15 results on '"Wiese, M"'
Search Results
2. Synthesis of new 2,4-diamino-5-benzylpyrimidines active against various bacterial species
- Author
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Kansyl, M, primary, Seydel, JK, additional, Wiese, M, additional, and Haller, R, additional
- Published
- 1992
- Full Text
- View/download PDF
3. Partial resistance of E. coli mutants against 2,4-diamino-5-benzylpyrimidines by interactions with bacterial membrane lippolysaccharides. Derivation of quantitative structure-binding relationships
- Author
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Schop, H., Wiese, M., Cordes, H.-P., and Seydel, J. K.
- Published
- 2000
- Full Text
- View/download PDF
4. Rational drug design of 6-substituted 4-anilino-2-phenylpyrimidines for exploration of novel ABCG2 binding site.
- Author
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Silbermann K, Li J, Namasivayam V, Stefan SM, and Wiese M
- Subjects
- ATP Binding Cassette Transporter, Subfamily G, Member 2 metabolism, Animals, Binding Sites drug effects, Cell Survival drug effects, Cells, Cultured, Dogs, Dose-Response Relationship, Drug, Humans, Molecular Structure, Neoplasm Proteins metabolism, Pyrimidines chemical synthesis, Pyrimidines chemistry, Structure-Activity Relationship, ATP Binding Cassette Transporter, Subfamily G, Member 2 antagonists & inhibitors, Drug Design, Neoplasm Proteins antagonists & inhibitors, Pyrimidines pharmacology
- Abstract
In the search for novel, highly potent, and nontoxic adjuvant chemotherapeutics to resolve the major issue of ABC transporter-mediated multidrug resistance (MDR), pyrimidines were discovered as a promising compound class of modern ABCG2 inhibitors. As ABCG2-mediated MDR is a major obstacle in leukemia, pancreatic carcinoma, and breast cancer chemotherapy, adjuvant chemotherapeutics are highly desired for future clinical oncology. Very recently, docking studies of one of the most potent reversers of ABCG2-mediated MDR were reported and revealed a putative second binding pocket of ABCG2. Based on this (sub)pocket, a series of 16 differently 6-substituted 4-anilino-2-phenylpyrimidines was designed and synthesized to explore the potential increase in inhibitory activity of these ABCG2 inhibitors. The compounds were assessed for their influence on the ABCG2-mediated pheophorbide A transport, as well as the ABCB1- and ABCC1-mediated transport of calcein AM. They were additionally evaluated in MDR reversal assays to determine their half-maximal reversal concentration (EC
50 ). The 6-substitution did not only show increased toxicity against ABCG2-overexpressing cells in combination with SN-38 but also a negative influence on cell viability in general. Nevertheless, several candidates had EC50 values in the low double-digit nanomolar concentration range, qualifying them as some of the most potent reversers of ABCG2-mediated MDR. In addition, five novel multitarget ABCB1, ABCC1, and ABCG2 inhibitors were discovered, four of them exerting their inhibitory power against the three stated transporters at least in the single-digit micromolar concentration range., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier Masson SAS. All rights reserved.)- Published
- 2021
- Full Text
- View/download PDF
5. Novel chalcone and flavone derivatives as selective and dual inhibitors of the transport proteins ABCB1 and ABCG2.
- Author
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Silbermann K, Shah CP, Sahu NU, Juvale K, Stefan SM, Kharkar PS, and Wiese M
- Subjects
- ATP Binding Cassette Transporter, Subfamily B antagonists & inhibitors, ATP-Binding Cassette Transporters antagonists & inhibitors, Antineoplastic Agents chemistry, Antineoplastic Agents pharmacology, Chalcones therapeutic use, Drug Resistance, Multiple drug effects, Flavones therapeutic use, Humans, Structure-Activity Relationship, ATP Binding Cassette Transporter, Subfamily G, Member 2 antagonists & inhibitors, Antineoplastic Agents chemical synthesis, Chalcones pharmacology, Flavones pharmacology
- Abstract
During cancer chemotherapy, certain cancers may become cross-resistant to structurally diverse antineoplastic agents. This so-called multidrug resistance (MDR) is highly associated with the overexpression of ATP-binding cassette (ABC) transport proteins. These membrane-bound efflux pumps export a broad range of structurally diverse endo- and xenobiotics, including chemically unrelated anticancer agents. This translocation of drugs from the inside to the outside of cancer cells is mediated at the expense of ATP. In the last 40 years, three ABC transporters - ABCB1 (P-gp), ABCC1 (MRP1), and ABCG2 (BCRP) - have mainly been attributed to the occurrence of MDR in cancer cells. One of the strategies to overcome MDR is to inhibit the efflux transporter function by small-molecule inhibitors. In this work, we investigated new chalcone- and flavone-based compounds for selective as well as broad-spectrum inhibition of the stated transport proteins. These include substituted chalcones with variations at rings A and B, and flavones with acetamido linker at position 3. The synthesized molecules were evaluated for their inhibitory potential against ABCB1, ABCC1, and ABCG2 in calcein AM and pheophorbide A assays. In further investigations with the most promising candidates from each class, we proved that ABCB1- and ABCG2-mediated MDR could be reversed by the compounds. Moreover, their intrinsic toxicity was found to be negligible in most cases. Altogether, our findings contribute to the understanding of ABC transport proteins and reveal new compounds for ongoing evaluation in the field of ABC transporter-mediated MDR., (Copyright © 2018 Elsevier Masson SAS. All rights reserved.)
- Published
- 2019
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- View/download PDF
6. Synthesis and biological evaluation of quinazoline derivatives - A SAR study of novel inhibitors of ABCG2.
- Author
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Krapf MK, Gallus J, Spindler A, and Wiese M
- Subjects
- ATP Binding Cassette Transporter, Subfamily G, Member 2 metabolism, Animals, Cell Survival drug effects, Cells, Cultured, Dogs, Dose-Response Relationship, Drug, Drug Resistance, Multiple drug effects, Humans, Molecular Structure, Neoplasm Proteins metabolism, Quinazolines chemical synthesis, Quinazolines chemistry, Structure-Activity Relationship, ATP Binding Cassette Transporter, Subfamily G, Member 2 antagonists & inhibitors, Neoplasm Proteins antagonists & inhibitors, Quinazolines pharmacology
- Abstract
Multidrug resistance (MDR) is a major obstacle for effective chemotherapeutic treatment of cancer frequently leading to failure of the therapy. MDR is often associated with the overexpression of ABC transport proteins like ABCB1 or ABCG2 which efflux harmful substances out of cells at the cost of ATP hydrolysis. One way to overcome MDR is to apply potent inhibitors of ABC transporters to restore the sensitivity of the cells toward cytostatic agents. This study focusses on the synthesis and evaluation of novel 2,4-disubstituted quinazoline derivatives regarding the structure-activity-relationship (SAR), their ability to reverse MDR and their mode of interaction with ABCG2. Hence, the inhibitory potency and selectivity toward ABCG2 was determined. Moreover, the intrinsic cytotoxicity and the reversal of MDR were investigated. Interaction type studies with the substrate Hoechst 33342 and conformational analyses of ABCG2 with 5D3 monoclonal antibody were performed for a better understanding of the underlying mechanisms. In our study we could further enhance the inhibitory effect against ABCG2 (compound 31, IC
50 : 55 nM) and identify the structural features that are crucial for inhibitory potency, the impact on transport activity and binding to the protein., (Copyright © 2018 Elsevier Masson SAS. All rights reserved.)- Published
- 2019
- Full Text
- View/download PDF
7. Structure activity relationships, multidrug resistance reversal and selectivity of heteroarylphenyl ABCG2 inhibitors.
- Author
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Köhler SC, Vahdati S, Scholz MS, and Wiese M
- Subjects
- Animals, Cell Survival drug effects, Cells, Cultured, Dogs, Dose-Response Relationship, Drug, Humans, Hydrocarbons, Aromatic chemical synthesis, Hydrocarbons, Aromatic chemistry, Molecular Structure, Structure-Activity Relationship, ATP Binding Cassette Transporter, Subfamily G, Member 2 antagonists & inhibitors, Drug Resistance, Multiple drug effects, Drug Resistance, Neoplasm drug effects, Hydrocarbons, Aromatic pharmacology, Neoplasm Proteins antagonists & inhibitors
- Abstract
An overexpression of the transmembrane ATP-binding cassette transporter G2 (ABCG2, BCRP) in cancer tissues is supposed to play a role in the multidrug resistance (MDR) of tumors resulting in an inefficient chemotherapy. Therefore, co-administration of selective and non-toxic ABCG2 inhibitors is a promising strategy for improving the efficacy of chemotherapy by blocking ABCG2-mediated export of the cytostatic drugs. In the present study, we designed a small library of 38 novel compounds containing a heteroaryl-phenyl scaffold possessing several (bioisosteric) moieties, and twelve new precursors. We investigated the library for ABCG2 inhibition, for the selectivity against MDR-involved efflux pump ABCB1 (P-gp) and for toxicity. Structure activity relationship (SAR) studies revealed that, at least a phenylheteroaryl-phenylamide scaffold is necessary for observing an ABCG2 inhibition. 4-Methoxy-N-(2-(2-(6-methoxypyridin-3-yl)-2H-tetrazol-5-yl)phenyl)benzamide (43) exhibited a high potency (IC
50 = 61 nM)), selectivity, low intrinsic toxicity and reversed the ABCG2-mediated drug resistance in presence of only 0.1 μM., (Copyright © 2018 Elsevier Masson SAS. All rights reserved.)- Published
- 2018
- Full Text
- View/download PDF
8. Synthesis and biological investigation of 2,4-substituted quinazolines as highly potent inhibitors of breast cancer resistance protein (ABCG2).
- Author
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Krapf MK, Gallus J, and Wiese M
- Subjects
- ATP Binding Cassette Transporter, Subfamily G, Member 2 metabolism, Animals, Cell Survival drug effects, Cells, Cultured, Dogs, Dose-Response Relationship, Drug, Humans, Molecular Structure, Neoplasm Proteins metabolism, Quinazolines chemical synthesis, Quinazolines chemistry, Structure-Activity Relationship, ATP Binding Cassette Transporter, Subfamily G, Member 2 antagonists & inhibitors, Neoplasm Proteins antagonists & inhibitors, Quinazolines pharmacology
- Abstract
Expression of ABCG2, a member of the ABC transporter superfamily, has been correlated to the clinical outcome of multiple cancers and is often associated with the occurrence of multidrug resistance (MDR) in chemotherapy. Inhibition of the transport protein by potent and selective inhibitors might be a way to treat cancer more efficiently and improve the therapy of cancer patients. Recently we reported the synthesis of new inhibitors based on a quinazoline scaffold. In the present study more structural variations were explored. Compounds with 3,4-dimethoxy groups and meta or para nitro substituents were found to be highly potent inhibitors of ABCG2. The most potent compound was more than five-fold more potent than Ko143, one of the best inhibitors of ABCG2. To determine the new compounds selectivity toward ABCG2 their inhibitory effects on ABCB1 and ABCC1 were also investigated identifying selective as well as broadspectrum inhibitors. Furthermore, intrinsic cytotoxicity and efficacy regarding the reversal of multidrug resistance toward SN-38 and mitoxantrone were explored. The most potent compounds were able to reverse the resistance toward the cytostatic agents with EC
50 values below 20 nM. Additionally, the type of interaction between inhibitors and the ABCG2 substrate Hoechst 33342 was investigated yielding competitive and non-competitive interactions suggesting different modes of binding. Finally the effect of the derivatives on vanadate-sensitive ATPase activity of ABCG2 was determined. According to the different effects on ATPase activity we conclude the existence of different binding sites. This study provides the structural requirements for high potency inhibition and elucidates the interaction with ABCG2 setting the basis for further studies., (Copyright © 2017 Elsevier Masson SAS. All rights reserved.)- Published
- 2017
- Full Text
- View/download PDF
9. Phenyltetrazolyl-phenylamides: Substituent impact on modulation capability and selectivity toward the efflux protein ABCG2 and investigation of interaction with the transporter.
- Author
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Köhler SC, Silbermann K, and Wiese M
- Subjects
- Amides metabolism, Animals, Dogs, Madin Darby Canine Kidney Cells, Protein Binding, Substrate Specificity, ATP Binding Cassette Transporter, Subfamily G, Member 2 metabolism, Amides chemistry, Amides pharmacology, Tetrazoles chemistry
- Abstract
We recently presented a novel class of ABCG2 modulators based on the third-generation ABCB1 inhibitor tariquidar bearing a 2,5-linked tetrazole instead of an amid linker. We investigated the modulating potential of the compound class by enlarging the substitution pattern on the outer phenyl rings of the scaffold. To identify the structural conditions for achieving a high response, we decided to determine the individual influence of substituents on the scaffold using monosubstituted derivatives. While electron withdrawing groups (with a few exceptions) and bulky moieties decreased the modulating potency, small electron donating groups ensured a high activity level. Interestingly, the unsubstituted derivative 32 reached a similar inhibitory potential as the best derivatives in the previous study. Enzyme kinetic assays indicated that our derivatives have the same binding site as reference inhibitor Ko143. They were found to interact competitively and non-competitively with the substrates Hoechst 33342 and pheophorbide A, respectively., (Copyright © 2016 Elsevier Masson SAS. All rights reserved.)
- Published
- 2016
- Full Text
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10. Design, synthesis and biological evaluation of thiosemicarbazones, hydrazinobenzothiazoles and arylhydrazones as anticancer agents with a potential to overcome multidrug resistance.
- Author
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Pape VF, Tóth S, Füredi A, Szebényi K, Lovrics A, Szabó P, Wiese M, and Szakács G
- Subjects
- Antineoplastic Agents chemistry, Antineoplastic Agents pharmacology, Benzothiazoles chemistry, Cell Line, Tumor, Drug Resistance, Multiple drug effects, Drug Resistance, Neoplasm drug effects, Humans, Hydrazones chemistry, Structure-Activity Relationship, Thiosemicarbazones chemistry, Benzothiazoles pharmacology, Hydrazones pharmacology, Thiosemicarbazones pharmacology
- Abstract
There is a constant need for new therapies against multidrug resistant (MDR) cancer. An attractive strategy is to develop chelators that display significant antitumor activity in multidrug resistant cancer cell lines overexpressing the drug efflux pump P-glycoprotein. In this study we used a panel of sensitive and MDR cancer cell lines to evaluate the toxicity of picolinylidene and salicylidene thiosemicarbazone, arylhydrazone, as well as picolinylidene and salicylidene hydrazino-benzothiazole derivatives. Our results confirm the collateral sensitivity of MDR cells to isatin-β-thiosemicarbazones, and identify several chelator scaffolds with a potential to overcome multidrug resistance. Analysis of structure-activity-relationships within the investigated compound library indicates that NNS and NNN donor chelators show superior toxicity as compared to ONS derivatives regardless of the resistance status of the cells., (Copyright © 2016 Elsevier Masson SAS. All rights reserved.)
- Published
- 2016
- Full Text
- View/download PDF
11. The combination of quinazoline and chalcone moieties leads to novel potent heterodimeric modulators of breast cancer resistance protein (BCRP/ABCG2).
- Author
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Kraege S, Stefan K, Juvale K, Ross T, Willmes T, and Wiese M
- Subjects
- Chalcones chemistry, Cytotoxins chemistry, Cytotoxins pharmacology, Female, Humans, Quinazolines chemistry, Structure-Activity Relationship, Tumor Cells, Cultured, ATP Binding Cassette Transporter, Subfamily G, Member 2 antagonists & inhibitors, Breast Neoplasms chemistry, Chalcones pharmacology, Neoplasm Proteins antagonists & inhibitors, Quinazolines pharmacology
- Abstract
During the last decade it has been found that chalcones and quinazolines are promising inhibitors of ABCG2. The combination of these two scaffolds offers a new class of heterocyclic compounds with potentially high inhibitory activity against ABCG2. For this purpose we investigated 22 different heterodimeric derivatives. In this series only methoxy groups were used as substituents as these had been proven superior for inhibitory activity of chalcones. All compounds were tested for their inhibitory activity, specificity and cytotoxicity. The most potent ABCG2 inhibitor in this series showed an IC50 value of 0.19 μM. It possesses low cytotoxicity (GI50 = 93 μM), the ability to reverse MDR and is nearly selective toward ABCG2. Most compounds containing dimethoxy groups showed slight activity against ABCB1 too. Among these three compounds (17, 19 and 24) showed even higher activity toward ABCB1 than ABCG2. All inhibitors were further screened for their effect on basal ATPase activity. Although the basal ATPase activity was partially stimulated, the compounds were not transported by ABCG2. Thus, quinazoline-chalcones are a new class of effective ABCG2 inhibitors., (Copyright © 2016 Elsevier Masson SAS. All rights reserved.)
- Published
- 2016
- Full Text
- View/download PDF
12. Synthesis and biological evaluation of flavones and benzoflavones as inhibitors of BCRP/ABCG2.
- Author
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Juvale K, Stefan K, and Wiese M
- Subjects
- ATP Binding Cassette Transporter, Subfamily G, Member 2, ATP-Binding Cassette Transporters metabolism, Animals, Benzoflavones chemical synthesis, Benzoflavones chemistry, Cells, Cultured, Dogs, Dose-Response Relationship, Drug, Flavones chemical synthesis, Flavones chemistry, Humans, Molecular Structure, Neoplasm Proteins metabolism, Structure-Activity Relationship, ATP-Binding Cassette Transporters antagonists & inhibitors, Benzoflavones pharmacology, Flavones pharmacology, Neoplasm Proteins antagonists & inhibitors
- Abstract
Multidrug resistance (MDR) often leads to a failure of cancer chemotherapy. Breast Cancer Resistance Protein (BCRP/ABCG2), a member of the superfamily of ATP binding cassette proteins has been found to confer MDR in cancer cells by transporting molecules with amphiphilic character out of the cells using energy from ATP hydrolysis. Inhibiting BCRP can be a solution to overcome MDR. We synthesized a series of flavones, 7,8-benzoflavones and 5,6-benzoflavones with varying substituents at positions 3, 3' and 4' of the (benzo)flavone structure. All synthesized compounds were tested for BCRP inhibition in Hoechst 33342 and pheophorbide A accumulation assays using MDCK cells expressing BCRP. All the compounds were further screened for their P-glycoprotein (P-gp) and Multidrug resistance-associated protein 1 (MRP1) inhibitory activity by calcein AM accumulation assay to check the selectivity towards BCRP. In addition most active compounds were investigated for their cytotoxicity. It was observed that in most cases 7,8-benzoflavones are more potent in comparison to the 5,6-benzoflavones. In general it was found that presence of a 3-OCH3 substituent leads to increase in activity in comparison to presence of OH or no substitution at position 3. Also, it was found that presence of 3',4'-OCH3 on phenyl ring lead to increase in activity as compared to other substituents. Compound 24, a 7,8-benzoflavone derivative was found to be most potent being 50 times selective for BCRP and showing very low cytotoxicity at higher concentrations., (Copyright © 2013 Elsevier Masson SAS. All rights reserved.)
- Published
- 2013
- Full Text
- View/download PDF
13. 3D-QSAR with the aid of pharmacophore search and docking-based alignments for farnesyltransferase inhibitors.
- Author
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Vaidya M, Weigt M, and Wiese M
- Subjects
- Computer Simulation, Farnesyltranstransferase chemistry, Models, Chemical, Models, Molecular, Molecular Structure, Protein Binding, Quantitative Structure-Activity Relationship, Enzyme Inhibitors chemistry, Enzyme Inhibitors pharmacology, Farnesyltranstransferase antagonists & inhibitors, Farnesyltranstransferase metabolism
- Abstract
Farnesyltransferase is a potential drug target for treating various types of cancers. Three-dimensional quantitative structure-activity relationships (3D-QSAR) for a series of farnesyltransferase inhibitors were investigated using comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) techniques. Pharmacophore search and molecular docking methods were used for construction of the molecular alignments. While the 3D-QSAR models were created for a training set of 33 compounds, their external predictivity was proven using a test set of 12 compounds. The results provided a comprehensive insight into the relationship between the structural features and the activities of farnesyltransferase inhibitors. This investigation will facilitate optimization of the design of new potential farnesyltransferase inhibitors.
- Published
- 2009
- Full Text
- View/download PDF
14. Computational aqueous solubility prediction for drug-like compounds in congeneric series.
- Author
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Du-Cuny L, Huwyler J, Wiese M, and Kansy M
- Subjects
- Benzodiazepines chemistry, Crystallography, X-Ray, Databases, Factual, Least-Squares Analysis, Principal Component Analysis, Solubility, Sulfonamides chemistry, Computer Simulation, Models, Chemical, Organic Chemicals chemistry, Pharmaceutical Preparations chemistry, Water chemistry
- Abstract
It was the aim of the present work to develop a quantitative structure-property relationship (QSPR) model for predicting the aqueous solubility of drug-like compounds in congeneric series. Lipophilicity combined with structural fragment information, fragmental based correction factors and congeneric series indices were used as descriptors for a principal component analysis (PCA) followed by multivariate partial least squares regression statistics (PLS). The derived PLS regression model for the prediction of solubility parameters was based on an in-house data set of 2473 drug-like compounds. The generated PLS model had a coefficient of determination (R(2))=0.844 and a root-mean-square (rms) error of 0.51 log units. It predicted the solubility of the test data set with a high degree of accuracy (R(2)=0.81). In addition, the PLS model was successful in predicting the solubility of new congeneric test sets when solubility values of corresponding scaffolds were accessible.
- Published
- 2008
- Full Text
- View/download PDF
15. Partial resistance of E. coli mutants against 2, 4-diamino-5-benzylpyrimidines by interactions with bacterial membrane lipopolysaccharides. Derivation of quantitative structure-binding relationships.
- Author
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Schop H, Wiese M, Cordes HP, and Seydel JK
- Subjects
- Cell Division drug effects, Cell Division genetics, Cell Wall drug effects, Cell Wall metabolism, Drug Resistance, Microbial genetics, Folic Acid Antagonists metabolism, Inhibitory Concentration 50, Magnetic Resonance Spectroscopy, Mutation, Photometry methods, Pyrimidines chemistry, Pyrimidines metabolism, Pyrimidines pharmacology, Structure-Activity Relationship, Sulfones chemistry, Sulfones metabolism, Sulfones pharmacology, Tetrahydrofolate Dehydrogenase drug effects, Ultracentrifugation methods, Escherichia coli drug effects, Escherichia coli genetics, Folic Acid Antagonists chemistry, Folic Acid Antagonists pharmacology, Lipopolysaccharides metabolism
- Abstract
A series of previously synthesized 2,4-diamino-5-benzylpyrimidines, inhibitors of bacterial dihydrofolate reductase (DHFR) showed decreased inhibition of E. coli cultures, despite increased inhibitory activity against DHFR. Preliminary studies using E. coli mutants with different degrees of outer membrane deficiencies suggested that the decrease in activity was partly due to inactivation because of binding to outer membrane constituents. In the present study antibacterial activities of the benzylpyrimidines have been systematically determined as a function of cell membrane defects in E. coli using bacterial growth kinetic techniques. It has been shown that the observed differences in activity were not due to different binding affinities to the target enzyme of the mutants. Lipopolysaccharides have been extracted from the mutants and used in binding studies by ultrafiltration, photometric and NMR techniques. The observed differences in binding affinity to the lipopolysaccharides have been related to the differences in the lipophilic properties and molecular weight of the substituents. Quantitative structure-activity relationships have been derived. The results of the study show the importance of drug-membrane interactions for the rational development of antibacterials.
- Published
- 2000
- Full Text
- View/download PDF
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