Main and papain-like proteases as prospective targets for pharmacological treatment of coronavirus SARS-CoV-2.

The pandemic caused by the coronavirus SARS-CoV-2 led to a global crisis in the world healthcare system. Despite some progress in the creation of antiviral vaccines and mass vaccination of the population, the number of patients continues to grow because of the spread of new SARS-CoV-2 mutations. There is an urgent need for direct-acting drugs capable of suppressing or stopping the main mechanisms of reproduction of the coronavirus SARS-CoV-2. Several studies have shown that the successful replication of the virus in the cell requires proteolytic cleavage of the protein structures of the virus. Two proteases are crucial in replicating SARS-CoV-2 and other coronaviruses: the main protease (Mpro) and the papain-like protease (PLpro). In this review, we summarize the essential viral proteins of SARS-CoV-2 required for its viral life cycle as targets for chemotherapy of coronavirus infection and provide a critical summary of the development of drugs against COVID-19 from the drug repurposing strategy up to the molecular design of novel covalent and non-covalent agents capable of inhibiting virus replication. We overview the main antiviral strategy and the choice of SARS-CoV-2 Mpro and PLpro proteases as promising targets for pharmacological impact on the coronavirus life cycle.

Synthesis, analysis of mol-ecular and crystal structures, estimation of inter-molecular inter-actions and biological properties of 1-benzyl-6-fluoro-3-[5-(4-methylcyclohexyl)-1,2,4-oxadiazol-3-yl]-7-(piperidin-1-yl)quinolin-4-one.

The title compound, C30H33N4O2F, can be obtained via a two-step synthetic scheme involving 1-benzyl-6-fluoro-4-oxo-7-(piperidin-1-yl)-1,4-di-hydro-quino-line-3-carbo-nitrile as a starting compound that undergoes substitution with hydroxyl-amine and subsequent cyclization with 4-methyl-cyclo-hexane-1-carb-oxy-lic acid. It crystallizes from 2-propanol in the triclinic space group P with a mol-ecule of the title compound and one of 2-propanol in the asymmetric unit. After the mol-ecular structure was clarified using NMR and LC/MS, the mol-ecular and crystalline arrangements were defined with SC-XRD. A Hirshfeld surface analysis was performed for a better understanding of the inter-molecular inter-actions. One strong (O-H⋯O) and three weak [C-H⋯F (intra-molecular) and two C-H⋯O] hydrogen bonds were found. The contributions of short contacts to the Hirshfeld surface were estimated using two-dimensional fingerprint plots showing that O⋯H/H⋯O, C⋯H/H⋯C and C⋯C contacts are the most significant for the title compound and O⋯H for the 2-propanol. The crystal structure appears to have isotropically packed tetra-mers containing two mol-ecules of the title compound and two mol-ecules of 2-propanol as the building unit according to analysis of the distribution of pairwise inter-action energies. A mol-ecular docking study was carried out to evaluate the inter-actions of the title compound with the active centers of macromolecules corresponding to viral targets, namely, anti-hepatitis B activity [HBV, capsid Y132A mutant (VCID 8772) PDB ID: 5E0I] and anti-COVID-19 main protease activity (PDB ID: 6LU7). The data obtained revealed a noticeable affinity towards them that exceeded that of the reference ligands.

A Comprehensive Review on Chemical Synthesis and Chemotherapeutic Potential of 3-Heteroaryl Fluoroquinolone Hybrids.

Fluoroquinolones have been studied for more than half a century. Since the 1960s, four generations of these synthetic antibiotics have been created and successfully introduced into clinical practice. However, they are still of interest for medicinal chemistry due to the wide possibilities for chemical modification, with subsequent useful changes in the pharmacokinetics and pharmacodynamics of the initial molecules. This review summarizes the chemical and pharmacological results of fluoroquinolones hybridization by introducing different heterocyclic moieties into position 3 of the core system. It analyses the synthetic procedures and approaches to the formation of heterocycles from the fluoroquinolone carboxyl group and reveals the most convenient ways for such procedures. Further, the results of biological activity investigations for the obtained hybrid pharmacophore systems are presented. The latter revealed numerous promising molecules that can be further studied to overcome the problem of resistance to antibiotics, to find novel anticancer agents and more.

Synthesis, docking, and biological evaluation of novel 1-benzyl-4-(4-(R)-5-sulfonylidene-4,5-dihydro-1H-1,2,4-triazol-3-yl)pyrrolidin-2-ones as potential nootropic agents.

In order to search for innovative nootropic agents, new 1-benzyl-4- (4- (R)-5-sulfonylidene-4,5-dihydro-1H-1,2,4-triazol-3-yl) pyrrolidine-2-ones was synthesized by reacting benzylamine with itaconic acid to 1-benzyl-5-oxopyrrolidine-3-carboxylic acid, which was then subjected to hydrazinolysis followed by the addition of substituted isothiacyanate followed by cyclization of intermediate thiosemicarbazides. The structure and purity of the obtained substances were confirmed by elemental analysis, 1H NMR spectroscopy, 13C NMR spectroscopy and LC/MS. Docking studies were performed for the substances synthesized using Autodock 4.2 software. Approximate values of LD50 (in silico determination) are around 870-1000 mg/kg. All synthesized substances were tested for nootropic activity by the passive avoidance test on the scopolamine amnesia model in doses that are about 1/10 of the estimated LD50. Based on the results of docking and pharmacological experiment, the most promising substances 7a, as well as 7e, 7f were identified. The results of molecular docking (hit compound 7a) indicate a positive correlation between the obtained values of docking studies and experimental data.

Synthesis, X-ray diffraction study, analysis of inter-molecular inter-actions and mol-ecular docking of ethyl 1-(3-tosyl-quinolin-4-yl)piperidine-4-carboxyl-ate.

The title compound, C24H26N2O4S, can be obtained via two synthetic routes. According to our investigations, the most suitable way is by the reaction of ethyl 2-bromo-acetate with sodium tosyl-sulfinate in dry DMF. It was crystallized from methanol into the monoclinic P21/n space group with a single mol-ecule in the asymmetric unit. Hirshfeld surface analysis was performed to define the hydrogen bonds and analysis of the two-dimensional fingerprint plots was used to distinguish the different types of inter-actions. Two very weak non-classical C-H⋯O hydrogen bonds were found and the contributions of short contacts to the Hirshfeld surface were determined. Mol-ecules form an isotropic network of inter-molecular inter-actions according to an analysis of the pairwise inter-action energies. A mol-ecular docking study evaluated the inter-actions in the title compound with the active centers of macromolecules of bacterial targets (Staphylococcus aureus DNA Gyrase PDB ID: 2XCR, Mycobacterium tuberculosis topoisomerase II PDB ID: 5BTL, Streptococcus pneumoniae topoisomerase IV PDB ID: 4KPF) and revealed high affinity towards them that exceeded the reference anti-biotics of the fluoro-quinolone group.

Dimensionality reduction in machine learning for nonadiabatic molecular dynamics: Effectiveness of elemental sublattices in lead halide perovskites.

Supervised machine learning (ML) and unsupervised ML have been performed on descriptors generated from nonadiabatic (NA) molecular dynamics (MD) trajectories representing non-radiative charge recombination in CsPbI3, a promising solar cell and optoelectronic material. Descriptors generated from every third atom of the iodine sublattice alone are sufficient for a satisfactory prediction of the bandgap and NA coupling for the use in the NA-MD simulation of nonradiative charge recombination, which has a strong influence on material performance. Surprisingly, descriptors based on the cesium sublattice perform better than those of the lead sublattice, even though Cs does not contribute to the relevant wavefunctions, while Pb forms the conduction band and contributes to the valence band. Simplification of the ML models of the NA-MD Hamiltonian achieved by the present analysis helps to overcome the high computational cost of NA-MD through ML and increase the applicability of NA-MD simulations.

Usage of Quantum Chemical Methods to Understand the Formation of Concomitant Polymorphs of Acetyl 2-(N-(2-Fluorophenyl)imino)coumarin-3-carboxamide.

Crystallization of concomitant polymorphs is a very intriguing process that is difficult to be studied experimentally. A comprehensive study of two polymorphic modifications of acetyl 2-(N-(2-fluorophenyl)imino)coumarin-3-carboxamide using quantum chemical methods has revealed molecular and crystal structure dependence on crystallization conditions. Fast crystallization associated with a kinetically controlled process results in the formation of a columnar structure with a nonequilibrium molecular conformation and more isotropic topology of interaction energies between molecules. Slow crystallization may be considered as a thermodynamically controlled process and leads to the formation of a layered crystal structure with the conformation of the molecule corresponding to local minima and anisotropic topology of interaction energies. Fast crystallization results in the formation of a lot of weak intermolecular interactions, while slow crystallization leads to the formation of small amounts of stronger interactions.

Crystal structure of the non-steroidal anti-inflammatory drug (NSAID) tolmetin sodium.

The asymmetric unit of the title compound, sodium 2-[1-methyl-5-(4-methyl-benzo-yl)-1H-pyrrol-2-yl]acetate dihydrate, Na+·C15H14NO3 -·2H2O, contains two sodium cations, two organic anions (A and B) and two water mol-ecules. The coordination geometry around the sodium cations corresponds to a distorted octa-hedron. Each pair of sodium cations (A-A or B-B) is chelated by two bridging anions coordinated by the O atoms of the deprotonated carb-oxy-lic groups, and each sodium atom is coordinated by an O atom of a third anion, which connects pairs of sodium atoms, and a water mol-ecule. As a result, a two-dimensional polymer is formed in the crystal. Hirshfeld surface analysis and two-dimensional fingerprint plots were used to analyze the inter-molecular contacts present in the crystal.

Conformational polymorphs of 3-cyclopropyl-5-(3-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-1,2,4-oxadiazole.

The dipharmacophore compound 3-cyclopropyl-5-(3-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-1,2,4-oxadiazole, C12H11N5O, was studied on the assumption of its potential biological activity. Two polymorphic forms differ in both their molecular and crystal structures. The monoclinic polymorphic form was crystallized from more volatile solvents and contains a conformer with a higher relative energy. The basic molecule forms an abundance of interactions with relatively close energies. The orthorhombic polymorph was crystallized very slowly from isoamyl alcohol and contains a conformer with a much lower energy. The basic molecule forms two strong interactions and a large number of weak interactions. Stacking interactions of the `head-to-head' type in the monoclinic structure and of the `head-to-tail' type in the orthorhombic structure proved to be the strongest and form stacked columns in the two polymorphs. The main structural motif of the monoclinic structure is a double column where two stacked columns interact through weak C-H...N hydrogen bonds and dispersive interactions. In the orthorhombic structure, a single stacked column is the main structural motif. Periodic calculations confirmed that the orthorhombic structure obtained by slow evaporation has a lower lattice energy (0.97 kcal mol-1) compared to the monoclinic structure.

Polymorphism of methyl 4-amino-3-phenylisothiazole-5-carboxylate: an experimental and theoretical study.

Being a close analogue of amflutizole, methyl 4-amino-3-phenylisothiazole-5-carboxylate (C11H10N2O2S) was assumed to be capable of forming polymorphic structures. Noncentrosymmetric and centrosymmetric polymorphs have been obtained by crystallization from a series of more volatile solvents and from denser tetrachloromethane, respectively. Identical conformations of the molecule are found in both structures. The two polymorphs differ mainly in the intermolecular interactions formed by the amino group and in the type of stacking interactions between the π-systems. The most effective method for revealing packing motifs in structures with intermolecular interactions of different types (hydrogen bonding, stacking, dispersion, etc.) is to study the pairwise interaction energies using quantum chemical calculations. Molecules form a column as the primary basic structural motif due to stacking interactions in both polymorphic structures under study. The character of a column (straight or zigzag) is determined by the orientations of the stacked molecules (in a `head-to-head' or `head-to-tail' manner). Columns bound by intermolecular N-H...O and N-H...N hydrogen bonds form a double column as the main structural motif in the noncentrosymmetric structure. Double columns in the noncentrosymmetric structure and columns in the centrosymmetric structure interact strongly within the ab crystallographic plane, forming a layer as a secondary basic structural motif. The noncentrosymmetric structure has a lower density and a lower (by 0.59 kJ mol-1) lattice energy, calculated using periodic calculations, compared to the centrosymmetric structure.

Phytochemical and Psychotropic Research of Motherwort (Leonurus cardiaca L.) Modified Dry Extracts.

The prospect of creating a new medicine with psychotropic activity is shown as a result of studying the chemical composition and pharmacological activity of modified dry extracts of motherwort (Leonurus cardiaca L.) tincture. The most promising substances were the dry extracts, modified by adding small amounts of arginine, valine, phenylalanine, glycine, lysine, and alanine. A total of 15 main phenolic substances were found in the extracts, and eight of them were identified. There were also 10 hydroxycinnamic acids in these extracts, three of which were identified (chlorogenic, caffeic, and rosmarinic acids). The dominant hydroxycinnamic acids were chlorogenic and caffeic acids. Among flavonoids, catechin, hyperoside, and rutin were identified. It should be noted that the extracts had a significant content of ellagic acid. On the basis of the results of the phytochemical analysis of the extracts, it can be concluded that the composition of phenolic compounds does not differ significantly, and the main differences are related to amino acids, which obviously have an impact on the overall pharmacological effect. The results obtained indicate the presence of anxiolytic activity in the motherwort extracts studied in complex with amino acids. The extracts with glycine, valine, and arginine were more effective in reducing anxiety in animals.

A Novel Series of [1,2,4]Triazolo[4,3-a]Pyridine Sulfonamides as Potential Antimalarial Agents: In Silico Studies, Synthesis and In Vitro Evaluation.

For the development of new and potent antimalarial drugs, we designed the virtual library with three points of randomization of novel [1,2,4]triazolo[4,3-a]pyridines bearing a sulfonamide fragment. The library of 1561 compounds has been investigated by both virtual screening and molecular docking methods using falcipain-2 as a target enzyme. 25 chosen hits were synthesized and evaluated for their antimalarial activity in vitro against Plasmodium falciparum. 3-Ethyl-N-(3-fluorobenzyl)-N-(4-methoxyphenyl)-[1,2,4]triazolo[4,3-a]pyridine-6-sulfonamide and 2-(3-chlorobenzyl)-8-(piperidin-1-ylsulfonyl)-[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one showed in vitro good antimalarial activity with inhibitory concentration IC50 = 2.24 and 4.98 µM, respectively. This new series of compounds may serve as a starting point for future antimalarial drug discovery programs.

(1R,3S)-3-(1H-Benzo[d]imidazol-2-yl)-1,2,2-tri-methyl-cyclo-pentane-1-carb-oxy-lic acid as a new anti-diabetic active pharmaceutical ingredient.

The chiral title compound, C16H20N2O2, which can be used for producing active pharmaceutical ingredients for treatment of type 2 pancreatic diabetes and other pathologies dependent on insulin resistance, was prepared from (1R,3S)-camphoric acid and o-phenyl-enedi-amine. It crystallized from an ethanol solution in the chiral monoclinic P21 space group. The five-membered ring adopts a twisted conformation with the methyl-substituted C atoms displaced by -0.273 (5) and 0.407 (5) Šfrom the mean plane through the other three atoms. In the crystal, mol-ecules are linked by O-H⋯N hydrogen bonds, forming chains along the a-axis direction. Hirshfeld surface analysis and two-dimensional fingerprint plots were used to analyze the inter-molecular contacts present in the crystal.

Methylation of Methyl 4-Hydroxy-2-thioxo-1,2-dihydroquinoline-3-carboxylate: Synthetic, Crystallographic, and Molecular Docking Studies.

Consecutive alkylation of 4-hydroxy-2-thioxo-1,2-dihydroquinoline-3-carboxylate by CH3I has been investigated to establish regioselectivity of the reaction for reliable design and synthesis of combinatorial libraries. In the first stage, the product of S-methylation-methyl 4-hydroxy-2-(methylthio)quinoline-3-carboxylate was obtained. The subsequent alkylation with CH3I led to the formation of both O- and N-methylation products mixture-methyl 4-methoxy-2-(methylthio)quinoline-3-carboxylate and methyl 1-methyl-2-(methylthio)-4-oxo-1,4-dihydroquinoline-3-carboxylate with a predominance of O-methylated product. The structure of synthesized compounds was confirmed by means of elemental analysis, 1H-NMR, 13C-NMR, LC/MS, and single-crystal X-ray diffraction. The quantum chemical calculations of geometry and electron structure of methyl 4-hydroxy-2-(methylthio)quinoline-3-carboxylate's anion were carried out. According to molecular docking simulations, the studied compounds can be considered as potent inhibitors of Hepatitis B Virus replication. Experimental in vitro biological studies confirmed that studied compounds demonstrated high inhibition of HBV replication in 10 µM concentration.

Concomitant polymorphic forms of 3-cyclopropyl-5-(2-hydrazinylpyridin-3-yl)-1,2,4-oxadiazole.

The dipharmacophore compound 3-cyclopropyl-5-(2-hydrazinylpyridin-3-yl)-1,2,4-oxadiazole, C10H11N5O, was studied on the assumption of its potential biological activity. Two concomitant polymorphs were obtained on crystallization from isopropanol solution and these were thoroughly studied. Identical conformations of the molecules are found in both structures despite the low difference in energy between the four possible conformers. The two polymorphs differ crucially with respect to their crystal structures. A centrosymmetric dimer formed due to both stacking interactions of the `head-to-tail' type and N-H...N(π) hydrogen bonds is the building unit in the triclinic structure. The dimeric building units form an isotropic packing. In the orthorhombic polymorphic structure, the molecules form stacking interactions of the `head-to-head' type, which results in their organization in a column as the primary basic structural motif. The formation of N-H...N(lone pair) hydrogen bonds between two neighbouring columns allows the formation of a double column as the main structural motif. The correct packing motifs in the two polymorphs could not be identified without calculations of the pairwise interaction energies. The triclinic structure has a higher density and a lower (by 0.60 kcal mol-1) lattice energy according to periodic calculations compared to the orthorhombic structure. This allows us to presume that the triclinic form of 3-cyclopropyl-5-(2-hydrazinylpyridin-3-yl)-1,2,4-oxadiazole is the more stable.

Crystal structure, Hirshfeld analysis and a mol-ecular docking study of a new inhibitor of the Hepatitis B virus (HBV): ethyl 5-methyl-1,1-dioxo-2-{[5-(pentan-3-yl)-1,2,4-oxa-diazol-3-yl]meth-yl}-2H-1,2,6-thia-diazine-4-carboxyl-ate.

The title compound, C15H22N4O5S, was prepared via alkyl-ation of 3-(chloro-meth-yl)-5-(pentan-3-yl)-1,2,4-oxa-diazole in anhydrous dioxane in the presence of tri-ethyl-amine. The thia-diazine ring has an envelope conformation with the S atom displaced by 0.4883 (6) Šfrom the mean plane through the other five atoms. The planar 1,2,4-oxa-diazole ring is inclined to the mean plane of the thia-diazine ring by 77.45 (11)°. In the crystal, mol-ecules are linked by C-H⋯N hydrogen bonds, forming chains propagating along the b-axis direction. Hirshfeld surface analysis and two-dimensional fingerprint plots have been used to analyse the inter-molecular contacts present in the crystal. Mol-ecular docking studies were use to evaluate the title compound as a potential system that inter-acts effectively with the capsid of the Hepatitis B virus (HBV), supported by an experimental in vitro HBV replication model.

Development and validation of a HPLC method for quantifica-tion of degradation impurities of salbutamol sulfate with following long-term stability studies in multicomponent cough syrup.

Medicines containing both a herbal extract and a synthetic substance are in high demand due to their beneficial effects and synergism. The novel combination of salbutamol sulfate and Hedera helix extracts seems to be prospective in terms of pharmacological activity. But for quality assurance, impurities of the synthetic component have to be determined and quantified. Plant extracts consist of various phytochemical components, therefore, it is more complicated to develop a selective analytical method due to the sample matrix. To prove the safety and efficacy of the dosage form, a new HPLC method for analysis of salbutamol sulfate impurities was developed and validated. The method was used to estimate the safety of the novel syrup by performing long-term stability studies for 24 months. Obtained results indicated the absence in both significant reducing of the main components content and increasing of related substances level. Also, force degradation was carried out to prognosticate the possibility of impurities producing.

Synthesis, X-ray crystal structure, Hirshfeld surface analysis, and molecular docking study of novel inhibitor of hepatitis B: methyl 4-fluoro-3-(morpholinosulfonyl)benzo[b]thiophene-2-carboxylate.

A method of 4-fluoro-3-(morpholinosulfonyl)benzo[b]thiophene-2-carboxylate synthesis has been developed and the electronic and spatial structure of a new biologically active molecule has been studied both theoretically and experimentally. The title compound was crystallized from acetonitrile and the single crystal X-ray analysis has revealed that it exists in a monoclinic P21/c space group, with one molecule in the asymmetric part of the unit cell. Hirshfeld surface analysis was used to study intermolecular interactions in the crystal. Molecular docking study evaluates the investigated compound as a new potential inhibitor of hepatitis B. Testing for anti-hepatitis B virus activity has shown that this substance demonstrates in vitro nanomolar inhibitory activity against HBV.

Polymorphism of 3-(5-phenyl-1,3,4-oxadiazol-2-yl)- and 3-[5-(pyridin-4-yl)-1,3,4-oxadiazol-2-yl]-2H-chromen-2-ones.

This study of 3-(5-phenyl-1,3,4-oxadiazol-2-yl)-2H-chromen-2-one, C17H10N2O3, 1, and 3-[5-(pyridin-4-yl)-1,3,4-oxadiazol-2-yl]-2H-chromen-2-one, C16H9N3O3, 2, was performed on the assumption of the potential anticancer activity of the compounds. Three polymorphic structures for 1 and two polymorphic structures for 2 have been studied thoroughly. The strongest intermolecular interaction is stacking of the `head-to-head' type in all the studied crystals. The polymorphic structures of 1 differ with respect to the intermolecular interactions between stacked columns. Two of the polymorphs have a columnar or double columnar type of crystal organization, while the third polymorphic structure can be classified as columnar-layered. The difference between the two structures of 2 is less pronounced. Both crystals can be considered as having very similar arrangements of neighbouring columns. The formation of polymorphic modifications is caused by a subtle balance of very weak intermolecular interactions and packing differences can be identified only using an analysis based on a study of the pairwise interaction energies.

Synthesis, in vivo and in silico anticonvulsant activity studies of new derivatives of 2-(2,4-dioxo-1,4-dihydroquinazolin-3(2H)-yl)acetamide.

In order to expand the arsenal of biologically active substances of anticonvulsive action by the interaction of 2-(2,4-dioxo-1,4-dihydroquinazolin-3(2H)-yl)acetic acid with the corresponding amines in the presence of N,N'-carbonyldiimidazole in the dioxane medium, a systematic series of 2-(2,4-dioxo-1,4-dihydroquinazolin-3(2H)-yl)-N-R-acetamides was obtained. A novel approach to synthesis of the key intermediate - 2-(2,4-dioxo-1,4-dihydro-quinazolin-3(2H)-yl)acetic acid was developed. The structure and purity of the resulting substances was confirmed by elemental analysis, 1H NMR, 13C NMR spectroscopy and LC/MS. Based on the results of docking studies using SCIGRESS software, selected compounds with the best affinity for anticonvulsant protein biomes (PDB codes: 4COF, 3F8E and 1 EOU) are promising for experimental studies of anticonvulsant activity. A comparative analysis of the results of molecular docking and in vivo results suggests that there is a positive correlation between scoring protein inhibition and experimental data. Pharmacological studies have revealed the leader compound 2-(2,4-dioxo-1,4-dihydroquinazolin-3(2H)-yl)-N-[(2,4-dichlorophenyl)methyl]acet-amide, which improved all the experimental convulsive syndrome rates in mice without motor coordination impairment and may be recommended for further research. The lowest values of the scoring function of the ligand-peptide interaction are obtained for the synthesized compound and сarbonic anhydrase II (gene name CA2) (PDB code 1 EOU), so its inhibition is proposed by us as the most probable mechanism of the anticonvulsive effect of the leader compound.