Synthesis, hydrolysis rates, supercomputer modeling, and antibacterial activity of bicyclic tetrahydropyridazinones.
Bicyclic tetrahydropyridazinones, such as 13, where X are strongly electron-withdrawing groups, were synthesized to investigate their antibacterial activity. These delta-lactams are homologues of bicyclic pyrazolidinones 15, which were the first non-beta-lactam containing compounds reported to bind to penicillin-binding proteins (PBPs). The delta-lactam compounds exhibit poor antibacterial activity despite having reactivity comparable to the gamma-lactams. Molecular modeling based on semiempirical molecular orbital calculations on a Cray X-MP supercomputer, predicted that the reason for the inactivity is steric bulk hindering high affinity of the compounds to PBPs, as well as high conformational flexibility of the tetrahydropyridazinone ring hampering effective alignment of the molecule in the active site. Subsequent PBP binding experiments confirmed that this class of compound does not bind to PBPs.
Jungheim
L N
LN
Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiania 46285.
Boyd
D B
DB
Indelicato
J M
JM
Pasini
C E
CE
Preston
D A
DA
Alborn
W E
WE
D000900:Anti-Bacterial Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D001643:Bridged Bicyclo Compounds / Q000138:chemical synthesis* / Q000494:pharmacology; D055598:Chemical Phenomena; D002621:Chemistry; D003198:Computer Simulation; D006090:Gram-Negative Bacteria / Q000187:drug effects; D006094:Gram-Positive Bacteria / Q000187:drug effects; D006868:Hydrolysis; D007769:Lactams; D008826:Microbial Sensitivity Tests; D008958:Models, Molecular; D011720:Pyrazoles / Q000494:pharmacology; D011724:Pyridazines / Q000138:chemical synthesis* / Q000494:pharmacology; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013844:Thiazoles / Q000494:pharmacology
D000900:Anti-Bacterial Agents; D001643:Bridged Bicyclo Compounds; D007769:Lactams; D011720:Pyrazoles; D011724:Pyridazines; D013844:Thiazoles; C063297:LY 186826