Copper(II) Chelates of Schiff Bases Enriched with Aliphatic Fragments: Synthesis, Crystal Structure, In Silico Studies of ADMET Properties and a Potency against a Series of SARS-CoV-2 Proteins

We report two complexes [Cu(LI)2] (1) and [Cu(LII)2] (2) (HLI = N-cyclohexyl-3-methoxysalicylideneimine, HLII = N-cyclohexyl-3-ethoxysalicylideneimine). The ligands in both complexes are trans-1,5-N,O-coordinated, yielding a square planar CuN2O2 coordination core. The molecule of 1 is planar with two cyclohexyl groups oriented to the opposite sites of the planar part of a molecule, while the molecule of 2 is significantly bent with two cyclohexyl groups oriented to the same convex site of a molecule. It was established that both complexes in MeOH absorb in the UV region due to intraligand transitions and LMCT. Furthermore, the UV-vis spectra of both complexes revealed two low intense shoulders in the visible region at about 460 and 520 nm, which were attributed to d–d transitions. Both complexes were predicted to belong to a fourth class of toxicity with the negative BBB property and positive gastrointestinal absorption property. According to the molecular docking analysis results, both complexes are active against all the applied SARS-CoV-2 proteins with the best binding affinity with Nsp 14 (N7-MTase), PLpro and Mpro. The obtained docking scores of complexes are either comparable to or even higher than those of the initial ligands. Complex 1 was found to be more efficient upon interaction with the applied proteins in comparison to complex 2. Ligand efficiency scores for the initial ligands, 1 and 2 were also revealed.

A Novel Ambroxol-Derived Tetrahydroquinazoline with a Potency against SARS-CoV-2 Proteins

We report synthesis of a novel 1,2,3,4-tetrahydroquinazoline derivative, named 2-(6,8-dibromo-3-(4-hydroxycyclohexyl)-1,2,3,4-tetrahydroquinazolin-2-yl)phenol (1), which was obtained from the hydrochloride of 4-((2-amino-3,5-dibromobenzyl)amino)cyclohexan-1-ol (ambroxol hydrochloride) and salicylaldehyde in EtOH. The resulting compound was produced in the form of colorless crystals of the composition 1∙0.5EtOH. The formation of the single product was confirmed by the IR and 1H spectroscopy, single-crystal and powder X-ray diffraction, and elemental analysis. The molecule of 1 contains a chiral tertiary carbon of the 1,2,3,4-tetrahydropyrimidine fragment and the crystal structure of 1∙0.5EtOH is a racemate. Optical properties of 1∙0.5EtOH were revealed by UV-vis spectroscopy in MeOH and it was established that the compound absorbs exclusively in the UV region up to about 350 nm. 1∙0.5EtOH in MeOH exhibits dual emission and the emission spectra contains bands at about 340 and 446 nm upon excitation at 300 and 360 nm, respectively. The DFT calculations were performed to verify the structure as well as electronic and optical properties of 1. ADMET properties of the R-isomer of 1 were evaluated using the SwissADME, BOILED-Egg, and ProTox-II tools. As evidenced from the blue dot position in the BOILED-Egg plot, both human blood–brain barrier penetration and gastrointestinal absorption properties are positive with the positive PGP effect on the molecule. Molecular docking was applied to examine the influence of the structures of both R-isomer and S-isomer of 1 on a series of the SARS-CoV-2 proteins. According to the docking analysis results, both isomers of 1 were found to be active against all the applied SARS-CoV-2 proteins with the best binding affinities with Papain-like protease (PLpro) and nonstructural protein 3 (Nsp3_range 207–379-AMP). Ligand efficiency scores for both isomers of 1 inside the binding sites of the applied proteins were also revealed and compared with the initial ligands. Molecular dynamics simulations were also applied to evaluate the stability of complexes of both isomers with Papain-like protease (PLpro) and nonstructural protein 3 (Nsp3_range 207–379-AMP). The complex of the S-isomer with Papain-like protease (PLpro) was found to be highly unstable, while the other complexes are stable.

A Novel Ambroxol-Derived Tetrahydroquinazoline with a Potency against SARS-CoV-2 Proteins.

We report synthesis of a novel 1,2,3,4-tetrahydroquinazoline derivative, named 2-(6,8-dibromo-3-(4-hydroxycyclohexyl)-1,2,3,4-tetrahydroquinazolin-2-yl)phenol (1), which was obtained from the hydrochloride of 4-((2-amino-3,5-dibromobenzyl)amino)cyclohexan-1-ol (ambroxol hydrochloride) and salicylaldehyde in EtOH. The resulting compound was produced in the form of colorless crystals of the composition 1∙0.5EtOH. The formation of the single product was confirmed by the IR and 1H spectroscopy, single-crystal and powder X-ray diffraction, and elemental analysis. The molecule of 1 contains a chiral tertiary carbon of the 1,2,3,4-tetrahydropyrimidine fragment and the crystal structure of 1∙0.5EtOH is a racemate. Optical properties of 1∙0.5EtOH were revealed by UV-vis spectroscopy in MeOH and it was established that the compound absorbs exclusively in the UV region up to about 350 nm. 1∙0.5EtOH in MeOH exhibits dual emission and the emission spectra contains bands at about 340 and 446 nm upon excitation at 300 and 360 nm, respectively. The DFT calculations were performed to verify the structure as well as electronic and optical properties of 1. ADMET properties of the R-isomer of 1 were evaluated using the SwissADME, BOILED-Egg, and ProTox-II tools. As evidenced from the blue dot position in the BOILED-Egg plot, both human blood-brain barrier penetration and gastrointestinal absorption properties are positive with the positive PGP effect on the molecule. Molecular docking was applied to examine the influence of the structures of both R-isomer and S-isomer of 1 on a series of the SARS-CoV-2 proteins. According to the docking analysis results, both isomers of 1 were found to be active against all the applied SARS-CoV-2 proteins with the best binding affinities with Papain-like protease (PLpro) and nonstructural protein 3 (Nsp3_range 207-379-AMP). Ligand efficiency scores for both isomers of 1 inside the binding sites of the applied proteins were also revealed and compared with the initial ligands. Molecular dynamics simulations were also applied to evaluate the stability of complexes of both isomers with Papain-like protease (PLpro) and nonstructural protein 3 (Nsp3_range 207-379-AMP). The complex of the S-isomer with Papain-like protease (PLpro) was found to be highly unstable, while the other complexes are stable.

Copper(II) Chelates of Schiff Bases Enriched with Aliphatic Fragments: Synthesis, Crystal Structure, In Silico Studies of ADMET Properties and a Potency against a Series of SARS-CoV-2 Proteins.

We report two complexes [Cu(LI)2] (1) and [Cu(LII)2] (2) (HLI = N-cyclohexyl-3-methoxysalicylideneimine, HLII = N-cyclohexyl-3-ethoxysalicylideneimine). The ligands in both complexes are trans-1,5-N,O-coordinated, yielding a square planar CuN2O2 coordination core. The molecule of 1 is planar with two cyclohexyl groups oriented to the opposite sites of the planar part of a molecule, while the molecule of 2 is significantly bent with two cyclohexyl groups oriented to the same convex site of a molecule. It was established that both complexes in MeOH absorb in the UV region due to intraligand transitions and LMCT. Furthermore, the UV-vis spectra of both complexes revealed two low intense shoulders in the visible region at about 460 and 520 nm, which were attributed to d-d transitions. Both complexes were predicted to belong to a fourth class of toxicity with the negative BBB property and positive gastrointestinal absorption property. According to the molecular docking analysis results, both complexes are active against all the applied SARS-CoV-2 proteins with the best binding affinity with Nsp 14 (N7-MTase), PLpro and Mpro. The obtained docking scores of complexes are either comparable to or even higher than those of the initial ligands. Complex 1 was found to be more efficient upon interaction with the applied proteins in comparison to complex 2. Ligand efficiency scores for the initial ligands, 1 and 2 were also revealed.

DFT, ADMET, molecular docking and molecular dynamics studies of pyridoxal

We report in silico studies of pyridoxal, which is of interest both as a precursor for further functionalization due to the presence of the aldehyde functionality, as well as a bioactive compound. So far, the crystal structure of pyridoxal has not been reported and, thus, we have optimized its structure both under water solvation and in gas phase using the DFT calculations. Under water solvation conditions the optimized structure of pyridoxal is 7.62 kcal/mol more favorable in comparison to that in gas phase. The DFT calculations were also applied to verify optical and electronic properties of the optimized structure of pyridoxal in water. The HOMO and LUMO were revealed to subtract a set of descriptors of the so-called global chemical reactivity as well as to probe pyridoxal as a potential corrosion inhibitor for some important metals used in implants. The title compound exhibits the best electron charge transfer from the molecule to the surface of Ni and Co. Some biological properties of pyridoxal were evaluated using the respective on-line tools. Molecular docking was additionally applied to study interaction of pyridoxal with some SARS-CoV-2 proteins as well as one of the monkeypox proteins. It was established that the title compound is active against all the applied proteins with the most efficient interaction with nonstructural protein 15 (endoribonuclease) and Omicron Spike protein of SARS-CoV-2. Pyridoxal was found to be also active against the studied monkeypox protein. Interaction of pyridoxal with nonstructural protein 15 (endoribonuclease) was further studied using molecular dynamics simulation.

A novel coumarin-triazole-thiophene hybrid: synthesis, characterization, ADMET prediction, molecular docking and molecular dynamics studies with a series of SARS-CoV-2 proteins.

Synthesis, characterization and theoretical studies of a novel coumarin-triazole-thiophene hybrid 4-(((4-ethyl-5-(thiophen-2-yl)-4H-1,2,4-triazol-3-yl)thio)methyl)-6,7-dimethyl-2H-chromen-2-one (1), which was fabricated from 4-ethyl-5-(thiophen-2-yl)-4H-1,2,4-triazole-3-thiol and 4-(chloromethyl)-6,7-dimethyl-2H-chromen-2-one, are reported. The resulting compound was characterized by microanalysis, IR, 1H, and 13C APT NMR spectroscopy. The DFT calculations examined the structure and electronic properties of 1 in gas phase. Its reactivity descriptors and molecular electrostatic potential revealed the reactivity and the reactive centers of 1. ADMET properties of 1 were evaluated using the respective online tools. It was established that 1 exhibit positive gastrointestinal absorption properties and negative human blood-brain barrier penetration. The Toxicity Model Report revealed that 1 belongs to toxicity class 4. Molecular docking was additionally applied to study the interaction of 1 with some SARS-CoV-2 proteins. It was established that the title compound is active against all the applied proteins with the most efficient interaction with Papain-like protease (PLpro). The interaction of 1 with the applied proteins was also studied using molecular dynamics simulations. Graphical abstract: A novel coumarin-triazole-thiophene hybrid 4-(((4-ethyl-5-(thiophen-2-yl)-4H-1,2,4-triazol-3-yl)thio)methyl)-6,7-dimethyl-2H-chromen-2-one (1) is reported. The structure and electronic properties of 1 were examined by the DFT calculations. ADMET properties of 1 were also evaluated. Molecular docking and molecular dynamics simulations were applied to study interactions of 1 with a series of the SARS-CoV-2 proteins. Supplementary Information: The online version contains supplementary material available at 10.1007/s12039-022-02127-0.

In silico analyses of betulin: DFT studies, corrosion inhibition properties, ADMET prediction, and molecular docking with a series of SARS-CoV-2 and monkeypox proteins

We report detailed computational studies of betulin — a pentacyclic naturally occuring triterpene, which is a precursor for a broad family of biologically active derivatives. The structure, electronic, and optical properties of betulin were studied by the density functional theory (DFT) calculations in gas phase. The reactivity and the reactive centers of betulin were revealed through its global reactivity descriptors and molecular electrostatic potential (MEP). The DFT calculations were also applied to probe betulin as a potential corrosion inhibitor for some important metals used in implants. Electron charge transfer from the molecule of betulin to the surface of all the examined metals (Ti, Fe, Zr, Co, Cu, Cr, Ni, Mn, Mo, Zn, Al, W, Ag, Au) was revealed, of which the best results were obtained for Ni, Au and Co. Bioavailability, druggability as well as absorption, distribution, metabolism, excretion and toxicity (ADMET) properties of betulin were evaluated using the SwissADME, BOILED-Egg and ProTox-II tools. Molecular docking was applied to examine the influence of the title compound on a series of the SARS-CoV-2 proteins as well as one of the monkeypox proteins. It was established that betulin is active against all the applied proteins with the best binding affinity with papain-like protease (PLpro) and spike protein (native) of SARS-CoV-2. The title compound is also active against the studied monkeypox protein. Interaction of betulin with papain-like protease (PLpro) was studied using molecular dynamics simulations.

Synthesis, Characterization and Computational Analysis of Thiophene-2,5-Diylbis((3-Mesityl-3-Methylcyclobutyl)Methanone)

In this work, we report synthesis, characterization and computational studies of the symmetric thiophene-based compound thiophene-2,5-diylbis((3-mesityl-3-methylcyclobutyl)methanone) (1) obtained from 2,2'-thiobis(1-(3-mesityl-3-methylcyclobutyl)ethan-1-one) and glyoxal using the Hinsberg thiophene ring synthesis approach. The Density Functional Theory (DFT) calculations were performed to probe the structure of 1, as well as its electronic and optical properties. The global reactivity descriptors, as well as molecular electrostatic potential (MEP), were revealed to probe the reactivity and to determine the reactive centers of 1. The DFT calculations were also applied to probe 1 as a potential corrosion inhibitor for some important metals used in implants. Electron charge transfer from the molecule of 1 to the surface of Ni, Au, Co, Cu, Mo, W, Fe and Cr was revealed. Bioavailability, druggability as well as absorption, distribution, metabolism, excretion and toxicity properties of 1 were predicted. Molecular docking was applied to examine the influence of this compound on a series of the SARS-CoV-2 proteins. Compound 1 exhibited the best binding affinity with the Nsp14 (N7-MTase), Papain-like protease (PLpro) and Nsp16 (MGP site) proteins as well as demonstrated a similar efficiency toward both the native and mutated Spike proteins, RDB. [ FROM AUTHOR] Copyright of Polycyclic Aromatic Compounds is the property of Taylor & Francis Ltd and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full . (Copyright applies to all s.)

Naphthalene-based bis-N-salicylidene aniline dyes: Crystal structures, Hirshfeld surface analysis, computational study and molecular docking with the SARS-CoV-2 proteins

In this work, we report structural and computational studies of a series of naphthalene-based bis-N-salicylidene aniline dyes, namely N,N′-bis-salicylidene-1,5-diaminonaphthalene (1), N,N′-bis(3-hydroxysalicylidene)-1,5-diaminonaphthalene (2) and N,N′-bis(3-methoxysalicylidene)-1,5-diaminonaphthalene (3). For 3, two polymorphs are known, namely 3red and 3yellow. Both polymorphs of 3 were analyzed and discussed. All the molecules adopt an enol-imine tautomer, stabilized by two intramolecular O–H⋯N hydrogen bonds. The structure of 2 is further stabilized by a couple of additional O–H⋯O hydrogen bonds and by intermolecular O–H⋯O interactions, yielding a 1D zig-zag supramolecular chain. Molecules of 2, 3red and 3yellow are interlinked through intermolecular C–H⋯π interactions, while the crystal packing of 1 and 2 is also described by intermolecular π⋯π interactions. More than 90% of the total Hirshfeld surface area for all the discussed molecules is occupied by H⋯H, H⋯C, H⋯O and C⋯C contacts. The polymorphs 3red and 3yellow, despite being chemically the same, differ geometrically, thus yielding remarkably different Hirshfeld surfaces. The Hirshfeld surface of 3yellow is very similar to that of 2. All structures are mainly characterized by the dispersion energy framework followed by the less significant electrostatic energy framework contribution. Molecular docking studies were employed to inspect the effect of 1–3 on the SARS-CoV-2 protein targets. The docking analysis revealed that the dye 2 showed the best binding energies toward Papain-like protease (PLpro, –10.40 kcal/mol), nonstructural protein 14 (nsp14 (N7-MTase), –10.10 kcal/mol), RdRp-RTP (–9.70 kcal/mol) and nonstructural protein 3 (nsp3_range 207-379-MES, –9.30 kcal/mol). The obtained results can give an insight into chemical and biological activities of the studied molecules that could aid in designing of potent reagents SARS-CoV-2.

A readily available structural analogue of integrastatins A and B: Insight into the crystal structure, Hirshfeld surface analysis and computational study

In this work detailed studies of 1-((5S,11S)-2,5-dimethyl-11,12-dihydro-5H-5,11-epoxybenzo (Demir et al., 2021;Shiryaev et al., 2021) [7,8]oxocino[4,3-b]pyridin-3-yl)ethan-1-one (1), which is of potential interest for HIV treatment, are reported. The overall crystal packing of 1 was examined through energy frameworks. The structure, electronic and optical properties of 1 were verified with DFT calculations. Molecular docking was applied to probe the interactions of 1 with binding sites of the HIV-1 integrase and a series of SARS-CoV-2 proteins as targets. The obtained results can be helpful to develop scoring functions to be used in force fields/docking calculations.

Computational Analysis of Molnupiravir.

In this work, we report in-depth computational studies of three plausible tautomeric forms, generated through the migration of two acidic protons of the N4-hydroxylcytosine fragment, of molnupiravir, which is emerging as an efficient drug to treat COVID-19. The DFT calculations were performed to verify the structure of these tautomers, as well as their electronic and optical properties. Molecular docking was applied to examine the influence of the structures of the keto-oxime, keto-hydroxylamine and hydroxyl-oxime tautomers on a series of the SARS-CoV-2 proteins. These tautomers exhibited the best affinity behavior (-9.90, -7.90, and -9.30 kcal/mol, respectively) towards RdRp-RTR and Nonstructural protein 3 (nsp3_range 207-379-MES).

Computational analysis of aspirin

In this work, we report structural and computational studies of Phase/Form I of aspirin. The structure is stabilized by the reciprocal intermolecular O–H∙∙∙O hydrogen bonds, yielding a centrosymmetric dimer with the eight-membered pseudo-aromatic hydrogen-bonded ring of the R22(8) motif. The structure of Phase/Form I of aspirin revealed a strong π∙∙∙π interaction between the phenylene ring and eight-membered hydrogen bonded ring, and is additionally stabilized by intermolecular C–H∙∙∙π and C=O∙∙∙π interactions. An overwhelming majority of the total Hirshfeld surface area for Phase/Form I of aspirin is occupied by reciprocal intermolecular H∙∙∙H, H∙∙∙C and H∙∙∙O contacts. The overall topology of the energy distributions in the crystal structure of Phase/Form I of aspirin is mainly characterized by the electrostatic energy framework followed by a dispersion energy framework contribution. The DFT calculations were performed to verify the structure of Phase/Form I of aspirin as well as its electronic and optical properties. Molecular docking was applied to examine the influence of Phase/Form I of aspirin on a series of the SARS-CoV-2 proteins.

α-Aminophosphonates 4-XC6H4-NH-CH(4-BrC6H4)-P(O)(OiPr)2 (X = H, Br, MeO): Crystal structures, Hirshfeld surface analysis, computational studies and in silico molecular docking with the SARS-CoV-2 proteins.

We report structural and computational studies of three α-aminophosphonates 4-XC6H4-NH-CH(4-BrC6H4)-P(O)(OiPr)2, namely diisopropyl((4-bromophenyl)(phenylamino)methyl)phosphonate (X = H, 1), diisopropyl((4-bromophenyl)((4-bromophenyl)amino)methyl)phosphonate (X = Br, 2) and diisopropyl((4-bromophenyl)((4-methoxyphenyl)amino)methyl)phosphonate (X = MeO, 3). The structures of 1-3 were fully confirmed by means of the 31P{1H} and 1H NMR spectroscopy. Crystal structures of 2 and 3 are isostructural and each contain two independent molecules in the asymmetric unit cell. Energy frameworks have been calculated to analyze the overall crystal packing of 1-3. The DFT calculations were performed to verify the structures of 1-3 as well as their electronic and optical properties. Molecular docking was applied to examine the influence of both the (S)- and (R)-enantiomers of 1-3 on a series of the SARS-CoV-2 proteins.

Favipiravir: insight into the crystal structure, Hirshfeld surface analysis and computational study

In this work we report structural and computational studies of favipiravir, which is now used as a drug for COVID-19 treatment. The molecule is completely flat and stabilized by an intramolecular O–H···O hydrogen bond, yielding a six-membered pseudo-aromatic ring. The aromaticity index of this pseudo-aromatic ring was found to be 0.748, while the same indix for the pyrazine ring in favipiravir was found to be 0.954. The crystal packing of favipiravir is mainly constructed through intermolecular N–H···O, N–H···N and C–H···O hydrogen bonds, yielding a 3D supramolecular framework with a zst topology defined by the point symbol of (65·8). The crystal structure of favipiravir is further stabilized by weak C–F···F–C intermolecular type II dihalogen interactions, yielding a 1D supramolecular polymeric chain. More than 80% of the total Hirshfeld surface area for favipiravir is occupied by H···H/C/N/O/F and C···N/O contacts. Energy frameworks have been calculated to additionally analyze the overall crystal packing. It was established that the structure of favipiravir is mainly characterized by the dispersion energy framework followed by the less significant electrostatic energy framework contribution. Finally, by using density functional theory (DFT) calculations and the quantum theory of atoms in molecules, we have assigned the interaction energy of each hydrogen bond, which can be helpful to develop scoring functions to be used in force fields/docking calculations. [ABSTRACT FROM AUTHOR] Copyright of Journal of the Iranian Chemical Society is the property of Springer Nature and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)