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Antimicrobial Agents and Chemotherapy, September 2009, p. 3620-3627, Vol. 53, No. 9
0066-4804/09/$08.00+0     doi:10.1128/AAC.00377-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

In Vitro and In Vivo Properties of Dihydrophthalazine Antifolates, a Novel Family of Antibacterial Drugs{triangledown}

Patrick Caspers,* Luc Bury, Bérangère Gaucher, Jutta Heim, Stuart Shapiro, Sibylle Siegrist, Anne Schmitt-Hoffmann, Laure Thenoz, and Heinrich Urwyler

Basilea Pharmaceutica International AG, CH-4005 Basel, Switzerland

Received 19 March 2009/ Returned for modification 15 April 2009/ Accepted 16 June 2009

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.

* Corresponding author. Mailing address: Basilea Pharmaceutica International AG, Postfach, CH-4005 Basel, Switzerland. Phone: (41 61) 606-1320. Fax: (41 61) 606-1112. E-mail: patrick.caspers{at}basilea.com

{triangledown} Published ahead of print on 22 June 2009.

Antimicrobial Agents and Chemotherapy, September 2009, p. 3620-3627, Vol. 53, No. 9
0066-4804/09/$08.00+0     doi:10.1128/AAC.00377-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.





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