Affiliation:
1. Basilea Pharmaceutica International AG, CH-4005 Basel, Switzerland
Abstract
ABSTRACT
Racemic 2,4-diaminopyrimidine dihydrophthalazine derivatives BAL0030543, BAL0030544, and BAL0030545 exhibited low in vitro MICs toward small, selected panels of
Enterococcus faecalis
,
Enterococcus faecium
,
Streptococcus pneumoniae
,
Moraxella catarrhalis
, and
Mycobacterium avium
, though the compounds were less active against
Haemophilus influenzae
. The constellation of dihydrofolate reductases (DHFRs) present in 20 enterococci and 40 staphylococci was analyzed and correlated with the antibacterial activities of the dihydrophthalazines and trimethoprim. DHFRs encoded by
dfrB
,
dfrA
(S1 isozyme),
dfrE
, and
folA
were susceptible to the dihydrophthalazines, whereas DHFRs encoded by
dfrG
(S3 isozyme) and
dfrF
were not. Studies with the separated enantiomers of BAL0030543, BAL0030544, and BAL0030545 revealed preferential inhibition of susceptible DHFRs by the (
R
)-enantiomers. BAL0030543, BAL0030544, and BAL0030545 were well tolerated by mice during 5- and 10-day oral toxicity studies at doses of up to 400 mg/kg of body weight. Using a nonoptimized formulation, the dihydrophthalazines displayed acceptable oral bioavailabilities in mice, and efficacy studies with a septicemia model of mice infected with trimethoprim-resistant, methicillin-resistant
Staphylococcus aureus
gave 50% effective dose values in the range of 1.6 to 6.25 mg/kg.
Publisher
American Society for Microbiology
Subject
Infectious Diseases,Pharmacology (medical),Pharmacology
Cited by
14 articles.
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