Amantadine and Rimantadine Analogues—Single-Crystal Analysis and Anti-Coronaviral Activity

In this study, we utilized the human coronavirus 229E (HCoV-229E) for evaluating the in vitro efficacy of some analogues of the ion-channel inhibitors and Amantadine and Rimantadine. The application of these investigated compounds did not result in any detectable cytotoxic effects. Furthermore, we observed that the derivatives of both analogues did not affect the viability of MDBK cells. Amantadine and Rimantadine applied at a concentration of 50 μg/mL inhibited the replication by 47% and 36%, respectively. The derivatives of Amantadine displayed a slightly weaker inhibitory effect in comparison with its own inhibitory effect. The derivative 4R of Rimantadine exhibited the same antiviral effect as the Rimantadine control, inhibiting viral replication by 37%. However, the other two derivatives of Rimantadine demonstrated lower activities. The molecular structures of the newly synthesized compounds were investigated thoroughly using single-crystal X-ray analysis. Molecular docking studies were performed using Autodock Vina. Two of the studied compounds 2A and 4A showed a promising binding affinity (−8.3 and −8.0 kcal/mol) towards SARS-CoV-2 RNA-dependent polymerase RNA site and SARS-CoV-2 Nsp3 (207-379, MES site) respectively.

[1]  A. Mardinoğlu,et al.  In Vitro and In Vivo Neuroprotective Effects of Sarcosine , 2022, BioMed research international.

[2]  R. Liu,et al.  Synthesis, Neuroprotective Effect and Physicochemical Studies of Novel Peptide and Nootropic Analogues of Alzheimer Disease Drug , 2022, Pharmaceuticals.

[3]  B. Shivachev,et al.  Development of N,N-Dimethylglycine-Amantadine for Adjunctive Dopaminergic Application: Synthesis, Structure and Biological Activity , 2022, Crystals.

[4]  Xingxing Ma,et al.  Unsymmetric monothiooxalamides from S8, bromodifluoro reagents and anilines: Synthesis and applications , 2022, Tetrahedron Chem.

[5]  Yang Yang,et al.  Recovery of N, N-dimethylglycine (DMG) from dimethylglycine hydrochloride by bipolar membrane electrodialysis , 2022, Chemical Engineering and Processing - Process Intensification.

[6]  J. Bukh,et al.  Efficacy of Ion-Channel Inhibitors Amantadine, Memantine and Rimantadine for the Treatment of SARS-CoV-2 In Vitro , 2021, Viruses.

[7]  E. Marengo,et al.  Understanding protection from SARS-CoV-2 using metabolomics , 2021, Scientific Reports.

[8]  R. Butterworth.  Potential for the Repurposing of Adamantane Antivirals for COVID-19 , 2021, Drugs in R&D.

[9]  Jorge L. Arias-Arias,et al.  In Vitro Inhibition of Zika Virus Replication with Amantadine and Rimantadine Hydrochlorides , 2021, Microbiology Research.

[10]  S. Olsen,et al.  Activity profiling and crystal structures of inhibitor-bound SARS-CoV-2 papain-like protease: A framework for anti–COVID-19 drug design , 2020, Science Advances.

[11]  G. Minasov,et al.  High-resolution structures of the SARS-CoV-2 2’-O-methyltransferase reveal strategies for structure-based inhibitor design , 2020, Science Signaling.

[12]  G. Melagraki,et al.  Synthetic Analogues of Aminoadamantane as Influenza Viral Inhibitors—In Vitro, In Silico and QSAR Studies , 2020, Molecules.

[13]  Jianping Hu,et al.  COVID-19 Docking Server: A meta server for docking small molecules, peptides and antibodies against potential targets of COVID-19 , 2020, Bioinform..

[14]  A. Joachimiak,et al.  Crystal structures of SARS-CoV-2 ADP-ribose phosphatase: from the apo form to ligand complexes , 2020, IUCrJ.

[15]  L. Dodd,et al.  Remdesivir for the Treatment of Covid-19 — Final Report , 2020, The New England journal of medicine.

[16]  Yan Zhang,et al.  Structural Basis for the Inhibition of the RNA-Dependent RNA Polymerase from SARS-CoV-2 by Remdesivir , 2020, bioRxiv.

[17]  Hualiang Jiang,et al.  Structure of Mpro from SARS-CoV-2 and discovery of its inhibitors , 2020, Nature.

[18]  A. Majouga,et al.  Synthesis and cytotoxicity of oxindoles dispiro derivatives with thiohydantoin and adamantane fragments , 2020 .

[19]  Z. Rao,et al.  Delicate structural coordination of the Severe Acute Respiratory Syndrome coronavirus Nsp13 upon ATP hydrolysis , 2019, Nucleic acids research.

[20]  M. Christmann,et al.  Corrigendum: Mechanistic Studies on the Organocatalytic α-Chlorination of Aldehydes: The Role and Nature of Off-Cycle Intermediates. , 2018, Angewandte Chemie.

[21]  I. Godovikov,et al.  Stereoselective synthesis of novel adamantane derivatives with high potency against rimantadine-resistant influenza A virus strains. , 2017, Organic & biomolecular chemistry.

[22]  Liming Yan,et al.  Structural basis and functional analysis of the SARS coronavirus nsp14–nsp10 complex , 2015, Proceedings of the National Academy of Sciences.

[23]  G. Sheldrick.  SHELXT – Integrated space-group and crystal-structure determination , 2015, Acta crystallographica. Section A, Foundations and advances.

[24]  Louis J. Farrugia,et al.  WinGX and ORTEP for Windows: an update , 2012 .

[25]  Roman A. Laskowski,et al.  LigPlot+: Multiple Ligand-Protein Interaction Diagrams for Drug Discovery , 2011, J. Chem. Inf. Model..

[26]  Silvia Domcke,et al.  Molecular mechanisms for the RNA-dependent ATPase activity of Upf1 and its regulation by Upf2. , 2011, Molecular cell.

[27]  David S. Goodsell,et al.  AutoDock4 and AutoDockTools4: Automated docking with selective receptor flexibility , 2009, J. Comput. Chem..

[28]  Arthur J. Olson,et al.  AutoDock Vina: Improving the speed and accuracy of docking with a new scoring function, efficient optimization, and multithreading , 2009, J. Comput. Chem..

[29]  S. Hamodrakas,et al.  A de novo Designed Possible 5‐Lipoxygenase Inhibitor: α‐Acetoxy‐N‐[1‐(1‐tricyclo[3.3.1.13,7]dec‐1‐yl)ethyl]benzeneacetamide , 1996 .

[30]  K. Sudo,et al.  A sensitive assay system screening antiviral compounds against herpes simplex virus type 1 and type 2. , 1994, Journal of virological methods.

[31]  S. Gellman,et al.  Effects of covalent modifications on the solid-state folding and packing of N-malonylglycine derivatives , 1992 .

[32]  G. M. Reisner,et al.  Space‐group changes – revised structures of seven compounds , 1990 .

[33]  T. Mosmann.  Rapid colorimetric assay for cellular growth and survival: application to proliferation and cytotoxicity assays. , 1983, Journal of immunological methods.

[34]  S. Brenner.  Repurposing of Adamantanes with Transmitter Receptor Antagonist Properties for the Prevention/Treatment of COVID-19 , 2020 .

[35]  A. Trzeciak,et al.  New coupling reagents in peptide chemistry , 1989 .

[36]  Paul D Adams,et al.  Electronic Reprint Biological Crystallography Electronic Ligand Builder and Optimization Workbench (elbow ): a Tool for Ligand Coordinate and Restraint Generation Biological Crystallography Electronic Ligand Builder and Optimization Workbench (elbow): a Tool for Ligand Coordinate and Restraint Gener , 2022 .