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Presently, the prime global focus is on SARS-CoV-2, as no fully established, licensed medicine has been found thus far, in spite of the existence of various reports and administration of partially proven certain class of natural products. However, in case of natural products, the extraction and purification limit their application. This situation drives researchers to explore synthetically viable drugs. In the present investigation, twenty-three 2-pyridone synthetic derivatives (P1-P23) have been theoretically tested for their suitability as potential inhibitors for COVID-19 main protease through DFT, molecular docking, and molecular dynamics simulations. DFT calculations offer insights into structure–property relationships, while ADMET studies indicate the pharmacological characteristics of these molecules. Molecular docking studies ascertain the nature and mode of interactions of these entities with COVID-19 main protease. Furthermore, covalent docking has been carried out to verify the feasibility of the formation of a covalent bond with the active site. The top protein-inhibitor complexes, such as P18, P11, and P12, were identified based on their glide score. These molecules, along with the covalent docked complexes, namely P18 and P16, were selected and subjected to molecular dynamics simulations. The 100 ns simulation process exhibited that the covalent docked ones, due to their stable form could serve as lead compounds against SARS-CoV-2. Hence, this study affirms the potential candidature of 2-pyridone-based inhibitors. [ABSTRACT FROM AUTHOR]

Aim. Using in silico technologies to search for potential SARS-CoV-2 inhibitors among novel tetracyclic ring systems, which are the common core of Crinipellin. Materials and methods. The study object was new compounds previously synthesized via oxidative dearomatization of Crinipellin A. The method of the flexible molecular docking was applied in the study. Results and discussion. Using the molecular docking, the affinity of five compounds for the receptor-ACE2 SARS-CoV-2 (PDB ID: 7DF4), a spike protein SARS-CoV-2 (PDB ID: 1WNC), a PL protein SARS-CoV-2 (PDB ID: 7CJD) and a reverse transcriptase enzyme SARSCoV-2 (PDB ID: 6YYT) was studied. The results of the molecular docking obtained suggest that 8,8-dimethyl-5-(phenylsulfonyl)-3,3a,4,5,8,9-hexahydroindeno[3a,4-b]furan-2(7H)-one may be a potential SARS-CoV-2 inhibitor; it is the basis for its further experimental pharmacological study. Conclusions. The study constitutes one of the stages of searching for SARS-CoV-2 inhibitors. According to the results obtained, a way to search for potential SARS-COV-2 inhibitors based on Crinipellin A derivatives was proposed. Using the most promising compound with hexahydroindeno[3a,4-b]furan core further studies open up another direction for searching for compounds of SARS-COV-2 inhibitors and will save time and laboratory animals while conducting targeted experimental research.

A series of new congeners, 1-[2-(1-adamantyl)ethyl]-1H-benzimidazole (AB) and 1-[2-(1-adamantyl)ethyl]-4,5,6,7-tetrahalogeno-1H-benzimidazole (Hal=Cl, Br, I; tClAB, tBrAB, tIAB), have been synthesized and studied. These novel multi-target ligands combine a benzimidazole ring known to show antitumor activity and an adamantyl moiety showing anti-influenza activity. Their crystal structures were determined by X-ray, while intermolecular interactions were studied using topological Bader's Quantum Theory of Atoms in Molecules, Hirshfeld Surfaces, CLP and PIXEL approaches. The newly synthesized compounds crystallize within two different space groups, P-1 (AB and tIAB) and P21/c (tClAB and tBrAB). A number of intramolecular hydrogen bonds, C−H⋯Hal (Hal=Cl, Br, I), were found in all halogen-containing congeners studied, but the intermolecular C−H⋯N hydrogen bond was detected only in AB and tIAB, while C−Hal⋯π only in tClAB and tBrAB. The interplay between C−H⋯N and C−H⋯Hal hydrogen bonds and a shift from the strong (C−H⋯Cl) to the very weak (C−H⋯I) attractive interactions upon Hal exchange, supplemented with Hal⋯Hal overlapping, determines the differences in the symmetry of crystalline packing and is crucial from the biological point of view. The hypothesis about the potential dual inhibitor role of the newly synthesized congeners was verified using molecular docking and the congeners were found to be pharmaceutically attractive as Human Casein Kinase 2, CK2, inhibitors, Membrane Matrix 2 Protein, M2, blockers and Severe Acute Respiratory Syndrome Coronavirus 2, SARS-CoV-2, inhibitors. The addition of adamantyl moiety seems to broaden and modify the therapeutic indices of the 4,5,6,7-tetrahalogeno-1H-benzimidazoles. [ABSTRACT FROM AUTHOR]

Given the rapid progression of the coronavirus disease 2019 (COVID‐19) pandemic, an ultrafast response was urgently required to handle this major public crisis. To contain the pandemic, investments are required to develop diagnostic tests, prophylactic vaccines, and novel therapies. Lately, nucleoside analog (NA) antivirals topped the scene as top options for the treatment of COVID‐19 caused by the severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) infections. Meanwhile, the continuous generation of new lineages of the SARS‐CoV‐2 Omicron variant caused a new challenge in the persistent COVID‐19 battle. Hitting the two crucial SARS‐CoV‐2 enzymes RNA‐dependent RNA polymerase (RdRp) and 3'‐to‐5' exoribonuclease (ExoN) collectively together using only one single ligand is a very successful new approach to stop SARS‐CoV‐2 multiplication and combat COVID‐19 irrespective of the SARS‐CoV‐2 variant type because RdRps and ExoNs are broadly conserved among all SARS‐CoV‐2 strains. Herein, the current comprehensive study investigated most NAs libraries, searching for the most ideal drug candidates expectedly able to perfectly act through this double tactic. Gradual computational filtration gave rise to six different promising NAs, which are riboprine, forodesine, tecadenoson, nelarabine, vidarabine, and maribavir, respectively. Further biological assessment proved for the first time, using the in vitro anti‐RdRp/ExoN and anti‐SARS‐CoV‐2 bioassays, that riboprine and forodesine, among all the six tested NAs, are able to powerfully inhibit the replication of the new virulent strains of SARS‐CoV‐2 with extremely minute in vitro anti‐RdRp and anti‐SARS‐CoV‐2 EC50 values of about 0.22 and 0.49 μM for riboprine and about 0.25 and 0.73 μM for forodesine, respectively, surpassing both remdesivir and the new anti‐COVID‐19 drug molnupiravir. The prior in silico data supported these biochemical findings, suggesting that riboprine and forodesine molecules strongly hit the key catalytic pockets of the SARS‐CoV‐2 (Omicron variant) RdRp′s and ExoN′s main active sites. Additionally, the ideal pharmacophoric features of riboprine and forodesine molecules render them typical dual‐action inhibitors of SARS‐CoV‐2 replication and proofreading, with their relatively flexible structures open for diverse types of chemical derivatization. In Brief, the current important results of this comprehensive study revealed the interesting repurposing potentials of, mainly, the two nucleosides riboprine and forodesine to effectively shut down the polymerase/exoribonuclease‐RNA nucleotides interactions of the SARS‐CoV‐2 Omicron variant and consequently treat COVID‐19 infections, motivating us to rapidly begin the two drugs′ broad preclinical/clinical anti‐COVID‐19 bioevaluations, hoping to combine both drugs soon in the COVID‐19 treatment protocols. [ABSTRACT FROM AUTHOR]

Consumption of legumes has long been linked to their nutritional and medicinal benefits. Vigna unguiculata (L.) Walp. (Cowpea) is a legume plant in the Fabaceae family and is a rich source of nutrients also is known for its beneficial effects for diseases treatment. In terms of phytochemicals analysis and bioactivities evaluations the major research has focused on the Cowpea seeds, whereas leaves and pods are remained understudied. Herein we have highlighted leaves methanolic extract phytochemicals identification, antimicrobial, and antioxidant activity assessment. Cowpea leaves methanolic extract Liquid Chromatography-Mass Spectrometry (LC-MS) analysis first time revealed the presence of α-hederin, which is a putative novel SARS-COV-2 inhibitor and Zearlenone mycotoxin. Leaves methanolic extract exhibited strong activity against Streptococcus pyogens and Candida albicans. The Cowpea leaves extract is a potent DPPH inhibitor with an IC50 of 62.04 ± 0.08 μg/mL. The bioactive compounds identification in this work supports the plant's nutritional and medicinal uses. [ABSTRACT FROM AUTHOR]

COVID-19, caused by the highly transmissible severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), has rapidly spread and become a pandemic since its outbreak in 2019. We have previously discovered that aloperine is a new privileged scaffold that can be modified to become a specific antiviral compound with markedly improved potency against different viruses, such as the influenza virus. In this study, we have identified a collection of aloperine derivatives that can inhibit the entry of SARS-CoV-2 into host cells. Compound 5 is the most potent tested aloperine derivative that inhibited the entry of SARS-CoV-2 (D614G variant) spike protein-pseudotyped virus with an IC50 of 0.5 µM. The compound was also active against several other SARS-CoV-2 variants including Delta and Omicron. Results of a confocal microscopy study suggest that compound 5 inhibited the viral entry before fusion to the cell or endosomal membrane. The results are consistent with the notion that aloperine is a privileged scaffold that can be used to develop potent anti-SARS-CoV-2 entry inhibitors. [ABSTRACT FROM AUTHOR]

Three new compounds of amidophosphoric acid esters with a [OCH2C(CH3)2CH2O]P(O)[X] segment (where X=cyclopentylamido (1), 2‐aminopyridinyl (2) and pyrrolidinyl (3)) were synthesized and studied using FT‐IR and 31P/13C/1H NMR spectroscopies and single‐crystal X‐ray diffraction analysis. The compounds crystallize in the triclinic space groups P1‾ for 1 and 3 and in the orthorhombic space group Pca21 for 2, where the asymmetric unit consists of three symmetrically‐independent molecules for 1 and one molecule for 2 and 3. The intermolecular interactions and supramolecular assemblies are assessed by Hirshfeld surface analysis and enrichment ratios. The results reveal that the substituent effect plays an important role in directing the supramolecular structures. The presence of the aromatic substituent aminopyridine in 2 providing the C−H...π interactions leads to a larger variety in interactions including H...H, H...O/O...H, H...C/C...H and H...N/N...H contacts, whereas the packings of the compounds 1 and 3 bearing aliphatic substituents only include H...H and H...O/O...H contacts. The enrichment ratios affirm the importance of O...H/H...O contacts reflecting the hydrogen bond N−H...O interactions to be the enriched contacts. Compounds 1–3 were also investigated along with five similar reported structures with a [OCH2C(CH3)2CH2O]P(O) segment for their inhibitory behavior against SARS‐CoV‐2. The molecular docking results illustrate that the presence of the aromatic amido substituent versus the aliphatic type provides a more favorable condition for their biological activities. [ABSTRACT FROM AUTHOR]

Chemical and biological investigation of the Madagascar endemic plant Saldinia proboscidea led to the isolation of an isomer of artemisinin, (−)-6-epi-artemisinin (2). Its structure was elucidated using a combination of NMR and mass spectrometry. The absolute configuration was established by chemical syntheses of compound 2 as well as a new stereoisomer (3). The comparable bioactivities of artemisinin (1) and its isomer (−)-6-epi-artemisinin (2) revealed that this change in configuration was not critical to their biological properties. Bioactivity was assessed using an apoptosis induction assay, a SARS-CoV-2 inhibitor assay, and a haematin polymerization inhibitory activity (HPIA) assay. This is the first report of an artemisinin-related compound from a genus not belonging to Artemisia and it is the first isolation of an artemisinin-related natural product that is the opposite enantiomeric series relative to artemisinin from Artemisia annua.

[Display omitted] The crystalline forms of three new phosphoric triamides are investigated by using single crystal X-ray diffraction (as two types of refinements with spherical (S) and aspherical (AS) form factors), spectral study and Hirshfeld surface analysis. The molecular docking simulation against SARS-CoV-2 for three series of ligand (L)-protein (P) complexes: L (with S form)-P (6M03), L (with AS form)-P (6M03) and L (AS)-P (6M03-N, with hydrogen atoms at their theoretical neutron values) is utilized for a biological analysis providing new insights of molecular docking study. • The crystalline forms of three new phosphoric triamides are investigated by using single crystal X-ray diffraction. • The favored contacts identified by Hirshfeld surface analysis are H...O/O...H interactions covering the N—H...O hydrogen bonds for all three structures. • The molecular docking simulation against SARS-CoV-2 for three series of ligand (L)-protein (P) complexes: L (with S form)-P (6M03), L (with AS form)-P (6M03) and L (AS)-P (6M03-N) is utilized for a biological analysis providing new insights of molecular docking study. In this work, we describe the crystal structures of two new phosphoramides containing the same [(3-Cl)C 6 H 4 NH]P(O) = Y segment (Y [ N (CH 3) CH 2 C 6 H 5 ] 2 (1) and Y [ NC 4 H 8 O ] 2 (2)) and an improved model of [C 6 H 11 (CH 3)N]P(O)[NHC(CH 3) 3 ] 2 (compound 3). The structures are experimentally investigated by single crystal X-ray diffraction using two types of refinements with spherical (S) and aspherical (AS) [Hirshfeld atomic refinements (HARs)] form factors, FT-IR and 1H, 13C, 31P NMR spectroscopy. A biological molecular docking investigation gives hints to suggest an appropriate inhibitory activity against MPro of SARS-COV-2 (6M03 and 6LU7) especially for 1 with a binding energy around −6 (6M03)/−7 (6LU7) kcal/mol. In the present work, the docking simulations are carried out for the first time for three series of ligand (L)-protein (P) complexes: L (with S form)-P (6M03), L (with AS form)-P (6M03) and L (AS)-P (6M03-N, with hydrogen atoms at their theoretical neutron values), where the binding energies are approximately proved to be 0.8 kcal/mol lower for simulations with 6M03-N than those for 6M03. Moreover, the structural study illustrates that the hydrogen bond patterns of all three structures consist of one-dimensional zigzag chains formed by classical N H...O hydrogen bond interactions. Further stabilization is provided by weak interactions such as C H...Cl (for 1 and 2), Cl...π (for 1 and 2) and C H...O (for 2 and 3). Furthermore, the intermolecular interactions are analyzed by three-dimensional (3D) Hirshfeld surfaces, 2D fingerprint plots and enrichment ratios. The favored contacts identified by Hirshfeld surface analysis are H...O/O...H interactions covering the N H...O hydrogen bonds for all three structures. For 1 and 2 , Cl...C/C...Cl contacts covering Cl...π interactions are recognized as the most enriched contacts. [ABSTRACT FROM AUTHOR]

Chemical and biological investigation of the Madagascar endemic plant Saldinia proboscidea led to the isolation of an isomer of artemisinin, (−)-6-epi-artemisinin (2). Its structure was elucidated using a combination of NMR and mass spectrometry. The absolute configuration was established by chemical syntheses of compound 2 as well as a new stereoisomer (3). The comparable bioactivities of artemisinin (1) and its isomer (−)-6-epi-artemisinin (2) revealed that this change in configuration was not critical to their biological properties. Bioactivity was assessed using an apoptosis induction assay, a SARS-CoV-2 inhibitor assay, and a haematin polymerization inhibitory activity (HPIA) assay. This is the first report of an artemisinin-related compound from a genus not belonging to Artemisia and it is the first isolation of an artemisinin-related natural product that is the opposite enantiomeric series relative to artemisinin from Artemisia annua. [ABSTRACT FROM AUTHOR]