Novel C-2 substituted carbapenem derivatives. Part II. Synthesis and structure-activity relationships of isoxazolin-2-yl, isoxazolidin-2-yl and 2-pyrazolin-2-yl carbapenems generated using 1,3-dipolar cycloaddition chemistry.
A series of carbapenems containing novel C-2 semisaturated heterocyclic substituents were synthesised by 1,3 dipolar cycloaddition reactions of nitrile oxides, nitrile imines and a nitrone to 2-vinylcarbapenem. The isoxazoline and isoxazolidine compounds showed potent antibacterial activity but moderate stability to human dehydropeptidase 1 (DHP-1). Stability to DHP-1 was improved by methyl substitution in the isoxazoline ring, but at the expense of antibacterial activity. The pyrazolines exhibited excellent stability to DHP-1, but reduced potency against Gram-negative organisms.
Burton
G
G
SmithKline Beecham Pharmaceuticals, Brockham Park, Betchworth, Surrey, U.K.
Clarke
G J
GJ
Douglas
J D
JD
Eglington
A J
AJ
Frydrych
C H
CH
Hinks
J D
JD
Hird
N W
NW
Hunt
E
E
Moss
S F
SF
Naylor
A
A
Nicholson
N H
NH
Pearson
M J
MJ
D015780:Carbapenems / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D004150:Dipeptidases / Q000378:metabolism; D006090:Gram-Negative Bacteria / Q000187:drug effects*; D006094:Gram-Positive Bacteria / Q000187:drug effects*; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D008826:Microbial Sensitivity Tests; D015394:Molecular Structure; D013329:Structure-Activity Relationship
D015780:Carbapenems; D004150:Dipeptidases; C038937:dipeptidase