In silico analysis of RNA-dependent RNA polymerase of the SARS-CoV-2 and therapeutic potential of existing antiviral drugs.

The continued sustained threat of the SARS-CoV-2 virus world-wide, urgently calls for far-reaching effective therapeutic strategies for treating this emerging infection. Accordingly, this study explores mode of action and therapeutic potential of existing antiviral drugs. Multiple sequence alignment and phylogenetic analyses indicate that the RNA-dependent RNA polymerase (RdRp) of SARS-CoV-2 was mutable and similar to bat coronavirus RaTG13. Successive interactions between RdRp (nsp12 alone or in complex with cofactors nsp7-8) and viral RNA demonstrated that the binding affinity values remained the same, but the sites of interaction of RdRp (highly conserved for homologous sequences from different organisms) were altered in the presence of selected antiviral drugs such as Remdesivir, and Sofosbuvir. The antiviral drug Sofosbuvir reduced the number of hydrogen bonds formed between RdRp and RNA. Remdesivir bound more tightly to viral RNA than viral RdRp alone or the nsp12-7-8 hexadecameric complex, resulting in a significant number of hydrogen bonds being formed in the uracil-rich region. The interaction between nsp12-7-8 complex and RNA was mediated by specific interaction sites of nsp7-8. Therefore, the conserved nature of RdRp interaction sites, and alterations due to drug intervention indicate the therapeutic potential of the selected drugs. In this article, we provide additional focus on the interacting amino acids of the nsp7-8 complex and highlight crucial regions that could be targeted for precluding a correct recognition of subunits involved in the hexadecameric assembly, to rationally design molecules endowed with a significant antiviral profile.

Analysis of the American Society of Anesthesiologists Physical Status Scale Reliability in Anaesthesia Practice: An Observational Study.

OBJECTIVE: Anaesthesiologists use the American Society of Anesthesiologists physical status (ASA PS) classification to assess patients' overall health. The primary objective of this study was to predict the prognostic value regarding peri-operative variables until discharge from hospital and post-operative outcomes. The secondary objective was to evaluate the inter-rater agreement of the ASA scores assigned at the outpatient department (OPD) vs. operating theatres (OT). METHODS: A total of 227 adults scheduled for elective surgery were assigned the ASA grade in preoperative OPD and on the day of surgery. The type of anaesthesia and surgery were noted. The operating time, post-operative ventilation, intensive care unit (ICU) stay, post-operative stay, bronchopulmonary complications, cardiac complications, renal dysfunction and any mortality until discharge from hospital were noted. Descriptive statistics were used to report the primary objective. For the secondary objective, Pearson's correlation test was used for inter-rater reliability. RESULTS: The ASA grading done at OPD and at OT was the same. It was found that the higher the ASA grade of a patient, the longer was the ICU stay. Patients with higher ASA PS scores were at a comparatively milder risk of developing remaining peri-operative and post-operative complications. CONCLUSION: The correlation was the highest with the ICU stay. The inter-rater ASA grades assignment at the clinics and the OT were found to be almost perfect.

Exceedingly Fast, Direct Access to Dihydroisoquinolino[1,2- b]quinazolinones through a Ruthenium(II)-Catalyzed Redox-Neutral C-H Allylation/Hydroamination Cascade.

A ruthenium(II)-catalyzed redox-neutral synthesis of dihydroisoquinoline-fused quinazolinone derivatives has been accomplished through the merger of C-H activation and alkene difunctionalization using quinazolinone as an inherent directing group. This intermolecular reaction proceeds rapidly and is complete within 10 min, providing the annulation product in high yields without any stoichiometric metal oxidant. Mechanistically, this tandem reaction proceeds through directed ortho C-H allylation followed by hydroamination with the proximal -CONH group, to furnish 6-methyl-5,6-dihydro-8 H-isoquinolino[1,2- b]quinazolin-8-ones in a single operation. The carboxylic acid additive has a dual role in the formation of active catalyst and protodemetalation.

Highly functionalized piperidines: Free radical scavenging, anticancer activity, DNA interaction and correlation with biological activity.

Twenty-five piperidines were studied as potential radical scavengers and antitumor agents. Quantitative interaction of compounds with ctDNA using spectroscopic techniques was also evaluated. Our results demonstrate that the evaluated piperidines possesses different abilities to scavenge the radical 2,2-diphenyl-1-picrylhydrazyl (DPPH) and the anion radical superoxide (•O2-). The piperidine 19 was the most potent radical DPPH scavenger, while the most effective to •O2- scavenger was piperidine 10. In general, U251, MCF7, NCI/ADR-RES, NCI-H460 and HT29 cells were least sensitive to the tested compounds and all compounds were considerably more toxic to the studied cancer cell lines than to the normal cell line HaCaT. The binding mode of the compounds and ctDNA was preferably via intercalation. In addition, these results were confirmed based on theoretical studies. Finally, a linear and exponential correlation between interaction constant (Kb) and GI50 for several human cancer cell was observed.

Ligand-Promoted γ-C(sp3)-H Arylation and Unsymmetrical Diarylation to Access Unnatural Amino Acid Derivatives.

A palladium(II)-catalyzed arylation of a γ-C(sp3)-H bond of protected amino acid is explored. The monoarylation is promoted by the commercially available, inexpensive phenanthroline ligand, and toxic silver salt is replaced by earth-abundant Mn(III)acetate. Subsequently, a hitherto unknown unsymmetrical diarylation at the γ-position is accomplished under the modified reaction conditions. Ligands have a prominent influence in both mono- and unsymmetrical diarylations.

Simulation of thermal stress and buckling instability in Si/Ge and Ge/Si core/shell nanowires.

The present study employs the method of atomistic simulation to estimate the thermal stress experienced by Si/Ge and Ge/Si, ultrathin, core/shell nanowires with fixed ends. The underlying technique involves the computation of Young's modulus and the linear coefficient of thermal expansion through separate simulations. These two material parameters are combined to obtain the thermal stress on the nanowires. In addition, the thermally induced stress is perceived in the context of buckling instability. The analysis provides a trade-off between the geometrical and operational parameters of the nanostructures. The proposed methodology can be extended to other materials and structures and helps with the prediction of the conditions under which a nanowire-based device might possibly fail due to elastic instability.

2-[4-(Piperidin-1-yl)-5H-chromeno[2,3-d]pyrimidin-2-yl]phenol.

In the title compound, C22H21N3O2, the pyrimidine ring is essentially planar [maximum deviation = 0.018 (2) Å] and forms dihedral angles of 22.70 (8) and 0.97 (7)°, respectively, with the fused benzene ring and the hy-droxy-substituted benzene ring. The piperidine ring has a chair conformation and the pyran ring has a flattened twist-boat conformation. The hy-droxy group was refined as disordered over two sets of sites in a 0.702 (4):0.298 (4) ratio. The disorder corresponds to a rotation of approxomiately 180° about the C-C bond connecting the phenol group to the pyrimidine ring and hence, both the major and minor components of disorder form intra-molecular O-H⋯N hydrogen bonds. In the crystal, pairs of weak C-H⋯π inter-actions form inversion dimers. In addition, π-π inter-actions are observed between the pyrimidine ring and the hy-droxy-substituted benzene ring [centroid-centroid separation = 3.739 (2) Å].

Ethyl 2,6-bis-(4-chloro-phen-yl)-4-(4-fluoro-anilino)-1-(4-fluoro-phen-yl)-1,2,5,6-tetra-hydro-pyridine-3-carboxyl-ate.

In the title compound, C32H26Cl2F2N2O2, the tetra-hydro-pyridine ring adopts a distorted boat conformation. The chlorophenyl rings are inclined to one another by 55.2 (1)°, while for the fluorophenyl rings the dihedral angle is 80.7 (1)°. The amino group and carbonyl O atom are involved in an intra-molecular N-H⋯O hydrogen bond. In the crystal, weak C-H⋯O, C-H⋯F and C-H⋯Cl inter-actions link the mol-ecules into a three-dimensional network.

Methyl 4-(4-fluoro-anilino)-1,2,6-tris-(4-fluoro-phen-yl)-1,2,5,6-tetra-hydro-pyri-dine-3-carboxyl-ate.

In the title mol-ecule, C31H24F4N2O2, the tetra-hydro-pyridine ring adopts a distorted boat conformation. An intra-molecular N-H⋯O hydrogen bond is formed by the amino group and ccarboxyl C=O atom. The crystal structure features weak C-H⋯F and C-H⋯O inter-actions.

Ethyl 2,6-bis-(4-chloro-phen-yl)-4-(4-methyl-anilino)-1-(4-methyl-phen-yl)-1,2,5,6-tetra-hydro-pyridine-3-carboxyl-ate.

In the title mol-ecule, C34H32Cl2N2O2, the tetra-hydro-pyridine ring adopts a distorted boat conformation and both 4-chloro-phenyl substituents are in axial positions. An intra-molecular N-H⋯O hydrogen bond is formed by the amino group and carbonyl O atom. In the crystal, weak C-H⋯Cl inter-actions link the mol-ecules into chains along [010].

Ethyl 4-anilino-2,6-bis-(4-fluoro-phen-yl)-1-phenyl-1,2,5,6-tetra-hydro-pyridine-3-carboxyl-ate.

In the title compound, C(32)H(28)F(2)N(2)O(2), the tetra-hydro-pyridine ring adopts a distorted boat conformation. The two fluoro-phenyl groups are attached to the tetra-hydro-pyridine ring in a trans orientation. The dihedral angle between the planes of the fluoro-substituted rings is 57.0 (1)°. The amino group and carbonyl O atom are involved in intra-molecular hydrogen bonding. In the crystal, weak C-H⋯O, C-H⋯F and C-H⋯π inter-actions link the mol-ecules into columns along [010].