ABSTRACT
Novel therapies are required to treat chronic bacterial infections in cystic fibrosis (CF) sufferers. The most common pathogen responsible for these infections is Pseudomonas aeruginosa, which persists within the lungs of CF sufferers despite intensive antibiotic treatment. P. aeruginosa elastase (also known as LasB or pseudolysin) is a key virulence determinant that contributes to the pathogenesis and persistence of P. aeruginosa infections in CF patients. The crucial role of LasB in pseudomonal virulence makes it a good target for the development of an adjuvant drug for CF treatment. Herein we discuss the discovery of a new series of LasB inhibitors by virtual screening and computer assisted drug design (CADD) and their optimization leading to compounds 29 and 39 (K i = 0.16 µM and 0.12 µM, respectively).
ABSTRACT
A novel selective benzoxazepin inhibitor of PI3Kδ has been discovered. Beginning from compound 3, an αPI3K inhibitor, we utilized structure-based drug design and computational analysis of dihedral torsion angles to optimize for PI3Kδ isoform potency and isoform selectivity. Further medicinal chemistry optimization of the series led to the identification of 24, a highly potent and selective inhibitor of PI3Kδ.
ABSTRACT
In this paper synthesis of macrolones 1-18 starting from azithromycin is reported. Two key steps in the construction of the linker between macrolide and quinolone moiety, are formation of central ether bond by alkylation of unactivated OH group, and formation of terminal C-C bond at 6-position of the quinolone unit. Due to the difficulty in formation of these two bonds the study of alternative synthetic methodologies and optimization of the conditions for the selected routes was required. Formation of C-4''-O-ether bond was completed by modified Michael addition, whereas O-alkylation via diazonium cation proved to be the most effective in formation of the central allylic or propargylic ether bond. Comparison of Heck and Sonogashira reaction revealed the former as preferred route to the C-C bond formation at C(6) position of the quinolone unit. Most of the target compounds exhibited highly favorable antibacterial activity against common respiratory pathogens, without significant cytotoxicity profile when tested in vitro on eukaryotic cell lines.
Subject(s)
Azithromycin/analogs & derivatives , Cross-Linking Reagents/chemistry , Ethers/chemistry , Macrolides/chemistry , Cross-Linking Reagents/chemical synthesis , Ethers/chemical synthesis , Humans , Macrolides/chemical synthesis , Models, Chemical , Molecular StructureABSTRACT
High throughput screening of Staphylococcus aureus phenylalanyl tRNA synthetase (FRS) identified ethanolamine 1 as a sub-micromolar hit. Optimisation studies led to the enantiospecific lead 64, a single-figure nanomolar inhibitor. The inhibitor series shows selectivity with respect to the mammalian enzyme and the potential for broad spectrum bacterial FRS inhibition.
Subject(s)
Anti-Bacterial Agents/chemical synthesis , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/pharmacology , Ethanolamines/chemical synthesis , Ethanolamines/pharmacology , Phenylalanine-tRNA Ligase/antagonists & inhibitors , Staphylococcus aureus/enzymology , Animals , Anti-Bacterial Agents/pharmacology , Drug Design , Kinetics , Mammals , Microbial Sensitivity Tests , Models, Molecular , Sensitivity and Specificity , Staphylococcus aureus/drug effects , Structure-Activity RelationshipABSTRACT
Potent inhibitors of bacterial methionyl tRNA synthetase (MRS) have previously been reported. Through SAR of the quinolone moiety, the right hand side pharmacophore for MRS inhibition has now been defined as an NH-C-NH functionality in the context of a bicyclic heteroaromatic system. Potent antibacterial fused-pyrimidone and fused-imidazole analogues have been obtained and enantioselective activity demonstrated. Compound 46 demonstrated very good antibacterial activity against panels of antibiotic-resistant staphylococci and enterococci.
Subject(s)
Anti-Bacterial Agents/chemical synthesis , Enzyme Inhibitors/chemical synthesis , Methionine-tRNA Ligase/antagonists & inhibitors , Anti-Bacterial Agents/pharmacology , Enterococcus faecalis/drug effects , Enzyme Inhibitors/pharmacology , Kinetics , Microbial Sensitivity Tests , Models, Molecular , Molecular Structure , Quinolones , Staphylococcus/drug effects , Structure-Activity RelationshipABSTRACT
Twenty two analogues of SB-203207 have been prepared by total synthesis, and evaluated as inhibitors of a range of tRNA synthetases. Changes to the bicyclic core, removing either the terminal amino substituent or the sulfonyl group from the side chain, and altering either the carbon skeleton or stereochemistry of the isoleucine residue, decreases the potency of inhibition of isoleucyl tRNA synthetase. Substituting the isoleucine residue with other amino acids produces inhibitors of the corresponding synthetases. In particular, a methionine derivative is 50-100 times more potent against methionyl tRNA synthetase than against any of the corresponding isoleucyl, leucyl, valyl, alanyl and prolyl synthetases.
Subject(s)
Indenes/chemical synthesis , Indenes/pharmacology , Isoleucine-tRNA Ligase/antagonists & inhibitors , Sulfonamides/chemical synthesis , Sulfonamides/pharmacology , Amino Acids/chemistry , Amino Acyl-tRNA Synthetases , Animals , Inhibitory Concentration 50 , Liver/enzymology , Rats , Staphylococcus aureus/enzymology , Stereoisomerism , Structure-Activity RelationshipABSTRACT
Optimisation of the left-hand-side aryl moiety of a file compound screening hit against Staphylococcus aureus methionyl tRNA synthetase led to the identification of a series of potent nanomolar inhibitors. The best compounds showed excellent antibacterial activity against staphylococcal and enterococcal pathogens, including strains resistant to clinical antibiotics.
Subject(s)
Anti-Infective Agents/chemical synthesis , Gram-Positive Bacteria/drug effects , Methionine-tRNA Ligase/antagonists & inhibitors , Drug Evaluation, Preclinical , Drug Resistance, Bacterial , Enterococcus/drug effects , Enterococcus/enzymology , Gram-Positive Bacteria/enzymology , Inhibitory Concentration 50 , Staphylococcus/drug effects , Staphylococcus/enzymology , Structure-Activity RelationshipABSTRACT
Potent nanomolar inhibitors of Staphylococcus aureus methionyl tRNA synthetase have been derived from a file compound high throughput screening hit. Optimized compounds show excellent antibacterial activity against staphylococcal and enterococcal pathogens, including strains resistant to clinical antibiotics. Compound 11 demonstrated in vivo efficacy in an S. aureus rat abscess infection model.