Medicinal Chemistry - Publications

Boldescu, V., Behnam, M.A.M., Vasilakis, N., Klein, C.D.* Broad-spectrum agents for flaviviral infections: dengue, Zika and beyond.
Nature Reviews Drug Discovery 2017, 16, 565–586.

Liang, C., Behnam, M.A.M., Sundermann, T., Klein, C.D.* Phenylglycine racemization in Fmoc-based solid-phase peptide synthesis: Stereochemical stability is achieved by choice of reaction conditions.
Tet. Lett. 2017, 58, 2325-2329.

Mahawaththa, M.C., Pearce, B.J.G., Szabo, M., Graham, B., Klein, C.D., Nitsche, C., Otting, G., Solution conformations of a linked construct of the Zika virus NS2B-NS3 protease.
Antiviral Research, 2017, 142 , 141-147

Nitsche, C., Zhang, L., Weigel, L.F., Schilz, J., Graf, D., Bartenschlager, R., Hilgenfeld, R., Klein, C.D.* Peptide-Boronic Acid Inhibitors of Flaviviral Proteases: Medicinal Chemistry and Structural Biology.
J. Med. Chem., 2017, 60, 511–516
Corresponding pdb entry: 5IDK

Lei, J., Hansen, G.,  Nitsche, C., Klein, C.D., Zhang, L., Hilgenfeld, R.* Crystal structure of Zika virus NS2B-NS3 protease in complex with a boronate inhibitor.
Science, 2016, 353, 503-505
Corresponding pdb entry: 5LC0

Behnam, M., Sundermann, T., Klein, C.D.* Solid Phase Synthesis of C-Terminal Boronic Acid Peptides.
Organic Letters, 2016, 18, 2016–2019

Chen, W., Nitsche, C., Pilla, K.B., Graham, B., Huber, T., Klein, C.D., Otting, G.* Sensitive NMR Approach for Determining the Binding Mode of Tightly Binding Ligand Molecules to Protein Targets.
J. Am. Chem. Soc. 2016, 138, 4539–4546
(Information for non-chemists: IF 2014 = 12.1)

Behnam, M., Nitsche, C., Boldescu, V., Klein, C.D.* The Medicinal Chemistry of Dengue Virus.
J. Med. Chem., 2016, 59, 5622-5649
FEATURED as ACS Editors' Choice Article ⇒ OPEN ACCESS

Weng, Z., Shao, X., Graf, D., Wang, C., Klein, C., Wang, J.,* Zhou, G.-C.* Identification of the fused bicyclic derivatives of pyrrolidine and imidazolidinone as dengue virus-2 NS2B-NS3 protease inhibitors.
Eur. J. Med. Chem., 2016, 125, 751-759

Osman, N.A., Ligresti, A., Klein, C.D., Allarà, M., Rabbito, A., Di Marzo, V., Abouzid, K.A.,* Abadi
, A.H. Discovery of novel Tetrahydrobenzo[b]thiophene and pyrrole based scaffolds as potent and selective CB2 receptor ligands: The structural elements controlling binding affinity, selectivity and functionality.
Eur. J. Med. Chem., 2016, 122, 619-634


Calcagno, S., Klein, C.D.* N-terminal methionine processing by the zinc-activated Plasmodium falciparum methionine aminopeptidase 1b.
Applied Microbiology and Biotechnology, 2016, 100, 7091-7102

Morgen, M., Joest, C., Malz, M., Janowski, R., Niessing, D., Klein, C.D., Gunkel, N., Miller, A.K. Spiroepoxytriazoles are Fumagillin-like Irreversible Inhibitors of MetAP2 with Potent Cellular Activity.
ACS Chemical Biology, 2016, 11, 1001–1011

Behnam, M., Graf, D., Bartenschlager, R., Zlotos, D.P., Klein, C.D.* Discovery of nanomolar dengue and West Nile virus protease inhibitors containing a 4-benzyloxyphenylglycine residue.
J. Med. Chem., 2015, 58, 9354-9370

Weigel, L.F., Nitsche, C., Graf, D., Bartenschlager, R., Klein, C.D.* Phenylalanine and Phenylglycine Analogs as Arginine Mimetics in Dengue Protease Inhibitors.
J. Med. Chem., 2015, 58, 7719-7733 

Bastos Lima, A., Behnam, M.A., El Sherif, Y., Nitsche, C., Vechi, S.M.,  Klein, C.D.* Dual inhibitors of the dengue and West Nile virus NS2B-NS3 proteases: Synthesis, biological evaluation and docking studies of novel peptide-hybrids.
Bioorg. Med. Chem., 2015, 17, 5748–5755

Marschner, A., Klein, C.D.* Metal promiscuity and metal-dependent substrate preferences of  Trypanosoma brucei methionine aminopeptidase 1.
Biochimie, 2015, 115, 35–43

Nitsche, C., Holloway, S., Schirmeister, T., Klein, C.D.* Biochemistry and Medicinal Chemistry of the Dengue Virus Protease.
Chem. Rev., 2014, 114, 11348–11381. Article graphic used for cover image: Chemical Reviews Cover
(Information for non-chemists: IF 2013 = 41)

Jöst, C., Nitsche, C., Scholz, T., Roux, L., Klein, C.D.* Promiscuity and selectivity in covalent enzyme inhibition: A systematic study of electrophilic fragments.
Journal of Medicinal Chemistry, 2014, 57, 7590.

Altmeyer, M., Amtmann, E., Heyl, C., Marschner, A., Scheidig, A.J., Klein, C.D.* Beta-aminoketones as prodrugs for selective irreversible inhibitors of type-1 methionine aminopeptidases.
Bioorg. Med. Chem. Lett., 2014, 24, 5310.
Corresponding pdb entry: 4PNC

Osman, N.A., Mahmoud, A.H., Klein, C.D., Allarà, M., Di Marzo, V., Abouzid, K.M., Abadi, A.H.* Naphthalene and 2,3-dihydrobenzo[b][1,4]dioxin Derivatives With Extended Side Chains as New Scaffolds of CB2 Selective Ligands.
Med. Chem. Comm., 2014, 5, 1571-1576.

Behnam, M.A., Nitsche, C., Vechi, S.M., Klein, C.D.* C-Terminal Residue Optimization and Fragment Merging: Discovery of a Potent Peptide-Hybrid Inhibitor of Dengue Protease.
ACS Med. Chem. Lett., 2014, 5, 1037, DOI: 10.1021/ml500245v, 2014

Nitsche, C., Schreier, A., Behnam, M.A.M., Kumar, A., Bartenschlager, R., Klein C.D.* Thiazolidinone–Peptide Hybrids as Dengue Virus Protease Inhibitors with Antiviral Activity in Cell Culture.
Journal of Medicinal Chemistry, 2013, 56, 8389-8403.


Nitsche, C., Klein C.D.* Fluorimetric and HPLC-Based Dengue Virus Protease Assays Using a FRET Substrate.
Methods in Molecular Biology 2013, 1030, 221-236. doi: 10.1007/978-1-62703-484-5_18.


Seehafer, K., Rominger, F., Helmchen, G.,* Langhans, M., Robinson, D.G., Özata, B., Brügger, B., Strating, J., van Kuppeveld, F.J.M., Klein, C.D., Synthesis and Biological Properties of Novel Brefeldin A Analogues
Journal of Medicinal Chemistry, 2013, 56, 5872–5884


Scholz, T., Heyl, C.L., Bernardi, D., Zimmermann, S., Kattner, L., Klein, C.D.* Chemical, Biochemical and Microbiological Properties of a Brominated Nitrovinylfuran with Broad-Spectrum Antibacterial Activity.
Bioorganic & Medicinal Chemistry, 2013, 21, 795–804

Nitsche, C., Klein, C.D.* Aqueous microwave-assisted one-pot synthesis of N-substituted rhodanines.
Tetrahedron Letters, 2012, 53, 5197-5201.


Nitsche, C., Behnam, M.A. Steuer, C., Klein, C.D.* Retro peptide-hybrids as selective inhibitors of the Dengue virus NS2B-NS3 protease.
Antiviral Research, 2012, 94, 72-79.


Poreba, M., Gajda, A., Picha, J., Jiracek, J., Marschner, A., Klein, C.D., Salvesen, G., Drag, M., S1 pocket fingerprints of human and bacterial methionine aminopeptidases determined using fluorogenic libraries of substrates and phosphorus based inhibitors.
Biochimie, 2012, 94, 704-10.


Mendgen, T., Steuer, C., Klein, C.D.* Privileged Scaffolds or Promiscuous Binders – A Comparative Study on Rhodanines and Related Heterocycles in Medicinal Chemistry.
Journal of Medicinal Chemistry, 2011, 55, 743–753.


Nitsche, C., Steuer, C., Klein, C.D.* Arylcyanoacrylamides as inhibitors of the Dengue and West Nile virus proteases.
Bioorganic & Medicinal Chemistry, 2011, 19, 7318-7337


Steuer,  C., Gege, C., Fischl, W., Heinonen, K.H., Bartenschlager, R., Klein, C.D.* Synthesis and biological evaluation of α-ketoamides as inhibitors of the dengue virus protease with antiviral activity in cell-culture.
Bioorganic & Medicinal Chemistry 2011, 19, 4067-4074


Förster, S.,  Persch, E., Tverskoy, O., Rominger, F., Helmchen, G.,* Klein, C.D.,  Gönen, B., Brügger, B.. Syntheses and Biological Properties of Brefeldin Analogues.
Eur. J. Org. Chem., 2011, 5, 878-891


Mendgen, T., Scholz, T., Klein, C.D.* Structure-Activity Relationships of Tulipalines, Tuliposides and Related Compounds as Inhibitors of MurA.
Bioorg. Med. Chem. Lett. 2010, 20, 5757-62.


Altmeyer, M.A., Marschner, A., Schiffmann. R., Klein, C.D.* Subtype-selectivity of metal-dependent methionine aminopeptidase inhibitors.
Bioorg. Med. Chem. Lett. 2010, 20, 4038-4044.


Steuer, C., Heinonen, K., Kattner, L., Klein, C.D.* Optimization of Assay Conditions for Dengue Virus Protease: Effect of Various Polyols and Non-Ionic Detergents.
J. Biomol. Screening, 2009, 14, 1102-1108



Ziegler, S., Kronenberger, B., Albrecht, B., Kaul, A., Gamer, A., Klein, C.D.*, Hartmann, R.W.* Development and Evaluation of a FACS-Based Medium Throughput Assay for HCV Entry Inhibitors.
J. Biomol. Screening, 2009, 14, 620-626



Gege, C., Klein, C.D.* Frontiers in Medicinal Chemistry 2009 - a Summary of the Meeting at Heidelberg University.
ChemMedChem. 2009, 4, 1371-1376

Steinbach, A., Scheidig, A.J., Klein, C.D.* The unusual binding mode of cnicin to the antibacterial target enzyme MurA revealed by X-ray crystallography.
J. Med. Chem., 2008, 51, 5143-5148


Holzer, M., Ziegler, S., Albrecht, B., Kronenberger, B., Bartenschlager, R., Kattner, L., Klein, C.D.*, Hartmann, R.W. Identification of Terfenadine as an Inhibitor of Human CD81-receptor HCV-E2 Interaction: Synthesis and Structure Optimization
Molecules, 2008, 13, 1081-1110.


Holzer, M., Ziegler, S., Neugebauer, A., Kronenberger, B., Klein, C.D.*, Hartmann, R.W.* Structural Modifications of Salicylates: Inhibitors of Human CD81-Receptor HCV-E2 Interaction.
Arch. Pharm., 2008, 341, 478-484


Holzer, M., Ziegler, S., Kronenberger, B., Klein, C.D., Hartmann, R.W. * Microwave assisted syntheses of amino acid ester substituted benzoic acid amides: Potential inhibitors of human CD81-receptor HCV-E2 interaction.
The Open Medicinal Chemistry Journal, 2008, 2, 21-25.

Neugebauer, A.; Hartmann, R.W.; Klein C.D.* Prediction of protein-protein interaction inhibitors by chemoinformatics and machine learning methods.
J. Med. Chem., 2007, 50, 4665-4668


Bachelier, A.; Mayer, R.; Klein, C.D.* Sesquiterpene Lactones are Potent and Irreversible Inhibitors of MurA.
Bioorg. Med. Chem. Letters, 2006, 21, 5605-5609

Klein, C.D.*; Bachelier, A. Molecular Modeling and Bioinformatical Analysis of the Antibacterial Target Enzyme MurA from a Drug Design Perspective.
Journal of Computer-Aided Molecular Design, 2006, 20, 621-628

Schiffmann, R.; Neugebauer, A.; Klein, C.D.* Metal-Mediated Inhibition of E. coli Methionine Aminopeptidase: Structure-Activity Relationships and Development of a Novel Scoring Function for Metal-Ligand Interactions.
J. Med. Chem. 2006, 49, 511-522



  Angewandte-titel-klein Schiffmann, R.; Heine, A.; Klebe, G.; Klein, C.D.* Metal Ions as Cofactors for Ligand Binding at Methionine Aminopeptidase: A Critical View on the Relevance of in vitro Metalloenzyme Assays.
Angewandte Chemie Int. Ed. 2005, 44, 3620-3623


Ashraf H. Abadi, A.H.; Sahar M. Abou-Seri, S.M.; Abdel-Rahman, S.E.; Klein, C.D.; Lozach, O.; Meijer, L. Synthesis of 3-substituted-2-oxoindole analogues and their evaluation as kinase inhibitors, anticancer and antiangiogenic agents.
Eur. J. Med. Chem. 2006, 41, 296–305

Ulmschneider, S.; Müller-Vieira, U.; Mitrenga, M.; Hartmann, R.W.; Oberwinkler-Marchais, S.; Klein, C.D.; Bureik, M.; Bernhardt, R.; Antes. I.; Lengauer, T. Synthesis and Evaluation of Imidazolylmethylene-tetrahydronaphthalenes and -indanes: Potent Inhibitors of Aldosterone Synthase (CYP11B2).
J. Med. Chem. 2005, 48, 1796-1805

Ulmschneider, S.; Müller-Vieira, U.; Klein, C.D.; Antes, I.; Lengauer, T.; Hartmann, R.W. Synthesis and Evaluation of Pyridylmethylene-tetrahydronaphthalenes / -indanes and structurally modified derivatives: Potent and Selective Inhibitors of Aldosterone Synthase (CYP11B2).
J. Med. Chem., 2005, 48, 1563-75

Neugebauer, A.; Klein, C.; Hartmann, R.W. Protein-Dynamics of the Putative HCV Receptor CD81 Large Extracellular Loop.
Bioorg. Med. Chem. Lett. 2004, 14, 1765-1769.

de Pol, S.; Zorn, C.; Klein, C.; Zerbe, O.; Reiser, O. Surprisingly Stable Helical Structures in altering a/b-Peptides by Incorporation of Cis-b-Amino­cyclopropane Carboxylic Acids.
Angew. Chem. Int. Ed. 2004, 43, 511 –514

Klein,C.*; Schiffmann, R.; Folkers, G.; Piana, S.; Röthlisberger, U. Protonation States of Methionine Aminopeptidase and Their Relevance For Inhibitor Binding and Catalytic Activity.
Journal of Biological Chemistry, 2003, 278, 47862–47867.

Klein, C.* Protonation States of Methionine Aminopeptidase Studied by QM/MM Car-Parrinello Molecular Dynamics Simulations.
High Performance Computing in Science and Engineering, 2003, 393-402.

Klein, C.*; Folkers, G. Understanding the Selectivity of Fumagillin for the Methionine Aminopeptidase Type II.
Oncology Research and AntiCancer Drug Design, 2003, 13, 513-520.

Hartmann, R.W.; Ehmer, P.B.; Haidar, S.; Hector, M.; Jose, J.; Klein, C.; Seidel, S.B.; Sergejew, T.F.; Wachall, B.G.; Wächter, G.A.; Zhuang, Y. Inhibition of CYP17, a New Strategy for the Treatment of Prostate Cancer.
Arch. Pharm. Pharm. Med. Chem., 2002, 4, 119-128.

Folkers, G.; Klein, C. Computational Methods Facilitate the Assignment of Protein Functions.
Angew. Chem. Int. Ed. Engl., 2001, 40, 4175-4177.

Baston, E.; Klein, C.; Hartmann, R.W.; et al. Synthesis, evaluation, and QSAR studies of highly potent aromatase inhibitors of the piperidinedione type.
Anti-Cancer Drug Design, 2001, 16, 37-47.

Klein, C.*; Tabeteh, G.F.; v. Laguna, A., Holzgrabe, U.; Mohr, K. Lipophilicity and Membrane Interactions of Cationic-Amphiphilic Compounds: Syntheses and Structure-Property Relationships.
Eu. J. Pharm. Sci. 2001, 14, 167-175.

Haidar, S.; Klein., C.; Hartmann, R.W. Synthesis and Evaluation of Steroidal Hydroxamic Acids as Inhibitors of P45017 (17a-Hydroxylase-C17-20-Lyase)
Arch. Pharm. Pharm. Med. Chem. 2001, 334, 138-140

Klein, C.; Klingmüller, M.; Schellinski, M.; Landmann, S.; Hauschild, S.; Heber, D.; Mohr, K.; Hopfinger, A.J. Synthesis, Pharmacological and Biophysical Characterization, and Membrane-Interaction QSAR Analysis of Cationic-Amphiphilic Model Compounds.
J. Med. Chem.
1999, 42, 3874-3888

Klein, C.; Hopfinger, A.J. Pharmacological Activity and Membrane Interactions of Antiarrhythmics: 4D-QSAR/QSPR Analysis.
Pharm. Res. 1998, 15, 303-311.


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