their synthesis, involving an Ullmann-type coupling followed by an intramolecular C-H arylation, catalyzed by copper in a domino fashion, is reported. A variety of para-substituted phenols are amenable to this methodology, affording the desired products in moderate to good yields. Our protocol is expedient and practical and is carried out under microwave irradiation in only 3 min under air. A plausible catalytic cycle is proposed based on experimental mechanistic investigations and density functional theory (DFT) calculations.

Metallocene-Naphthalimide Derivatives: The Effect of Geometry, DFT Methodology, and Transition Metals on Absorption Spectra.

In the present paper, the photophysical properties of metallocene-4-amino-1,8-naphthalimide-piperazine molecules (1-M2+), as well as their oxidized and protonated derivatives (1-M3+, 1-M2+-H+, and 1-M3+-H+), where M = Fe, Co, and Ni, were studied via DFT and TD-DFT, employing three functionals, i.e., PBE0, TPSSh, and wB97XD. The effect of the substitution of the transition metal M on their oxidation state, and/or the protonation of the molecules, was investigated. The present calculated systems have not been investigated before and, except for the data regarding their photophysical properties, the present study provides important information regarding the effect of geometry and of DFT methodology on absorption spectra. It was found that small differences in geometry, specifically in the geometry of N atoms, reflect significant differences in absorption spectra. The common differences in spectra due to the use of different functionals can be significantly increased when the functionals predict minima even with small geometry differences. For most of the calculated molecules, the main absorption peaks in visible and near-UV areas correspond mainly to charge transfer excitations. The Fe complexes present larger oxidation energies at 5.4 eV, whereas Co and Ni complexes have smaller ones, at about 3.5 eV. There are many intense UV absorption peaks with excitation energies similar to their oxidation energies, showing that the emission from these excited states can be antagonistic to their oxidation. Regarding the use of functionals, the inclusion of dispersion corrections does not affect the geometry, and consequently the absorption spectra, of the present calculated molecular systems. For certain applications, where there is a need for a redox molecular system including metallocene, the oxidation energies could be lowered significantly, to about 40%, with the replacement of the iron with cobalt or nickel. Finally, the present molecular system, using cobalt as the transition metal, has the potential to be used as a sensor.

Thiocarbohydrazone and Chalcone-Derived 3,4-Dihydropyrimidinethione as Lipid Peroxidation and Soybean Lipoxygenase Inhibitors.

The potential of the 4,6-diphenyl-3,4-dihydropyrimidine-2(1H)-thione (abbreviated as KKII5) and (E)-N'-benzylidenehydrazinecarbothiohydrazide (abbreviated as DKI5) compounds as possible drug leads is investigated. KKII5 and DKI5 are synthesized in high yield of up to 97%. Their structure, binding in the active site of the LOX-1 enzyme, and their toxicity are studied via joint experimental and computational methodologies. Specifically, the structure assignment and conformational analysis were achieved by applying homonuclear and heteronuclear 2D nuclear magnetic resonance (NMR) spectroscopy (2D-COSY, 2D-NOESY, 2D-HSQC, and 2D-HMBC) and density functional theory (DFT). The obtained DFT lowest energy conformers were in agreement with the NOE correlations observed in the 2D-NOESY spectra. Additionally, docking and molecular dynamics simulations were performed to discover their ability to bind and remain stabile in the active site of the LOX-1 enzyme. These in silico experiments and DFT calculations indicated favorable binding for the enzyme under study. The strongest binding energy, -9.60 kcal/mol, was observed for dihydropyrimidinethione KKII5 in the active site of LOX-1. ADMET calculations showed that the two molecules lack major toxicities and could serve as possible drug leads. The redox potential of the active center of LOX-1 with the binding molecules was calculated via DFT methodology. The results showed a significantly smaller energy attachment of 2.8 eV with KKII5 binding in comparison to DKI5. Thus, KKII5 enhanced the ability of the active center to receive electrons compared to DKI5. This is related to the stronger binding interaction of KKII5 relative to that of DK15 to LOX-1. The two very potent LOX-1 inhibitors exerted IC50 19 µΜ (KKII5) and 22.5 µΜ (DKI5). Furthermore, they both strongly inhibit lipid peroxidation, namely, 98% for KKII5 and 94% for DKI5.

An Efficient Light-Mediated Protocol for the Direct Amide Bond Formation via a Novel Carboxylic Acid Photoactivation Mode by Pyridine-CBr4.

The direct amide bond formation between a carboxylic acid and an amine still constitutes a challenging reaction for both academia and industry. We demonstrate herein that several pairs of amines (halogen bond acceptors) and organohalogen sources may be used for the photochemical amidation reaction under either UVA or sunlight irradiation. Our studies led to the identification of pyridine-CBr4 as an efficient agent to perform amide synthesis under LED 370 nm irradiation, avoiding super-stoichiometric quantities. An extended substrate scope was demonstrated, showing that the widely used amino and carboxyl protecting groups are compatible with this photochemical protocol, while a number of industrially interesting products and bioactive compounds were synthesized. Direct infusion-high resolution mass spectrometry studies suggest an unprecedented type of carboxylic acid activation mode upon irradiation, involving the generation of a symmetric anhydride, an active ester with pyridine N-oxide and a mixed anhydride with hypobromous acid.

Magnetic anisotropy and structural flexibility in the field-induced single ion magnets [Co{(OPPh2)(EPPh2)N}2], E = S, Se, explored by experimental and computational methods.

During the last few years, a large number of mononuclear Co(II) complexes of various coordination geometries have been explored as potential single ion magnets (SIMs). In the work presented herein, the Co(II) S = 3/2 tetrahedral [Co{(OPPh2)(EPPh2)N}2], E = S, Se, complexes (abbreviated as CoO2E2), bearing chalcogenated mixed donor-atom imidodiphosphinato ligands, were studied by both experimental and computational techniques. Specifically, direct current (DC) magnetometry provided estimations of their zero-field splitting (zfs) axial (D) and rhombic (E) parameter values, which were more accurately determined by a combination of far-infrared magnetic spectroscopy and high-frequency and -field EPR spectroscopy studies. The latter combination of techniques was also implemented for the S = 3/2 tetrahedral [Co{(EPiPr2)2N}2], E = S, Se, complexes, confirming the previously determined magnitude of their zfs parameters. For both pairs of complexes (E = S, Se), it is concluded that the identity of the E donor atom does not significantly affect their zfs parameters. High-resolution multifrequency EPR studies of CoO2E2 provided evidence of multiple conformations, which are more clearly observed for CoO2Se2, in agreement with the structural disorder previously established for this complex by X-ray crystallography. The CoO2E2 complexes were shown to be field-induced SIMs, i.e., they exhibit slow relaxation of magnetization in the presence of an external DC magnetic field. Advanced quantum-chemical calculations on CoO2E2 provided additional insight into their electronic and structural properties.

Structure assignment, conformational properties and discovery of potential targets of the Ugi cinnamic adduct NGI25.

The structure assignment and conformational analysis of cinnamic derivative N-benzyl-N-(2-(cyclohexylamino)-2-oxoethyl) cinnamamide (NGI25) was carried out through Nuclear Magnetic Resonance (NMR) spectroscopy, Molecular Dynamics (MD) and Quantum Mechanics (QM), i.e. semiempirical and Density Functional Theory (DFT) calculations. Moreover, Homonuclear (COSY, NOESY) and heteronuclear (HSQC, HMBC) experiments were applied to assign its protons and carbons. After structure identification, NGI25 was subjected to computational calculations to reveal its most favorable conformations. In particular, MD studies were performed in two different solvents, DMSO of intermediate polarity and hydrophobic CHCl3. The obtained results suggest that NGI25 adopts similar conformations in both environments. In particular, the two aromatic rings of the molecule reside in spatial vicinity, while they remain quite distant from the cyclohexane. 2D NOESY experiments confirmed the in silico MD and QM calculations. Finally, molecular docking calculations were performed in order to reveal possible enzyme-targets for NGI25. Swiss target module was used to guide the discovery of new targets based on the structure of NGI. Indeed, it was predicted that NGI25 inhibited butyrylcholinesterase (BCHE) and lipoxygenase (LOX). Molecular docking experiments, followed by Molecular Dynamics studies, confirmed the favorable binding of NGI25 to both enzymes.Communicated by Ramaswamy H. Sarma.

Self Cycloaddition of o-Naphthoquinone Nitrosomethide to (±) Spiro{naphthalene(naphthopyranofurazan)}-one Oxide: An Insight into its Formation.

2-Hydroxy-1-naphthaldehyde oxime was oxidized by AgO (or Ag2 O), in presence of N-methyl morpholine N-oxide (NMMO), to the title spiro adduct-dimer (±)-Spiro{naphthalene-1(2H),4'-(naphtho[2',1':2,3]pyrano[4,5-c]furazan)}-2-one-11'-oxide by a Diels-Alder(D-A) type self-cycloaddition, through the agency of an o-naphthoquinone nitrosomethide (o-NQM). Moreover, 2-hydroxy-8-methoxy-1-naphthaldehyde oxime was prepared and subjected to the same oxidation conditions. Its sterically guided result, 9-methoxynaphtho[1,2-d]isoxazole, was isolated, instead of the expected spiro adduct. The peri intramolecular H bonding in the oxime is considered to have a key contribution to the outcome. Geometry and energy features of the oxidant- and stereo-guided selectivity of both oxidation outcomes have been explored by DFT, perturbation theory and coupled cluster calculations. The reaction free energy of the D-A intermolecular cycloaddition is calculated at -82.0 kcal/mol, indicating its predominance over the intramolecular cyclization of ca. -37.6 kcal/mol. The cycloaddition is facilitated by NMMO through dipolar interactions and hydrogen bonding with both metal complexes and o-NQM. The 8(peri)-OMe substitution of the reactant oxime sterically impedes formation of the spiro adduct, instead it undergoes a more facile cyclodehydration to the isoxazole structure by ca. 4.9 kcal/mol.

The many-body expansion for metals. I. The alkaline earth metals Be, Mg, and Ca.

We examine the many-body expansion (MBE) for alkaline earth metal clusters, Ben, Mgn, Can (n = 4, 5, 6), at the Møller-Plesset second order perturbation theory, coupled-cluster singles and doubles with perturbative triples, multi-reference perturbation theory, and multi-reference configuration interaction levels of theory. The magnitude of each term in the MBE is evaluated for several geometrical configurations. We find that the behavior of the MBE for these clusters depends strongly on the geometrical arrangement and, to a lesser extent, on the level of theory used. Another factor that affects the MBE is the in situ (ground or excited) electronic state of the individual atoms in the cluster. For most geometries, the three-body term is the largest, followed by a steady decrease in absolute energy for subsequent terms. Though these systems exhibit non-negligible multi-reference effects, there was little qualitative difference in the MBE when employing single vs multi-reference methods. Useful insights into the connectivity and stability of these clusters have been drawn from the respective potential energy surfaces and quasi-atomic orbitals for the various dimers, trimers, and tetramers. Through these analyses, we investigate the similarities and differences in the binding energies of different-sized clusters for these metals.

Comparative Interaction Studies of Quercetin with 2-Hydroxyl-propyl-ß-cyclodextrin and 2,6-Methylated-ß-cyclodextrin.

Quercetin (QUE) is a well-known natural product that can exert beneficial properties on human health. However, due to its low solubility its bioavailability is limited. In the present study, we examine whether its formulation with two cyclodextrins (CDs) may enhance its pharmacological profile. Comparative interaction studies of quercetin with 2-hydroxyl-propyl-ß-cyclodextrin (2HP-ß-CD) and 2,6-methylated cyclodextrin (2,6Me-ß-CD) were performed using NMR spectroscopy, DFT calculations, and in silico molecular dynamics (MD) simulations. Using T1 relaxation experiments and 2D DOSY it was illustrated that both cyclodextrin vehicles can host quercetin. Quantum mechanical calculations showed the formation of hydrogen bonds between QUE with 2HP-ß-CD and 2,6Μe-ß-CD. Six hydrogen bonds are formed ranging between 2 to 2.8 Å with 2HP-ß-CD and four hydrogen bonds within 2.8 Å with 2,6Μe-ß-CD. Calculations of absolute binding free energies show that quercetin binds favorably to both 2,6Me-ß-CD and 2HP-ß-CD. MM/GBSA results show equally favorable binding of quercetin in the two CDs. Fluorescence spectroscopy shows moderate binding of quercetin in 2HP-ß-CD (520 M-1) and 2,6Me-ß-CD (770 M-1). Thus, we propose that both formulations (2HP-ß-CD:quercetin, 2,6Me-ß-CD:quercetin) could be further explored and exploited as small molecule carriers in biological studies.

Analysis of chemical bonding of the ground and low-lying states of Mo2 and of Mo2Clx complexes, x = 2-10.

In this study, we perform accurate calculations via multireference configuration interaction and coupled cluster methodologies on the dimolybdenum molecule in conjunction with complete series of correlation and weighted core correlation consistent basis sets up to quintuple size. The bonding, the dissociation energies, and the spectroscopic parameters of the seven states that correlate with the ground state products are calculated. The ground state has a sextuple chemical bond, and each of the calculated excited states has one less bond than the previous state. The calculated values for the ground X1Σg + state of Mo2 have been extrapolated to the complete basis set limits. Our final values, re = 1.9324 Å and De (D0) = 4.502 ± 0.007(4.471 ± 0.009) eV, are in excellent agreement with the experimental values of re = 1.929, 1.938(9) Å and D0 = 4.476(10) eV. Mo2 in the Σg+13 state is a weakly bound dimer, forming 5s⋯5pz bonds, with De = 0.120 eV at re = 3.53 Å. All calculated excited states (except Σg+13) have a highly multireference character (C0 = 0.25-0.55). The ordering of the molecular bonding orbitals changes as the spin is increased from quintet to septet state resulting in a change in energy separation ΔS,S-1 of the calculated states. The quite low bond dissociation energy of the ground state is due to the splitting of the molecular bonding orbitals in two groups differing in energy by ∼3 eV. Finally, the bond breaking of Mo2, as the multiplicity of spin is increased, is analyzed in parallel with the Mo-Mo bond breaking in a series of Mo2Clx complexes when x is increased. Physical insight into the nature of the sextuple bond and its low dissociation energy is provided.