Rolf W Hartmann

Helmholtz Institute for Pharmaceutical Research Saarland, Saarbrücken, Saarland, Germany

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Publications (365)1048.3 Total impact

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    ABSTRACT: Typically, 4,6-disubstituted 2-thiomethylpyrimidines are synthesized starting from 4,6-dichloro-2-thiomethylpyrimidine or an amino-substituted precursor. However, these reactions take several hours up to days and require multiple steps. Herein, we report a novel, easy, and quick-to-prepare synthetic intermediate, namely 2-(methylthio)-4,6-di(1H-tetrazol-1-yl)pyrimidine, for the synthesis of these interesting target compounds. The intermediate can be transformed within minutes into desired substituted pyrimidines under mild conditions with moderate to excellent yields. The reaction can be conducted in an automated microwave system, at room temperature or by conventional heating. Furthermore, we demonstrate the robustness of the method in a one-pot procedure.
    Synlett 10/2015; 26(18). DOI:10.1055/s-0035-1560577 · 2.42 Impact Factor
  • A Thomann · J Zapp · M Hutter · M Empting · R W Hartmann ·
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    ABSTRACT: This paper focuses on an interesting constitutional isomerism called azido-tetrazole equilibrium which is observed in azido-substituted N-heterocycles. We present a systematic investigation of substituent effects on the isomer ratio within a 2-substituted 4-azidopyrimidine model scaffold. NMR- and IR-spectroscopy as well as X-ray crystallography were employed for thorough analysis and characterization of synthesized derivatives. On the basis of this data, we demonstrate the possibility to steer this valence tautomerism towards the isomer of choice by means of substituent variation. We show that the tetrazole form can act as an efficient disguise for the corresponding azido group masking its well known reactivity in azide-alkyne cycloadditions (ACCs). In copper(i)-catalyzed AAC reactions, substituent-stabilized tetrazoles displayed a highly decreased or even abolished reactivity whereas azides and compounds in the equilibrium were directly converted. By use of an acid sensitive derivative, we provide, to our knowledge, the first experimental basis for a possible exploitation of this dynamic isomerism as a pH-dependent azide-protecting motif for selective SPAAC conjugations in aqueous media. Finally, we demonstrate the applicability and efficiency of stabilized tetrazolo[1,5-c]pyrimidines for Fragment-Based Drug Design (FBDD) in the field of quorum sensing inhibitors.
    Organic & Biomolecular Chemistry 09/2015; 13(43). DOI:10.1039/c5ob01006c · 3.56 Impact Factor
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    ABSTRACT: Design and synthesis of a new class of inhibitors for the treatment of osteoporosis and its comparative h17β-HSD2 and m17β-HSD2 SAR study are described. 17a is the first compound to show strong inhibition of both h17β-HSD2 and m17β-HSD2, intracellular activity, metabolic stability, selectivity toward h17β-HSD1, m17β-HSD1 and estrogen receptors α and β as well as appropriate physicochemical properties for oral bioavailability. These properties make it eligible for pre-clinical animal studies, prior to human studies.
    PLoS ONE 07/2015; 10(7). DOI:10.1371/journal.pone.0134754 · 3.23 Impact Factor
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    ABSTRACT: Hit-to-lead efforts resulted in the discovery of compound 19, a potent CYP11B2 inhibitor that displays high selectivity vs related CYPs, good pharmacokinetic properties in rat and rhesus, and lead-like physical properties. In a rhesus pharmacodynamic model, compound 19 displays robust, dose-dependent aldosterone lowering efficacy, with no apparent effect on cortisol levels.
    ACS Medicinal Chemistry Letters 07/2015; 6(8). DOI:10.1021/acsmedchemlett.5b00048 · 3.12 Impact Factor
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    ABSTRACT: The aim of this work was to develop clarithromycin microparticles (CLARI-MP) and evaluate their aerodynamic behavior, safety in bronchial cells and anti-bacterial efficacy. Microparticles containing clarithromycin were prepared as dry powder carrier for inhalation, using leucine and chitosan. CLARI-MP were deposited on Calu-3 grown at air-interface condition, using the pharmaceutical aerosol deposition device on cell cultures (PADDOCC). Deposition efficacy, transport across the cells and cytotoxicity were determined. Anti-antibacterial effect was evaluated against Pseudomonas aeruginosa, Escherichia coli and Staphylococcus aureus. Microparticles were of spherical shape, smooth surface and size of about 765 nm. Aerosolization performance showed a fine particle fraction (FPF) of 73.3%, and a mass median aerodynamic diameter (MMAD) of 1.8 μm. Deposition on Calu-3 cells using the PADDOCC showed that 8.7 μg/cm(2) of deposited powder were transported to the basolateral compartment after 24 h. The safety of this formulation is supported by the integrity of the cellular epithelial barrier and absence of toxicity, and the antimicrobial activity demonstrated for Gram positive and Gram negative bacteria. The appropriate aerodynamic properties and the excellent deposition on Calu-3 cells indicate that clarithromycin microparticles are suitable for administration via pulmonary route and are efficient to inhibit bacteria proliferation.
    Pharmaceutical Research 06/2015; 32(12). DOI:10.1007/s11095-015-1745-8 · 3.42 Impact Factor
  • Chris J van Koppen · Rolf W Hartmann ·
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    ABSTRACT: Introduction: About 2% of the Western world population suffer from chronic wounds, resulting from underlying disorders (e.g., diabetes, excessive pressure, vascular insufficiencies and vasculitis), with a significant adverse effect on Quality of Life. Despite high incidence and economic burden, management of chronic wounds is still far from effective and novel therapies are in urgent need. Wound healing is a dynamic process of transient expression, function and clearance of mediators, enzymes and cell types. Failure to initiate, terminate or regulate leads to pathologic wound healing. Areas covered: The present review discusses patents of the seven most promising classes of biological agents, mostly published in 2009 - 2014 (CYP11B1 inhibitors, peptide growth factors, prolyl-4-hydroxylase and matrix metalloproteinase inhibitors, bone marrow-derived mesenchymal stem cells, elastase and connexin43 inhibitors). Relevant information from peer-reviewed journals is also presented. Expert opinion: The aforementioned biological agents have different mechanisms of action, and considering the multifactorial pathogenesis of chronic wounds, they hold promise in treating chronic wounds. However, as administration of a certain biological agent may be beneficial in an early phase, it may slow down wound healing in a later phase. Basic and clinical research on chronic wound healing should therefore investigate the efficacy of these agents, alone and in concert, during the consecutive phases of wound healing.
    Expert Opinion on Therapeutic Patents 06/2015; 25(8):1-7. DOI:10.1517/13543776.2015.1045879 · 4.30 Impact Factor
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    ABSTRACT: Loop diuretics are used for fluid control in patients with heart failure. Furosemide and torasemide may exert differential effects on myocardial fibrosis. Here, we studied the effects of torasemide and furosemide on atrial fibrosis and remodeling during atrial fibrillation METHODS AND RESULTS: In primary neonatal cardiac fibroblasts, torasemide (50 μM, 24 h) but not furosemide (50 μM, 24 h) reduced the expression of connective tissue growth factor (CTGF; 65±6%) and the pro-fibrotic miR-21 (44±23%), as well as the expression of lysyl oxidase (LOX; 57±8%), a regulator of collagen crosslinking. Mineralocorticoid receptor (MR) expression and activity were not altered. Torasemide but not furosemide inhibited human aldosterone synthase (CYP11B2) activity in transfected lung fibroblasts (V79MZ cells) by 75±1.8%. The selective CYP11B2 inhibitor SL242 mimicked the torasemide effects. Mice with cardiac overexpression of Rac1 GTPase (RacET), which develop atrial fibrosis and spontaneous AF with aging, were treated long-term (8 months) with torasemide (10mg/kg/day), furosemide (40mg/kg/day) or vehicle. Treatment with torasemide but not furosemide prevented atrial fibrosis in RacET as well as the up-regulation of CTGF, LOX and miR-2, whereas MR expression and activity remained unaffected. These effects correlated with a reduced prevalence of atrial fibrillation (33% RacET+Tora vs. 80% RacET). Torasemide but not furosemide inhibits CYP11B2 activity and reduces the expression of CTGF, LOX and miR-21. These effects are associated with prevention of atrial fibrosis and a reduced prevalence of atrial fibrillation in mice. Copyright © 2015. Published by Elsevier Ltd.
    Journal of Molecular and Cellular Cardiology 06/2015; 85. DOI:10.1016/j.yjmcc.2015.05.019 · 4.66 Impact Factor
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    ABSTRACT: Pseudomonas aeruginosa employs a quorum sensing (QS) communication system that makes use of small diffusible molecules. Among other effects, the QS system coordinates the formation of biofilm which decisively contributes to difficulties in the therapy of Pseudomonas infections. The present work deals with the structure-activity exploration of ureidothiophene-2-carboxylic acids as inhibitors of PqsD, a key enzyme in the biosynthetic pathway of signal molecules in the Pseudomonas QS system. We describe an improvement of the inhibitory activity by successfully combining features from two different PqsD inhibitor classes. Furthermore the functional groups, which are responsible for the inhibitory potency, were identified. Moreover, the inability of the new inhibitors, to prevent signal molecule formation in whole cell assays, is discussed. Copyright © 2015 Elsevier Masson SAS. All rights reserved.
    European Journal of Medicinal Chemistry 05/2015; 96. DOI:10.1016/j.ejmech.2015.04.007 · 3.45 Impact Factor
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    Qingzhong Hu · Jessica Kunde · Nina Hanke · Rolf W. Hartmann ·
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    ABSTRACT: The inhibition of 11β-hydroxylase is a promising strategy for the treatment of Cushing's syndrome, in particular for the recurrent and subclinical cases. To achieve proof of concept in rats, efforts were paid to identify novel lead compounds inhibiting both human and rat CYP11B1. Modifications on a potent promiscuous inhibitor of hCYP11B1, hCYP11B2 and hCYP19 (compound IV) that exhibited moderate rCYP11B1 inhibition led to compound 8 as a new promising lead compound. Significant improvements compared to starting point IV were achieved regarding inhibitory potency against both human and rat CYP11B1 (IC50 values of 2 and 163 nM, respectively) as well as selectivity over hCYP19 (IC50 = 1900 nM). Accordingly, compound 8 was around 7- and 28-fold more potent than metyrapone regarding the inhibition of human and rat CYP11B1 and exhibited a comparable selectivity over hCYP11B2 (SF of 3.5 vs 4.9). With further optimizations on this new lead compound 8, drug candidates with satisfying profiles are expected to be discovered. Copyright © 2015 Elsevier Masson SAS. All rights reserved.
    European Journal of Medicinal Chemistry 05/2015; 96. DOI:10.1016/j.ejmech.2015.04.013 · 3.45 Impact Factor
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    ABSTRACT: The first total synthesis of cystobactamid 507, a member of a class of new natural products with strong inhibitory activity towards bacterial topoisomerases, is reported. Synthetic key challenges are the central tetrasubstitued arene and the low chemical reactivity of anilines and ortho-phenolic and isopropoxy-substituted benzoic acids. Biological evaluations demonstrate that cystobactamid 507 inhibits several Gram-positive pathogens but at significantly lower concentrations than described for the larger members of this natural product family.
    Synlett 05/2015; 26(09):1175-1178. DOI:10.1055/s-0034-1380509 · 2.42 Impact Factor
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    ABSTRACT: Myxopyronins are α-pyrone antibiotics produced by the terrestrial bacterium Myxococcus fulvus Mx f50 and possess antibacterial activity against Gram-positive and Gram-negative pathogens. They target the bacterial RNA polymerase (RNAP) “switch region” as non-competitive inhibitors and display no cross-resistance to the established RNAP inhibitor rifampicin. Recent analysis of the myxopyronin biosynthetic pathway lead to the hypothesis that this secondary metabolite is produced from two separate polyketide parts, which are condensed by the stand-alone ketosynthase MxnB. Using in vitro assays we show that MxnB catalyzes a unique condensation reaction forming the α-pyrone ring of myxopyronins from two activated acyl chains in form of their β-keto intermediates. MxnB is able to accept thioester substrates coupled to either N-acetylcysteamine (NAC) or a specific carrier protein (CP). The turnover rate of MxnB for substrates bound to CP was 12-fold higher than for SNAC substrates, demonstrating the importance of protein-protein interactions in multimodular polyketide synthases (PKSs). The crystal structure of MxnB reveals the enzyme to be an unusual member of the ketosynthase group capable of binding and condensing two long alkyl chains bound to carrier proteins. The geometry of the two binding tunnels supports the biochemical data and allows us to propose an order of reaction, which is supported by the identification of novel myxopyronin congeners in the extract of the producer strain. Insights into the mechanism of this unique condensation reaction do not only expand our knowledge regarding the thiolase enzyme family but also opens up opportunities for PKS bioengineering to achieve directed structural modifications.
    Chemical Science 05/2015; 6(8). DOI:10.1039/C5SC01013F · 9.21 Impact Factor
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    ABSTRACT: Myxopyronin is a natural α-pyrone antibiotic from the soil bacterium Myxococcus fulvus Mx f50. Myxopyronin inhibits bacterial RNA polymerase (RNAP) by binding to a part of the enzyme not targeted by the clinically used rifamycins. This mode of action makes myxopyronins promising molecules for the development of novel broad-spectrum antibacterials. We describe the derivatization of myxopyronins by an advanced mutasynthesis approach as a first step towards this goal. Site-directed mutagenesis of the biosynthetic machinery was used to block myxopyronin biosynthesis at different stages. The resulting mutants were fed with diverse precursors that mimic the biosynthetic intermediates to restore production. Mutasynthon incorporation and production of novel myxopyronin derivatives were analyzed by HPLC-MS/MS. This work sets the stage for accessing numerous myxopyronin derivatives, thus significantly expanding the chemical space of f α-pyrone antibiotics. © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.
    ChemBioChem 03/2015; 16(6). DOI:10.1002/cbic.201402666 · 3.09 Impact Factor
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    ABSTRACT: CYP11B2 inhibition is a promising treatment for diseases caused by excessive aldosterone. To improve the metabolic stability in human liver miscrosomes of previously reported CYP11B2 inhibitors, scaffold hopping was performed via a combination of ligand- and structure-based drug design approaches leading to pyridyl 4,5-dihydro-[1,2,4]triazolo[4,3-a]quinolones. Compound 26 not only exhibited a much longer half-life (t1/2 > 120 min), but also sustained inhibitory potency (IC50 = 4.2 nM) and selectivity over CYP11B1 (SF = 422), CYP17, CYP19 and a panel of hepatic CYP enzymes.
    Journal of Medicinal Chemistry 02/2015; 58(5). DOI:10.1021/acs.jmedchem.5b00079 · 5.45 Impact Factor
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    ABSTRACT: 1-Phenylsulfinyl-3-(pyridin-3-yl)naphthalen-2-ols and related compounds were synthesized and evaluated for inhibition of aldosterone synthase (CYP11B2), a potential target for cardiovascular diseases associated with elevated plasma aldosterone levels like congestive heart failure and myocardial fibrosis. Introduction of substituents at the phenylsulfinyl moiety and changes of the substitution pattern at the naphthalene core were examined. Potent compounds were further examined for selectivity versus other important steroidogenic CYP enzymes, i.e. the highly homologous 11 beta-hydroxylase (CYP11B1), CYP17 and CYP19. The most potent compound (IC50 = 14 nM) discovered was the meta-trifluoromethoxy derivative 11, which also exhibited excellent selectivity toward CYP11B1 (SF = 415), and showed no inhibition of CYP17 and CYP19.
    European Journal of Medicinal Chemistry 01/2015; 89. DOI:10.1016/j.ejmech.2014.10.027 · 3.45 Impact Factor
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    ABSTRACT: Diseases triggered by an abnormally high level of cortisol (hypercortisolism), such as the Cushing's and metabolic syndromes, could be successfully tackled by inhibitors of CYP11B1, a steroidal cytochrome P450 enzyme that catalyzes the last hydroxylation step of the cortisol biosynthesis. Structural optimization of 7-(benzyloxy)-4-(1H-imidazol-1-ylmethyl)-2H-chromen-2-one 2, a selective aromatase inhibitor, afforded the 4-(1H-imidazol-1-ylmethyl)-7-{[3-(trifluoromethoxy)benzyl]oxy}-2H-chromen-2-one 7, with improved inhibitory potency at human CYP11B1 (IC50 = 5 nM) and an enhanced selectivity over human CYP11B2 (SIB = 25) compared to lead compound 2 (IC50 = 72 nM, SIB = 4.0) and metyrapone (IC50 = 15 nM, SIB = 4.8), a non-selective drug used in the therapy of the Cushing's syndrome. Structure-activity relationship studies allowed the design and optimization of a novel series of potent and selective compounds, that can be regarded as open analogues of 2H-chromen-2-one derivatives. Compound 23, 2-(1H-imidazol-1-yl)-1-(4-{[3(trifluoromethoxy)benzyl]oxy}phenyl) ethanone, was the most interesting inhibitor of the series displaying a high potency at CYP11B1 (IC50 = 15 nM), increased selectivities over CYP11B2 (SIB = 33), CYP19 (SIB = 390) and CYP17 (5% inhibition at 2.5 μM concentration). Copyright © 2014 Elsevier Masson SAS. All rights reserved.
    European Journal of Medicinal Chemistry 01/2015; 89:106–114. DOI:10.1016/j.ejmech.2014.10.021 · 3.45 Impact Factor
  • C.K. Maurer · C. Lu · M. Empting · R.W. Hartmann ·
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    ABSTRACT: Pseudomonas aeruginosa masters quorum sensing (QS) communication to coordinately regulate pathogenicity-associated group behaviors including the production of virulence factors and biofilm formation, which facilitate the invasion into the hosts, counteract host immune system, as well as promote the resistance/tolerance toward conventional antibiotics. Three main QS systems are employed by the pathogen, denoted as las (Gambello and Iglewski 1991; Passador et al. 1993), rhl (Ochsner et al. 1994; Ochsner and Reiser 1995), and pqs (Pesci et al. 1999). All the networks are hierarchically interconnected: Las controls the other two systems; pqs positively regulates the rhl signaling, whereas rhl in turn puts a negative feedback upon pqs (Wilder et al. 2011; McGrath et al. 2004). Regarding the central role of QS for the infectious process, the interruption of these pathways by blocking the receptors or inhibiting the signal synthesis via small molecules is an attractive therapeutic strategy to attenuate the bacterial pathogenicity, thereby overcoming intractable P. aeruginosa infections (Rasmussen and Givskov 2006).
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    ABSTRACT: Aldosterone synthase (CYP11B2) catalyzes the conversion of 11-deoxycorticosterone to aldosterone via corticosterone and 18-hydroxycorticosterone. CYP11B2 is regarded as a new target for several cardiovascular diseases which are associated with chronically elevated aldosterone levels such as hypertension, congestive heart failure and myocardial fibrosis. In this paper, we optimized heterocycle substituted 3,4-dihydropyridin-2(1H)-ones as CYP11B inhibitors by systematic introduction of heteroatoms and by bioisosteric exchange of the lactame moiety by a sultame moiety. The most promising compounds regarding inhibition of human CYP11B2 and selectivity versus human enzymes CYP11B1, CYP17, and CYP19 were tested for inhibition of rat CYP11B2. Thus, we discovered compounds 4 and 9 which show potent inhibition of hCYP11B2 (IC50 < 1 nM) and the corresponding rat enzyme (4: 64%, 9: 51% inhibition, at 2 μM). Copyright © 2014. Published by Elsevier Masson SAS.
    European Journal of Medicinal Chemistry 12/2014; 90C:788-796. DOI:10.1016/j.ejmech.2014.12.022 · 3.45 Impact Factor

Publication Stats

5k Citations
1,048.30 Total Impact Points


  • 2010-2015
    • Helmholtz Institute for Pharmaceutical Research Saarland
      • Department of Microbial Natural Products
      Saarbrücken, Saarland, Germany
    • University of Vienna
      Wien, Vienna, Austria
  • 1990-2015
    • Universität des Saarlandes
      • Pharmazeutische und Medizinische Chemie
      Saarbrücken, Saarland, Germany
    • Freie Universität Berlin
      • Institute of Pharmacy
      Berlín, Berlin, Germany
  • 1980-2010
    • Universität Regensburg
      • • Institute of Pharmacy
      • • Lehrstuhl für Pharmazeutische Chemie II
      Ratisbon, Bavaria, Germany
  • 2006-2007
    • University of Bologna
      • Department of Pharmacy and Biotechnology FaBiT
      Bolonia, Emilia-Romagna, Italy
  • 2005
    • Panjab University
      Chandigarh, Chandigarh, India
    • Università degli Studi di Bari Aldo Moro
      • Dipartimento di Farmacia - Scienze del Farmaco
      Bari, Apulia, Italy

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