ABSTRACT
A systematic approach for improving the water-solubility of anti-MRSA (methicillin-resistant Staphylococcus aureus) cephalosporin derivatives is described. We first tried to improve the water-solubility of 7beta-[2-(5-amino-1,2,4-thiadiazol-3-yl)-2(Z)-fluoromethoxyiminoacetamido]-3-[(E)-2-(1-methylimidazo[1,2-b]pyridazinium-6-yl)thiovinyl]-3-cephem-4-carboxylate (1a) by substitution of the C-3' pharmacophore. Replacement of the C-3' pharmacophore with a 1-methyl-4-pyridinio group improved the water-solubility without decreasing the anti-MRSA activity. Furthermore, we applied the N-modified prodrug strategy to the C-7 acyl group in order to enhance the water-solubility drastically. Among the compounds prepared, the N-phosphono type prodrugs 2a(1-methylimidazo[1,2-b]pyridazinium derivative) and 2b (1-methyl-4-pyridinio derivative) showed water-solubility appropriate for a product intended for intravenous injection and in vivo anti-MRSA activity comparable to that of vancomycin.
Subject(s)
Bacterial Proteins , Carrier Proteins , Cephalosporins/pharmacology , Methicillin Resistance/physiology , Muramoylpentapeptide Carboxypeptidase , Prodrugs/pharmacology , Staphylococcus aureus/drug effects , Animals , Cephalosporins/administration & dosage , Cephalosporins/pharmacokinetics , Gram-Negative Bacteria/drug effects , Gram-Positive Bacteria/drug effects , Hexosyltransferases/metabolism , Hydrogen-Ion Concentration , Injections , Male , Mice , Mice, Inbred ICR , Microbial Sensitivity Tests , Multienzyme Complexes/metabolism , Penicillin-Binding Proteins , Peptidyl Transferases/metabolism , Prodrugs/administration & dosage , Prodrugs/pharmacokinetics , Protein Binding , Solubility , Spectrophotometry, InfraredABSTRACT
The internal motion of yeast phenylalanine transfer RNA is studied by normal mode analysis in extended dihedral angle space in which the flexibility of five-membered ribose rings is treated faithfully by introducing a variable for its pseudo-rotational motion. Analysis of global molecular motion reveals that the molecule is very soft. We show that this softness comes not from the property of the "material" comprising the molecule but from its slender shape. Analysis of thermal distance fluctuations reveals that this molecule can be regarded as consisting dynamically of three blocks. Thermal fluctuations of the mainchain dihedral angles show rigidity of the anticodon region. They also show flexibility of regions around non-stacking bases. Base-stacking interactions cause suppression of the correlated functions of mainchain dihedral angles beyond a ribose ring. We analyze the thermal fluctuation of parameters describing the positions of two adjacent bases. Fluctuations of relative translational parameters in the anticodon and acceptor stem regions are found to be larger that those in other stem regions. The relative translational motions cause the two stem regions to undergo global twisting and bending motions. We show that the role of pseudo-rotational motion of sugars is important in regions around bases which are involved in nonregular interactions.
Subject(s)
Nucleic Acid Conformation , RNA, Transfer, Phe/chemistry , Algorithms , Anticodon/chemistry , Base Composition , Base Sequence , Models, Molecular , Molecular Sequence Data , Ribose/chemistry , Saccharomyces cerevisiae/chemistry , ThermodynamicsABSTRACT
In expectation of improving the antibacterial activity of sulfazecin by chemical modification at the 3- and 4-positions, a number of 3-[2-(2-aminothiazol-4-yl)-(Z)-2-(substituted oxyimino)-acetamido]-4-(substituted methyl)-2-azetidinone-1-sulfonic acids were synthesized. Among various 4-substituents explored, the carbamoyloxymethyl group was found to provide a good effect to the antibacterial activity of these 2-azetidinone derivatives. An extensive study of structure-activity relationships led to selecting (3S,4S)-3-[2-(2-aminothiazol-4-yl)-(Z)-2-carboxymethoxyiminoace tamido]-4- carbamoyloxymethyl-2-azetidinone-1-sulfonic acid, AMA-1080 (Ro 17-2301), which has highly potent antibacterial activity against Gram-negative bacteria including Pseudomonas aeruginosa, for further biological and subsequent clinical evaluation.
