5‐Substituted (1‐Thiolan‐2‐yl)cytosines as Inhibitors of A. aeolicus and E. coli IspE Kinases: Very Different Affinities to Similar Substrate‐Binding Sites

The enzymes of the non-mevalonate pathway for isoprenoid biosynthesis are potential new targets for the development of selective drugs for the treatment of important infectious diseases. This pathway is used by major human pathogens, such as Plasmodium falciparum and Mycobacterium tuberculosis, but not by humans. The fourth enzyme in the pathway is the kinase IspE, and we report here the development and biological evaluation of new ligands for this enzyme from Escherichia coli and Aquifex aeolicus species as model systems for the pathogenic enzymes. The study focuses on analysis of the methylerythritol pocket of the 4-diphosphocytidyl-2-C-methyl-D-erythritol binding site. A series of 5-substituted 1-(thiolan-2-yl)cytosines with increasingly polar substituents were synthesized, opting for possible water-replacements in that sub-pocket as well as a high water-solubility of the ligands. In vitro studies showed IC50 values in the micromolar range against E. coli IspE, but, unexpectedly, no inhibition against A. aeolicus IspE within the measurement range of the biological tests.

[1]  Luzi J. Barandun,et al.  From lin-benzoguanines to lin-benzohypoxanthines as ligands for Zymomonas mobilis tRNA-guanine transglycosylase: replacement of protein-ligand hydrogen bonding by importing water clusters. , 2012, Chemistry.

[2]  A. Hirsch,et al.  The isoprenoid-precursor dependence of Plasmodium spp. , 2012, Natural product reports.

[3]  F. Diederich,et al.  Exploring the Ribose Sub-Pocket of the Substrate-Binding Site in Escherichia coli IspE: Structure-Based Design, Synthesis, and Biological Evaluation of Cytosines and Cytosine Analogues , 2012 .

[4]  Xuehui Chen,et al.  Crystal structure of 4‐diphosphocytidyl‐2‐C‐methyl‐D‐erythritol kinase (IspE) from Mycobacterium tuberculosis , 2011, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[5]  J. Hoebeke,et al.  Mechanisms of genetically-based resistance to malaria. , 2010, Gene.

[6]  C. Wongsrichanalai,et al.  Extensive Drug Resistance in Malaria and Tuberculosis , 2010, Emerging infectious diseases.

[7]  Alan Rolfe,et al.  Formal [4+3] epoxide cascade reaction via a complementary ambiphilic pairing strategy. , 2010, Organic letters.

[8]  Gerhard Klebe,et al.  How to Replace the Residual Solvation Shell of Polar Active Site Residues to Achieve Nanomolar Inhibition of tRNA‐Guanine Transglycosylase , 2009, ChemMedChem.

[9]  Manuel Ellermann,et al.  Molekulare Erkennung in der aktiven Tasche der Catechol-O- Methyltransferase: energetisch günstige Verdrängung eines von einem Bisubstratinhibitor importierten Wassermoleküls† , 2009 .

[10]  G. Klebe,et al.  High-affinity inhibitors of tRNA-guanine transglycosylase replacing the function of a structural water cluster. , 2009, Chemistry.

[11]  S. Abdulla,et al.  Dispersible formulation of artemether/lumefantrine: specifically developed for infants and young children , 2009, Malaria Journal.

[12]  K. Silamut,et al.  Artemisinin resistance in Plasmodium falciparum malaria. , 2009, The New England journal of medicine.

[13]  A. Dicko,et al.  Efficacy and safety of a fixed dose artesunate-sulphamethoxypyrazine-pyrimethamine compared to artemether-lumefantrine for the treatment of uncomplicated falciparum malaria across Africa: a randomized multi-centre trial , 2009, Malaria Journal.

[14]  N. Day,et al.  Plasmodium falciparum pfmdr1 Amplification, Mefloquine Resistance, and Parasite Fitness , 2009, Antimicrobial Agents and Chemotherapy.

[15]  Luzi J. Barandun,et al.  Inhibitors of the kinase IspE: structure-activity relationships and co-crystal structure analysis. , 2008, Organic & biomolecular chemistry.

[16]  Murray N. Robertson,et al.  Characterization of Aquifex aeolicus 4-diphosphocytidyl-2C-methyl-d-erythritol kinase – ligand recognition in a template for antimicrobial drug discovery , 2008, The FEBS journal.

[17]  F. Diederich,et al.  Synthesis and Characterization of Cytidine Derivatives that Inhibit the Kinase IspE of the Non‐Mevalonate Pathway for Isoprenoid Biosynthesis , 2008, ChemMedChem.

[18]  B. Kuhn,et al.  Small Molecule Conformational Preferences Derived from Crystal Structure Data. A Medicinal Chemistry Focused Analysis , 2008, J. Chem. Inf. Model..

[19]  Jianming Xu,et al.  Highly selective anti-Markovnikov addition of thiols to vinyl ethers under solvent-and catalyst-free conditions , 2007 .

[20]  A. Djimde,et al.  Monitoring and deterring drug-resistant malaria in the era of combination therapy. , 2007, The American journal of tropical medicine and hygiene.

[21]  F. Diederich,et al.  Nonphosphate Inhibitors of IspE Protein, a Kinase in the Non‐Mevalonate Pathway for Isoprenoid Biosynthesis and a Potential Target for Antimalarial Therapy , 2007, ChemMedChem.

[22]  K. Kaliappan,et al.  A new versatile strategy for C-aryl glycosides. , 2007, Organic letters.

[23]  A. Nishiguchi,et al.  Sulfonyl chloride formation from thiol derivatives by N-chlorosuccinimide mediated oxidation , 2006 .

[24]  Markus Fischer,et al.  Nonmevalonate terpene biosynthesis enzymes as antiinfective drug targets: substrate synthesis and high-throughput screening methods. , 2006, The Journal of organic chemistry.

[25]  K. Lackey,et al.  Optimization and SAR for dual ErbB-1/ErbB-2 tyrosine kinase inhibition in the 6-furanylquinazoline series. , 2006, Bioorganic & medicinal chemistry letters.

[26]  S. Yokoyama,et al.  Crystal Structure of 4-(Cytidine 5′-diphospho)-2-C-methyl-d-erythritol kinase, an Enzyme in the Non-mevalonate Pathway of Isoprenoid Synthesis* , 2003, Journal of Biological Chemistry.

[27]  W. Eisenreich,et al.  Biosynthesis of isoprenoids: Crystal structure of 4-diphosphocytidyl-2C-methyl-d-erythritol kinase , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[28]  A. Vasella,et al.  Oligosaccharide Analogues of Polysaccharides Part 23. Synthesis of a Dimeric Acetyleno Cyclodextrin from a Mannopyranose-Derived Dialkyne , 2001 .

[29]  Paul R. Gerber,et al.  Charge distribution from a simple molecular orbital type calculation and non-bonding interaction terms in the force field MAB , 1998, J. Comput. Aided Mol. Des..

[30]  Paul R. Gerber,et al.  MAB, a generally applicable molecular force field for structure modelling in medicinal chemistry , 1995, J. Comput. Aided Mol. Des..

[31]  J. Soto,et al.  Synthesis of isomeric 5-(phenylsulphonyl)pyrimidines , 1985 .

[32]  J. Tronchet,et al.  Préparation de dérivés de sucres acétyléniques terminaux et d'acides ynuroniques par réaction de Wittig. Note de laboratoire† , 1980 .

[33]  Y. Cheng,et al.  Relationship between the inhibition constant (K1) and the concentration of inhibitor which causes 50 per cent inhibition (I50) of an enzymatic reaction. , 1973, Biochemical pharmacology.