1,4,9,9-tetramethyloctahydro-4,7-(epoxymethano)azulen-5(1H)-one, a natural product as a potential inhibitor of COVID-19: Extraction, crystal structure, and virtual screening approach

In the present work, we describe the extraction of a natural product namely 1,4,9,9-tetramethyloctahydro-4,7-(epoxymethano)azulen-5(1H)-one, and its structure was confirmed by single crystal X-ray diffraction analysis. The conformations of the 5-, 6-, and 7-membered rings in the title compound, C15H24O2, have been probed by a Cremer-Pople puckering analysis. C—H···O hydrogen bonds generate chains in the crystal that stretch along the c-axis direction. The Hirshfeld surface analysis method was used to stabilize the crystal packing of the natural compound. Accompanied by experimental studies, quantum chemical calculations were also performed to compare the structural elucidation and the results of these geometrical parameters exhibited excellent agreement. The compound was also docked with several drug targets of the SARS-CoV-2 virus and found to show the best binding with the main protease enzyme, having a binding energy of -12.31 kcal/mol and interacting with His41 and Cys145 residues. The dynamic stability deciphered the complex to be stable with an average RMSD of 3.8 Å. The compound dynamics with the enzyme showed the compound conformation to be highly stable. The intermolecular binding free energy determined the compound-main protease enzyme to show high interaction energy of < 40 kcal/mol. Together, these studies demonstrate the compound to be a lead structure against SARS-CoV-2.

1,4,9,9-tetramethyloctahydro-4,7-(epoxymethano)azulen-5(1H)-one, a natural product as a potential inhibitor of COVID-19: Extraction, crystal structure, and virtual screening approach.

In the present work, we describe the extraction of a natural product namely 1,4,9,9-tetramethyloctahydro-4,7-(epoxymethano)azulen-5(1H)-one, and its structure was confirmed by single crystal X-ray diffraction analysis. The conformations of the 5-, 6-, and 7-membered rings in the title compound, C15H24O2, have been probed by a Cremer-Pople puckering analysis. C-H···O hydrogen bonds generate chains in the crystal that stretch along the c-axis direction. The Hirshfeld surface analysis method was used to stabilize the crystal packing of the natural compound. Accompanied by experimental studies, quantum chemical calculations were also performed to compare the structural elucidation and the results of these geometrical parameters exhibited excellent agreement. The compound was also docked with several drug targets of the SARS-CoV-2 virus and found to show the best binding with the main protease enzyme, having a binding energy of -12.31 kcal/mol and interacting with His41 and Cys145 residues. The dynamic stability deciphered the complex to be stable with an average RMSD of 3.8 Å. The compound dynamics with the enzyme showed the compound conformation to be highly stable. The intermolecular binding free energy determined the compound-main protease enzyme to show high interaction energy of < 40 kcal/mol. Together, these studies demonstrate the compound to be a lead structure against SARS-CoV-2.

Synthesis, X-ray crystal structure, Hirshfeld surface analysis and computational investigation into the potential inhibitory action of novel 6-(p-tolyl)-2-((p-tolyl)thio)methyl-7H-[1.2.4]triazolo[5,1-b][1,3,4]thiadiazine inhibits the main protease of COVID-19.

In recent times, the novel coronavirus disease (COVID-19) caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has now become a worldwide pandemic. With over 71 million confirmed cases, even though the effectiveness and side effects of the specific drugs and vaccines approved for this disease are still limited. Scientists and researchers from all across the world are working to find a vaccine and a cure for COVID-19 by using large-scale drug discovery and analysis. Heterocyclic compounds are regarded to be valuable sources for the discovery of new antiviral medications against SARS-CoV-2 because virus occurrences are still on the rise, and infectivity and mortality may also rise shortly. In this regard, we have synthesized a new triazolothiadiazine derivative. The structure was characterized by NMR spectra and confirmed by X-ray diffraction analysis. The structural geometry coordinates of the title compound are well reproduced by DFT calculations. NBO and NPA analyses have been performed to determine the interaction energies between bonding and antibonding orbital, and natural atomic charges of heavy atoms. Molecular docking suggests that the compounds may have good affinity for SAR-CoV-2 main protease, RNA-dependent RNA polymerase and nucleocapsid enzymes, particularly the main protease enzyme (binding energy of -11.9 kcal mol-1). The predicted docked pose of the compound is dynamically stable and reports a major van der Waals contribution (-62.00 kcal mol-1) to overall net energy.Communicated by Ramaswamy H. Sarma.

Synthesis, crystal structure, and a molecular modeling approach to identify effective antiviral hydrazide derivative against the main protease of SARS-CoV-2.

In the fall of 2019, a new type of coronavirus took place in Wuhan city, China, and rapidly spread across the world and urges the scientific community to develop antiviral therapeutic agents. In our effort we have synthesized a new hydrazide derivative, (E)-N'-(1-(4-bromophenyl)ethylidene)-2-(6-methoxynaphthalen-2-yl)propanehydrazide for this purpose because of its potential inhibitory proprieties. The asymmetric unit of the title molecule consists of two independent molecules differing noticeably in conformation. In the crystal, the independent molecules are linked by N-H···O and C-H···O hydrogen bonds and C-H···π(ring) interactions into helical chains extending along the b-axis direction. The chains are further joined by additional C-H···π(ring) interactions into the full 3-D structure. To obtain a structure-activity relationship, the DFT-NBO analysis is performed to study the intrinsic electronic properties of the title compound. Molecular modeling studies were also conducted to examine the binding affinity of the compound for the SARS-CoV-2 main protease enzyme and to determine intermolecular binding interactions. The compound revealed a stable binding mode at the enzyme active pocket with a binding energy value of -8.1 kcal/mol. Further, stable dynamics were revealed for the enzyme-compound complex and reported highly favorable binding energies. The net MMGBSA binding energy of the complex is -37.41 kcal/mol while the net MMPBSA binding energy is -40.5 kcal/mol. Overall, the compound disclosed the strongest bond of ing the main protease enzyme and might be a good lead for further structural optimization.

A possible potential COVID-19 drug candidate: Diethyl 2-(2-(2-(3-methyl-2-oxoquinoxalin-1(2H)-yl)acetyl)hydrazono)malonate: Docking of disordered independent molecules of a novel crystal structure, HSA/DFT/XRD and cytotoxicity.

This study reports the synthesis, characterization and importance of a novel diethyl 2-(2-(2-(3-methyl-2-oxoquinoxalin-1(2H)-yl)acetyl)hydrazono)malonate (MQOAHM). Two independent molecular structures of the disordered MQOAHM have been established by XRD­single­crystal analysis in a ratio of 0.596(3)/0.404(3), MQOAHM (a) and MQOAHM (b), respectively. MQOAHM was characterized by means of various spectroscopic tools ESI-MS, IR, 1H &13C NMR analyses. Density Functional Theory (DFT) method, B3LYP, 6-311++G(d,p) basis set was used to optimize MQOAHM molecule. The obtained theoretical structure and experimental structure were superimposed on each other, and the correlation between them was calculated. The Highest Occupied Molecular Orbital (HOMO) and Lowest Unoccupied Molecular Orbital (LUMO) were created, and the energy gap between these orbitals was calculated. For analyzing intermolecular interactions, Molecular Electrostatic Potential (MEP) and Hirshfeld Surface Analysis were studied. For a fair comparative study, the two forms of the title compound were docked together with 18 approved drugs and N3 under precisely the same conditions. The disordered molecule structure's binding scores against 7BQY were -7.0 and -6.9 kcal/mol-1 for MQOAHM (a) and MQOAHM (b), respectively. Both the forms show almost identical superimposed structures and scores indicating that the disorder of the molecule, in this study, has no obvious effect. The high binding score of the molecule was attributed to the multi-hydrogen bond and hydrophobic interactions between the ligand and the receptor's active amino acid residues. Worth pointing out here that the aim of using the free energy in Silico molecular docking approach is to rank the title molecule compared to the wide range of approved drugs and a well-established ligand N3. The binding scores of all the molecules used in this study are ranged from -9.9 to -4.5 kcal/mol-1. These results and the supporting statistical analyses suggest that this malonate-based ligand merits further research in the context of possible therapeutic agents for COVID-19. Cheap computational techniques, PASS, Way2drug and ADMET, online software tools, were used in this study to uncover the title compound's potential biological activities and cytotoxicity.

Docking of Disordered Independent Molecules of Novel Crystal Structure of (N-(4-methoxyphenyl)-2-(3-methyl-2-oxo-3,4-dihydroquinoxalin-1(2H)-yl)acetamide as anti-Covid-19 and anti-Alzheimer's disease. Crystal structure, HSA/DFT/XRD

New quinoxaline derivative, N-(4-methyl-2-nitrophenyl)-2-(3-methyl-2-oxoquinoxalin-1(2H)-yl)acetamide (NMPOQA= disordered molecules NMPOQAa(50.3% and NMPOQAb(49.7%)) has been synthesized and characterized by ESI-MS, IR, 1H &13C NMR. The geometric parameters of NMPOQA compound which crystallographic structure has been defined by X-ray diffraction have been calculated by Density Functional Theory (DFT), B3LYP, 6-311++G(d,p) basis set. The correlation between experimental and theoretical structure was checked by superimposing the experimental and theoretical structure. Frontier Molecular Orbitals (FMO's) have been created and the gap energy between High Occupied Molecular Orbital (HOMO) and Low Unoccupied Molecular Orbital (LUMO) has been calculated. Additionally, Molecular Electrostatic Potential (MEP) and Hirshfeld studies have been conducted to analyze intermolecular interactions. Interesting molecular docking of NMPOQA and Remdesivir drug with 6M03 was conducted using the same parameters for a fair comparison. A low binding affinity of the NMPOQA (−6.9 kcal/mol) compared to the Remdesivir drug, (−7.1 kcal/mol) and other good reasons make NMPOQA a good candidate against COVID-19. A similar study was calculated with 1EVE producing evidences that suggest NMPOQA may serve as a potential drug for developing Alzheimer's disease (AD) treatment

Synthesis and Identification of Novel Potential Molecules Against COVID-19 Main Protease Through Structure-Guided Virtual Screening Approach.

The novel coronavirus disease that arises in the end of 2019 (COVID-19) in Wuhan, China, has rapidly spread over the globe and was considered as a world pandemic. Currently, various antiviral therapies or vaccines are available, and many researches are ongoing for further treatments. Targeting the coronavirus' main protease (key enzyme: 3CLpro) is growing in importance in anti-SARS-CoV-2 drug discovery process. The present study aims at predicting the antiviral activity of two novel compounds using in silico approaches that might become potential leads against SARS-CoV-2. The 3D structures of the new compounds are elucidated by single-crystal X-ray techniques. The interactions between different units of 4 and 5 were emphasized by analyzing their corresponding Hirshfeld surfaces and ESP plots. NBO and FMO analyses were investigated as well. Molecular docking combined with molecular dynamics simulations (MDs) was performed to investigate the binding modes and molecular interactions of 4 and 5 with the amino acids of coronavirus main protease (6LU7) protein. The best docking scores were obtained for both ligands through the major binding interactions via hydrogen/hydrophobic bonds with the key amino acids in the active site: HIS41, CYS145, MET49, MET165, HIS172, and GLU166 amino acids. A MD simulation study was also performed for 100 ns to validate the stability behavior of the main protease 3CLpro-ligand complexes. The MD simulation study successfully confirmed the stability of the ligands in the binding site as potent anti-SARS-CoV-2 (COVID-19) inhibitors. Additionally, MMPBSA energy of both docked complexes was determined as a validation assay of docking and MD simulations to validate compound conformation and interaction stability with 3CLpro. The synthesized compounds might be helpful in the fight against COVID-19 prior to biological activity confirmation in vitro and in vivo.

Crystal structure, Hirshfeld surface analysis, DFT and mol-ecular docking investigation of 2-(2-oxo-1,3-oxazolidin-3-yl)ethyl 2-[2-(2-oxo-1,3-oxazolidin-3-yl)eth-oxy]quinoline-4-carboxyl-ate.

In the mol-ecular structure of the title compound, C20H21N3O7, the quinoline ring system is slightly bent, with a dihedral angle between the phenyl and the pyridine rings of 3.47 (7)°. In the crystal, corrugated layers of mol-ecules extending along the ab plane are generated by C-H⋯O hydrogen bonds. The inter-molecular inter-actions were qu-anti-fied by Hirshfeld surface analysis and two-dimensional fingerprint plots. The most significant contributions to the crystal packing are from H⋯H (42.3%), H⋯O/O⋯H (34.5%) and H⋯C/ C⋯H (17.6%) contacts. Mol-ecular orbital calculations providing electron-density plots of the HOMO and LUMO as well as mol-ecular electrostatic potentials (MEP) were computed, both with the DFT/B3LYP/6-311 G++(d,p) basis set. A mol-ecular docking study between the title mol-ecule and the COVID-19 main protease (PDB ID: 6LU7) was performed, showing that it is a good agent because of its affinity and ability to adhere to the active sites of the protein.