- Structure aided design of chimeric antibiotics
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The rise of antibiotic resistance is of great clinical concern. One approach to reducing the development of resistance is to co-administer two or more antibiotics with different modes of action. However, it can be difficult to control the distribution and
- Karoli, Tomislav,Mamidyala, Sreeman K.,Zuegg, Johannes,Fry, Scott R.,Tee, Ernest H.L.,Bradford, Tanya A.,Madala, Praveen K.,Huang, Johnny X.,Ramu, Soumya,Butler, Mark S.,Cooper, Matthew A.
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supporting information; experimental part
p. 2428 - 2433
(2012/05/19)
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- Probing riboswitch-ligand interactions using thiamine pyrophosphate analogues
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The Escherichia coli thiM riboswitch forms specific contacts with its natural ligand, thiamine pyrophosphate (TPP or thiamine diphosphate), allowing it to generate not only nanomolar binding affinity, but also a high degree of discrimination against similar small molecules. A range of synthetic TPP analogues have been used to probe each of the riboswitch-ligand interactions. The results show that the pyrimidine-sensing helix of thiM is exquisitely tuned to select for TPP by recognising the H-bonding donor and acceptors around its aminopyrimidine ring and also by forming π-stacking interactions that may be sensitive to the electronics of the ring. The central thiazolium ring of TPP appears to be more important for ligand recognition than previously thought. It may contribute to binding via long-range electrostatic interactions and/or by exerting an electron withdrawing effect on the pyrimidine ring, allowing its presence to be sensed indirectly and thereby allowing discrimination between thiamine (and its phosphate esters) and other aminopyrimidines found in vivo. The pyrophosphate moiety is essential for submicromolar binding affinity, but unexpectedly, it does not appear to be strictly necessary for modulation of gene expression.
- Chen, Liuhong,Cressina, Elena,Dixon, Neil,Erixon, Karl,Agyei-Owusu, Kwasi,Micklefield, Jason,Smith, Alison G.,Abell, Chris,Leeper, Finian J.
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supporting information; experimental part
p. 5924 - 5931
(2012/08/28)
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- Design, synthesis, biological evaluation and computational investigation of novel inhibitors of dihydrofolate reductase of opportunistic pathogens
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The present work deals with design, synthesis and biological evaluation of novel, diverse compounds as potential inhibitors of dihydrofolate reductase (DHFR) from opportunistic microorganisms; Pneumocystis carinii (pc), Toxoplasma gondii (tg) and Mycobacterium avium (ma). A set of 14 structurally diverse compounds were designed with varying key pharmacophoric features of DHFR inhibitors, bulky distal substitutions and different bridges joining the distal part and 2,4-diaminopyrimidine nucleus. The designed compounds were synthesized and evaluated in enzyme assay against pc, tg and ma DHFR. The rat liver (rl) DHFR was used as mammalian standard. As the next logical step of the project, flexible molecular docking studies were carried out to predict the binding modes of these compounds in pcDHFR active site and the obtained docked poses were post processed using MM-GBSA protocol for prediction of relative binding affinity. The predicted binding modes were able to rationalize the experimental results in most cases. Of particular interest, both the docking scores and MM-GBSA predicted ΔGbind were able to distinguish between the active and low active compounds. Furthermore, good correlation coefficient of 0.797 was obtained between the IC50 values and MM-GBSA predicted ΔGbind. Taken together, the current work provides not only a novel scaffold for further optimization of DHFR inhibitors but also an understanding of the specific interactions of inhibitors with DHFR and structural modifications that improve selectivity.
- Bag, Seema,Tawari, Nilesh R.,Degani, Mariam S.,Queener, Sherry F.
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experimental part
p. 3187 - 3197
(2010/07/08)
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- Folate-Synthesizing Enzyme System as Target for Development of Inhibitors and Inhibitor Combinations against Candida albicans - Synthesis and Biological Activity of New 2,4-Diaminopyrimidines and 4′-Substituted 4-Aminodiphenyl Sulfones
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The paper describes the design, synthesis, and testing of inhibitors of folate-synthesizing enzymes and of whole cell cultures of Candida albicans. The target enzymes used were dihydropteroic acid synthase (SYN) and dihydrofolate reductase (DHFR). Several series of new 2,4-diaminopyrimidines were synthesized and tested as inhibitors of DHFR and compared with their activity against DHFR derived from mycobacteria and Escherichia coli. To test for selectivity, also rat DHFR was used. A series of substituted 4-aminodiphenyl sulfones was tested for inhibitory activity against SYN and the I50 values compared to those obtained previously against Plasmodium berghei- and E. coll-derived SYN. Surprisingly, QSAR equations show very similar structural dependencies. To find an explanation for the large difference in the I50 values observed for enzyme inhibition (SYN, DHFR) and for inhibition of cell cultures of Candida, mutant strains with overexpressed efflux pumps and strains in which such pumps are deleted were included in the study and the MICs compared. Efflux pumps were responsible for the low activity of some of the tested derivatives, others showed no increase in activity after pumps were knocked out. In this case it may be speculated that these derivatives are not able to enter the cells.
- Otzen, Thomas,Wempe, Ellen G.,Kunz, Brigitte,Bartels, Rainer,Lehwark-Yvetot, Gudrun,H?nsel, Wolfram,Schaper, Klaus-Jürgen,Seydel, Joachim K.
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p. 240 - 253
(2007/10/03)
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- Process for substituted 5-benzyl-2,4-diamino-pyrimidines
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A process for preparing a compound of the formula STR1 wherein R1 and R2 are lower alkoxy or taken together are METHYLENEDIOXY; R3 is lower alkyl or hydrogen, which comprises the step of reacting an aromatic compound of the formula STR2 wherein R1, R2 and R3 are as previously described, with a diamino-pyrimidine of the formula STR3 wherein R4 is lower alkoxy, benzyloxy, hydroxy or halogen, in the presence of an inorganic or organic acid selected from the group consisting of ortho-phosphoric acid, poly-phosphoric acid, hydrohalic acids and tri-haloacetic acids, at a temperature in the range of from about 50° C. to about 110° C., is described.
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