New antibacterial agents derived from the DNA gyrase inhibitor cyclothialidine.
Cyclothialidine (1, Ro 09-1437) is a potent DNA gyrase inhibitor that was isolated from Streptomyces filipinensis NR0484 and is a member of a new family of natural products. It acts by competitively inhibiting the ATPase activity exerted by the B subunit of DNA gyrase but barely exhibits any growth inhibitory activity against intact bacterial cells, presumably due to insufficient permeation of the cytoplasmic membrane. To explore the antibacterial potential of 1, we developed a flexible synthetic route allowing for the systematic modification of its structure. From a first set of analogues, structure-activity relationships (SAR) were established for different substitution patterns, and the 14-hydroxylated, bicyclic core (X) of 1 seemed to be the structural prerequisite for DNA gyrase inhibitory activity. The variation of the lactone ring size, however, revealed that activity can be found among 11- to 16-membered lactones, and even seco-analogues were shown to maintain some enzyme inhibitory properties, thereby reducing the minimal structural requirements to a rather simple, hydroxylated benzyl sulfide (XI). On the basis of these "minimal structures" a modification program afforded a number of inhibitors that showed in vitro activity against Gram-positive bacteria. The best activities were displayed by 14-membered lactones, and representatives of this subclass exhibit excellent and broad in vitro antibacterial activity against Gram-positive pathogens, including Staphylococcus aureus, Streptococcus pyogenes, and Enterococcus faecalis, and overcome resistance against clinically used drugs. By improving the pharmacokinetic properties of the most active compounds (94, 97), in particular by lowering their lipophilic properties, we were able to identify congeners of cyclothialidine (1) that showed efficacy in vivo.
F. Hoffmann-La Roche Ltd., Pharmaceutical Division, Preclinical Research, CH-4070 Basel, Switzerland.
Peter
P
Angehrn
Stefan
S
Buchmann
Christoph
C
Funk
Erwin
E
Goetschi
Hans
H
Gmuender
Paul
P
Hebeisen
Dirk
D
Kostrewa
Helmut
H
Link
Thomas
T
Luebbers
Raffaello
R
Masciadri
Joergen
J
Nielsen
Peter
P
Reindl
Fabienne
F
Ricklin
Anne
A
Schmitt-Hoffmann
Frank-Peter
FP
Theil
D000818:Animals; D000900:Anti-Bacterial Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D027081:DNA Gyrase / Q000737:chemistry; D024901:Drug Resistance, Multiple, Bacterial; D006094:Gram-Positive Bacteria / Q000187:drug effects; D006367:HeLa Cells; D006801:Humans; D007769:Lactams / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D007783:Lactones / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D051379:Mice; D008826:Microbial Sensitivity Tests; D008958:Models, Molecular; D010069:Oxadiazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D010456:Peptides, Cyclic / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D021122:Protein Subunits / Q000037:antagonists & inhibitors; D013203:Staphylococcal Infections / Q000188:drug therapy; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D059005:Topoisomerase II Inhibitors; D018675:Toxicity Tests
C483898:1,3,4,5,6,7,8,10-octahydro-14-hydroxy-12-methoxy-11-methyl-4-(3-methyl-1,2,4-oxadiazol-5-yl)-6-thioxo-9,2,5-benzoxanthiaazacyclododecine-10-one; C483899:1,3,4,5,6,7,8,9,10,12-decahydro-16-hydroxy-14-methoxy-13-methyl-4-(3-methyl-1,2,4-oxadiazol-5-yl)-6-thioxo-11,2,5-benzoxathiaazacyclotetradecine-12-one; D000900:Anti-Bacterial Agents; D007769:Lactams; D007783:Lactones; D010069:Oxadiazoles; D010456:Peptides, Cyclic; D021122:Protein Subunits; D059005:Topoisomerase II Inhibitors; C085889:cyclothialidine; D027081:DNA Gyrase