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1.
J Bus Econ ; 93(8): 1277-1307, 2023.
Article in English | MEDLINE | ID: mdl-37746634

ABSTRACT

We examine distortions caused by tax base allocation systems-separate accounting (SA) or formula apportionment (FA)-with respect to the allocation of assets and workforce within multinational entities (MNEs). The effects of both systems are intensively debated by EU Member States as they are striving to implement a European tax system. Its introduction would lead to a switch from SA to FA. Moreover, Pillar One of the recent global tax reform includes a mix of both tax base allocation systems. We find that, against the claims of the EU, FA does not necessarily create lower distortions of the factor allocation. Decisive for that assessment is the level of profit shifting under SA. Our results indicate that, in tendency, the factor allocation is more severely distorted by FA when the profit shifting possibilities were rather low under SA. In contrast to former studies, we highlight the importance of analyzing the status quo under the recently applied system (SA) in order to be able to assess the consequences of a switch from SA to FA. Our results are interesting for policy-makers as they help anticipating reactions of MNEs to a change in the applied tax base allocation system and for companies as a basis for future tax planning. Supplementary Information: The online version contains supplementary material available at 10.1007/s11573-022-01133-5.

2.
Financ Res Lett ; 37: 101717, 2020 Nov.
Article in English | MEDLINE | ID: mdl-32837386

ABSTRACT

How do retail investors respond to the outbreak of COVID-19? We use transaction-level trading data to show that investors significantly increase their trading activities as the COVID-19 pandemic unfolds, both at the extensive and at the intensive margin. Investors, on average, increase their brokerage deposits and open more new accounts. The average weekly trading intensity increases by 13.9% as the number of COVID-19 cases doubles. The increase in trading is especially pronounced for male and older investors, and affects stock and index trading. Following the 9.99%-drop of the Dow Jones on March 12, investors significantly reduce the usage of leverage.

3.
Virulence ; 7(6): 718-28, 2016 08 17.
Article in English | MEDLINE | ID: mdl-27260413

ABSTRACT

FR-900098 is an inhibitor of 1-deoxy-d-xylulose-5-phosphate (DXP) reductoisomerase, the second enzyme in the non-mevalonate isoprenoid biosynthesis pathway. In previous studies, FR-900098 was shown to possess potent antimalarial activity in vitro and in a murine malaria model. In order to provide a basis for further preclinical and clinical development, we studied the acute toxicity and genotoxicity of FR-900098. We observed no acute toxicity in rats, i.e. there were no clinical signs of toxicity and no substance-related deaths after the administration of a single dose of 3000 mg/kg body weight orally or 400 mg/kg body weight intravenously. No mutagenic potential was detected in the Salmonella typhimurium reverse mutation assay (Ames test) or an in vitro mammalian cell gene mutation test using mouse lymphoma L5178Y/TK(+/-) cells (clone 3.7.2C), both with and without metabolic activation. In addition, FR-900098 demonstrated no clastogenic or aneugenic capability or significant adverse effects on blood formation in an in vivo micronucleus test with bone marrow erythrocytes from NMRI mice. We conclude that FR-900098 lacks acute toxicity and genotoxicity, supporting its further development as an antimalarial drug.


Subject(s)
Antimalarials/toxicity , DNA Damage , Fosfomycin/analogs & derivatives , Administration, Intravenous , Animals , Antimalarials/administration & dosage , Drug Discovery , Erythrocytes/drug effects , Fosfomycin/administration & dosage , Fosfomycin/toxicity , Male , Mice , Mutagenicity Tests , Rats , Salmonella typhimurium/drug effects , Salmonella typhimurium/genetics
4.
Int J Med Microbiol ; 302(4-5): 165-71, 2012 Oct.
Article in English | MEDLINE | ID: mdl-22898490

ABSTRACT

There are quite a number of antimalarial compounds in different states of preclinical and clinical development. Among those in advanced stages, combinations of known drugs or new substances from drug classes already used in antimalarial therapy are predominant. More compounds with novel or even unknown mechanism of action are found among those compounds which are in less advanced stages of development.


Subject(s)
Antimalarials/pharmacology , Malaria, Falciparum/drug therapy , Malaria, Falciparum/prevention & control , Aminoquinolines/chemistry , Aminoquinolines/pharmacology , Animals , Antimalarials/chemistry , Clinical Trials as Topic , Drug Combinations , Drug Evaluation, Preclinical , Drug Resistance , Humans , Inhibitory Concentration 50 , Malaria, Falciparum/parasitology , Plasmodium falciparum/pathogenicity
5.
Int J Antimicrob Agents ; 38(3): 261-4, 2011 Sep.
Article in English | MEDLINE | ID: mdl-21724375

ABSTRACT

The Burkholderia cepacia complex (BCC) is a group of 17 closely related opportunistic pathogens that are able to infect the respiratory tract of cystic fibrosis patients. BCC bacteria are intrinsically resistant to many antibiotics and are therefore difficult to eradicate. Fosmidomycin could be a new therapeutic agent to treat BCC infections as it inhibits 1-deoxy-d-xylulose-5-phosphate reductoisomerase (Dxr), a key enzyme in the non-mevalonate pathway essential in BCC bacteria for isoprenoid synthesis. In this study, the antimicrobial activity of fosmidomycin and eight fosmidomycin derivatives towards 40 BCC strains was investigated. All BCC strains were resistant to fosmidomycin, although addition of glucose-6-phosphate reduced the minimum inhibitory concentration values of FR900098, the fosmidomycin acetyl derivative, from 512 mg/L to 64 mg/L for Burkholderia multivorans and B. cepacia. This enhanced activity was linked to increased expression of the genes involved in glycerol-3-phosphate transport, which appears to be the only route for fosmidomycin import in BCC bacteria. Furthermore, upregulation of a fosmidomycin resistance gene (fsr) encoding an efflux pump was observed during fosmidomycin and FR900098 treatment. These results strongly suggest that the observed resistance in BCC bacteria is due to insufficient uptake accompanied by fosmidomycin and FR900098 efflux.


Subject(s)
Anti-Bacterial Agents/pharmacology , Burkholderia cepacia complex/drug effects , Drug Resistance, Bacterial , Fosfomycin/analogs & derivatives , Fosfomycin/pharmacology , Gene Expression/drug effects , Gene Expression Profiling , Humans , Membrane Transport Proteins/biosynthesis , Microbial Sensitivity Tests , Up-Regulation
6.
Eur J Med Chem ; 46(4): 1331-42, 2011 Apr.
Article in English | MEDLINE | ID: mdl-21345543

ABSTRACT

Previously we described a series of 5-acylaminobenzophenones with considerable antimalarial activity. Unfortunately, most compounds also displayed high cytotoxicity resulting in low selectivity towards malaria parasites. Through the replacement of the 5-acylamino moiety by simple chlorine and further modifications of the 2-acylamino residue we could obtain inhibitors with improved selectivity towards malaria parasites combined with an acceptable reduction of antimalarial activity.


Subject(s)
Antimalarials/chemistry , Antimalarials/pharmacology , Benzophenones/chemistry , Benzophenones/pharmacology , Malaria/parasitology , Plasmodium falciparum/drug effects , Animals , Antimalarials/chemical synthesis , Antimalarials/toxicity , Benzophenones/chemical synthesis , Benzophenones/toxicity , HeLa Cells , Humans , Inhibitory Concentration 50
9.
Bioorg Med Chem ; 17(22): 7690-7, 2009 Nov 15.
Article in English | MEDLINE | ID: mdl-19819706

ABSTRACT

Here, we describe a series of readily obtainable benzophenone derivatives with antimalarial and antitrypanosomal activity. The most active compounds display submicromolar activity against Plasmodium falciparum. Micromolar activity is obtained against Trypanosoma brucei. Main problem of the compounds is low selectivity. However, there are indications that separation of antimalarial and cytotoxic activity might by possible. In addition, some compounds inhibit human ABC transporter with nanomolar activity.


Subject(s)
Amides/chemistry , Amides/pharmacology , Antimalarials/chemical synthesis , Benzophenones/chemistry , Plasmodium falciparum/drug effects , Sulfonamides/pharmacology , Trypanosoma brucei brucei/drug effects , Amides/chemical synthesis , Antimalarials/chemistry , Antimalarials/pharmacology , Benzophenones/chemical synthesis , Benzophenones/pharmacology , Inhibitory Concentration 50 , Malaria/drug therapy , Malaria/parasitology , Parasitic Sensitivity Tests , Plasmodium falciparum/growth & development , Plasmodium falciparum/metabolism , Structure-Activity Relationship , Sulfonamides/chemical synthesis , Sulfonamides/chemistry , Trypanosoma brucei brucei/growth & development , Trypanosoma brucei brucei/metabolism
10.
ChemMedChem ; 4(5): 809-19, 2009 May.
Article in English | MEDLINE | ID: mdl-19301313

ABSTRACT

Diabetes mellitus is a universal health problem. The World Health Organization (WHO) estimates that 150 million people suffer from diabetes mellitus worldwide in 2005. Long-term complications are a serious problem in the treatment of diabetes, manifesting in macrovascular and microvascular complications. Sorbitol accumulation has been proposed to be an important factor in the development of microvascular complications such as nephropathy, neuropathy, retinopathy or cataract. Catalyzing the NADPH-dependent reduction of glucose to sorbitol, aldose reductase (ALR2) is an important target in the prevention of these complications. The development of novel aldose reductase inhibitors is expected to benefit strongly from a structure-based design approach. A virtual screening based on the ultrahigh-resolution crystal structure of the inhibitor IDD 594 in complex with human ALR2 identified two compounds with IC(50) values in the low micro- to submicromolar range. Based on the known interactions between the ligands and their binding pocket, we simplified the lead structures to give the minimal structural requirements and developed synthetic pathways from commercially available compounds. The newly synthesized compounds were assayed for their inhibition of ALR2, showing inhibitory activities down to the nanomolar range. Crystal structure analysis of the most potent derivative of our series revealed insights into the binding mode of the inhibitors.


Subject(s)
Aldehyde Reductase/antagonists & inhibitors , Enzyme Inhibitors/chemistry , Oxadiazoles/chemistry , Aldehyde Reductase/metabolism , Binding Sites , Computer Simulation , Crystallography, X-Ray , Drug Design , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/pharmacology , Humans , Oxadiazoles/pharmacology , Structure-Activity Relationship
11.
ChemMedChem ; 3(8): 1232-41, 2008 Aug.
Article in English | MEDLINE | ID: mdl-18470849

ABSTRACT

Fosmidomycin and its homologue FR900098 are inhibitors of 1-deoxy-D-xylulose-5-phosphate reductoisomerase, which is part of the mevalonate-independent isoprenoid biosynthetic pathway. Replacement of the phosphonate moiety by uncharged sulfone or sulfonamide partial structures resulted in complete loss of activity. Dropping one of the two negative charges resulted in a marked decrease in activity. Through occupation of a hydrophobic binding site, some activity could be regained, leading to compounds with micromolar activity against cultured malaria parasites.


Subject(s)
Aldose-Ketose Isomerases/chemistry , Aldose-Ketose Isomerases/metabolism , Fosfomycin/analogs & derivatives , Multienzyme Complexes/chemistry , Multienzyme Complexes/metabolism , Oxidoreductases/chemistry , Oxidoreductases/metabolism , Aldose-Ketose Isomerases/antagonists & inhibitors , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacology , Fosfomycin/chemical synthesis , Fosfomycin/chemistry , Fosfomycin/pharmacology , Models, Molecular , Molecular Structure , Multienzyme Complexes/antagonists & inhibitors , Oxidoreductases/antagonists & inhibitors , Structure-Activity Relationship
12.
ChemMedChem ; 3(8): 1217-31, 2008 Aug.
Article in English | MEDLINE | ID: mdl-18470859

ABSTRACT

The development of farnesyltransferase inhibitors directed against Plasmodium falciparum is a strategy towards new drugs against malaria. Previously, we described benzophenone-based farnesyltransferase inhibitors with high in vitro antimalarial activity but no in vivo activity. Through the introduction of a methylpiperazinyl moiety, farnesyltransferase inhibitors with in vivo antimalarial activity were obtained. Subsequently, a structure-based design approach was chosen to further improve the antimalarial activity of this type of inhibitor. As no crystal structure of the farnesyltransferase of the target organism is available, homology modeling was used to reveal differences between the active sites of the rat/human and the P. falciparum farnesyltransferase. Based on flexible docking data, the piperazinyl moiety was replaced by a N,N,N'-trimethylethylenediamine moiety. This resulted in an inhibitor with significantly improved in vitro and in vivo antimalarial activity. Furthermore, this inhibitor displayed a notable increase in selectivity towards malaria parasites relative to human cells.


Subject(s)
Antimalarials/chemical synthesis , Antimalarials/pharmacology , Benzophenones/chemical synthesis , Benzophenones/pharmacology , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/pharmacology , Farnesyltranstransferase/antagonists & inhibitors , Animals , Antimalarials/chemistry , Benzophenones/chemistry , Drug Evaluation, Preclinical , Enzyme Inhibitors/chemistry , Farnesyltranstransferase/chemistry , Farnesyltranstransferase/metabolism , HeLa Cells , Humans , Models, Molecular , Molecular Structure , Plasmodium falciparum/drug effects , Plasmodium falciparum/enzymology , Stereoisomerism , Structure-Activity Relationship
13.
Bioorg Med Chem ; 16(6): 3361-71, 2008 Mar 15.
Article in English | MEDLINE | ID: mdl-18158249

ABSTRACT

To expand the structure-activity relationships of fosmidomycin and FR900098, two potent antimalarials interfering with the MEP-pathway, we decided to replace a methylene group in beta-position of the phosphonate moiety of these leads by an oxygen atom. beta-oxa-FR900098 (11) proved equally active as the parent compound. When applied to 4-[hydroxyl(methyl)amino]-4-oxobutyl phosphonic acid, featuring a hydroxamate instead of the retrohydroxamate moiety, a beta-oxa modification yielded a derivative (13) with superior activity against the Plasmodium falciparum 3D7 strain than fosmidomycin, while a gamma-oxa modification resulted in less active derivatives. A bis(pivaloyloxymethyl)ester of phosphonate 13 proved twice as active in inhibiting cultured parasites as a similar prodrug of FR900098.


Subject(s)
Antimalarials/chemistry , Fosfomycin/analogs & derivatives , Animals , Antimalarials/chemical synthesis , Antimalarials/pharmacology , Fosfomycin/chemical synthesis , Fosfomycin/chemistry , Fosfomycin/pharmacology , Parasitic Sensitivity Tests , Plasmodium falciparum/drug effects , Structure-Activity Relationship
14.
Arch Pharm (Weinheim) ; 340(12): 667-9, 2007 Dec.
Article in English | MEDLINE | ID: mdl-17994601

ABSTRACT

Fosmidomycin and FR900098 are inhibitors of the 1-deoxy-D-xylulose 5-phosphate reductoisomerase (DXR; IspC), a key enzyme of the mevalonate-independent isoprenoid biosynthesis pathway. We have determined the in-vitro antimalarial activity of two double ester prodrugs 2, 3 in direct comparison with the unmodified FR900098 1 against intraerythrocytic forms of Plasmodium falciparum. Temporarily masking the polar properties of the phosphonate moiety of the DXR inhibitor FR900098 1 enhanced not only its oral bioavailability but also the intrinsic activity of this series against the parasites.


Subject(s)
Antimalarials/pharmacology , Fosfomycin/analogs & derivatives , Prodrugs/pharmacology , Aldose-Ketose Isomerases/antagonists & inhibitors , Animals , Antimalarials/chemical synthesis , Antimalarials/pharmacokinetics , Biological Availability , Drug Resistance , Esters , Fosfomycin/chemical synthesis , Fosfomycin/pharmacokinetics , Fosfomycin/pharmacology , Mice , Multienzyme Complexes/antagonists & inhibitors , Oxidoreductases/antagonists & inhibitors , Parasitic Sensitivity Tests , Plasmodium falciparum/drug effects , Prodrugs/chemical synthesis , Prodrugs/pharmacokinetics , Structure-Activity Relationship
15.
Arch Pharm (Weinheim) ; 340(9): 483-90, 2007 Sep.
Article in English | MEDLINE | ID: mdl-17806130

ABSTRACT

1-deoxy-D-xylulose-5-phosphate reductoisomerase (Dxr) represents an essential enzyme of the mevalonate-independent pathway of the isoprenoid biosynthesis. Using fosmidomycin as a specific inhibitor of Dxr, this enzyme was previously validated as target for the treatment of malaria and bacterial infections. The replacement of the formyl residue of fosmidomycin by spacious acyl residues yielded inhibitors active in the micromolar range. As predicted by flexible docking, evidence was obtained for the formation of a hydrogen bond between an appropriately placed carbonyl group in the acyl residue and the main-chain NH of Met214 located in the flexible catalytic loop of the enzyme.


Subject(s)
Aldose-Ketose Isomerases/antagonists & inhibitors , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/pharmacology , Fosfomycin/analogs & derivatives , Multienzyme Complexes/antagonists & inhibitors , Oxidoreductases/antagonists & inhibitors , Enzyme Inhibitors/chemistry , Structure-Activity Relationship
16.
J Med Chem ; 48(23): 7186-91, 2005 Nov 17.
Article in English | MEDLINE | ID: mdl-16279776

ABSTRACT

Less toxic drugs are needed to combat the human parasite Trypanosoma cruzi (Chagas's disease). One novel target for antitrypanosomal drug design is farnesyltransferase. Several farnesyltransferase inhibitors based on the benzophenone scaffold were assayed in vitro and in vivo with the parasite. The common structural feature of all inhibitors is an amino function which can be protonated. Best in vitro activity (LC50 values 1 and 10 nM, respectively) was recorded for the R-phenylalanine derivative 4a and for the N-propylpiperazinyl derivative 2f. These inhibitors showed no cytotoxicity to cells. When tested in vivo, the survival rates of infected animals receiving the inhibitors at 7 mg/kg body weight/day were 80 and 60% at day 115 postinfection, respectively.


Subject(s)
Benzophenones/chemical synthesis , Farnesyltranstransferase/antagonists & inhibitors , Trypanocidal Agents/chemical synthesis , Trypanosoma cruzi/drug effects , Animals , Benzophenones/chemistry , Benzophenones/pharmacology , Chagas Disease/mortality , Chagas Disease/parasitology , Farnesyltranstransferase/chemistry , Male , Mice , Mice, Inbred BALB C , Models, Molecular , Protein Subunits/chemistry , Sequence Homology, Amino Acid , Structure-Activity Relationship , Trypanocidal Agents/chemistry , Trypanocidal Agents/pharmacology , Trypanosoma cruzi/enzymology
17.
Arch Pharm (Weinheim) ; 338(7): 305-14, 2005 Jul.
Article in English | MEDLINE | ID: mdl-15996004

ABSTRACT

FR900098 represents a derivative of the new antimalarial drug fosmidomycin with enhanced activity. The mechanism of action is the inhibition of the 1-desoxy-D-xylulose 5-phosphate (DOXP) reductoisomerase, an essential enzyme of the mevalonate independent pathway of isoprenoid biosynthesis. Prodrugs with increased oral activity in mice infected with the rodent malaria parasite Plasmodium vinckei were obtained by masking the phosphonate moiety of FR900098 as alkoxycarbonyloxyethyl esters.


Subject(s)
Antimalarials/therapeutic use , Fosfomycin/analogs & derivatives , Malaria/prevention & control , Prodrugs/therapeutic use , Administration, Oral , Aldose-Ketose Isomerases/antagonists & inhibitors , Aldose-Ketose Isomerases/metabolism , Animals , Antimalarials/chemical synthesis , Antimalarials/pharmacokinetics , Biological Availability , Dose-Response Relationship, Drug , Fosfomycin/blood , Fosfomycin/chemical synthesis , Fosfomycin/pharmacokinetics , Fosfomycin/therapeutic use , Malaria/parasitology , Mice , Mice, Inbred BALB C , Multienzyme Complexes/antagonists & inhibitors , Multienzyme Complexes/metabolism , Oxidoreductases/antagonists & inhibitors , Oxidoreductases/metabolism , Plasmodium/drug effects , Prodrugs/chemical synthesis , Prodrugs/pharmacokinetics , Quantitative Structure-Activity Relationship
18.
Eur J Med Chem ; 40(1): 93-101, 2005 Jan.
Article in English | MEDLINE | ID: mdl-15642414

ABSTRACT

Water solubility was previously found to be essential for in vivo-antimalarial activity of a novel type of benzophenone-based farnesyltransferase inhibitors. Introduction of a alpha-amino group into the phenylacetic acid substructure provided more soluble compounds with high farnesyltransferase inhibitory activity. The in vitro-antimalarial activity was detrimentally influenced by this structural modification.


Subject(s)
Acrylamides/chemical synthesis , Alkyl and Aryl Transferases/antagonists & inhibitors , Antimalarials/chemical synthesis , Enzyme Inhibitors/chemical synthesis , Acrylamides/pharmacology , Animals , Antimalarials/pharmacology , Cell Survival/drug effects , Enzyme Inhibitors/pharmacology , Farnesyltranstransferase , HeLa Cells , Humans , Inhibitory Concentration 50 , Models, Molecular , Plasmodium falciparum/drug effects , Plasmodium falciparum/growth & development , Solubility , Structure-Activity Relationship
20.
Angew Chem Int Ed Engl ; 42(43): 5274-93, 2003 Nov 10.
Article in English | MEDLINE | ID: mdl-14613157

ABSTRACT

Approximately 40% of the world population live in areas with the risk of malaria. Each year, 300-500 million people suffer from acute malaria, and 0.5-2.5 million die from the disease. Although malaria has been widely eradicated in many parts of the world, the global number of cases continues to rise. The most important reason for this alarming situation is the rapid spread of malaria parasites that are resistant to antimalarial drugs, especially chloroquine, which is by far the most frequently used. The development of new antimalarial drugs has been neglected since the 1970s owing to the end colonialism, changes in the areas of military engagement, and the restricted market potential. Only in recent years, in part supported by public funding programs, has interest in the development of antimalarial drugs been renewed. New data available from the recently sequenced genome of the malaria parasite Plasmodium falciparum and the application of methods of modern drug design promise to bring significant development in the fight against this disease.


Subject(s)
Antimalarials/pharmacology , Antimalarials/therapeutic use , Fosfomycin/analogs & derivatives , Proguanil/analogs & derivatives , Aminoquinolines/pharmacology , Aminoquinolines/therapeutic use , Animals , Artemisinins/pharmacology , Artemisinins/therapeutic use , Artesunate , Atovaquone , Clinical Trials as Topic , Dapsone/pharmacology , Dapsone/therapeutic use , Drug Combinations , Drug Design , Drug Resistance/genetics , Ethanolamines/pharmacology , Ethanolamines/urine , Flavonoids/pharmacology , Flavonoids/therapeutic use , Fluorenes/pharmacology , Fluorenes/urine , Fosfomycin/pharmacology , Fosfomycin/therapeutic use , Global Health , Humans , Lumefantrine , Malaria/drug therapy , Malaria/epidemiology , Malaria/prevention & control , Naphthoquinones/pharmacology , Naphthoquinones/therapeutic use , Naphthyridines/pharmacology , Naphthyridines/therapeutic use , Plasmodium falciparum/drug effects , Plasmodium falciparum/genetics , Plasmodium falciparum/physiology , Proguanil/pharmacology , Proguanil/therapeutic use , Sesquiterpenes/pharmacology , Sesquiterpenes/therapeutic use
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