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, published online.

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, published online.

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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