Journal
BIOORGANIC & MEDICINAL CHEMISTRY
Volume 23, Issue 1, Pages 203-211Publisher
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bmc.2014.11.009
Keywords
Bacillus anthracis inhibition; Dihydrofolate reductase; Antibiotics; Antifolates; Antimicrobial agents
Funding
- National Institutes of Allergy and Infectious Diseases of the NIH/NIAID [R01-AI090685]
- Sitlington Chair in Infectious Diseases [BIR-9512269]
- Oklahoma State Regents for Higher Education
- W.M. Keck Foundation
- Conoco, Inc
- OSU College of Arts and Sciences
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The current Letter describes the synthesis and biological evaluation of dihydrophthalazine-appended 2,4-diaminopyrimidine (DAP) inhibitors (1) oxidized at the methylene bridge linking the DAP ring to the central aromatic ring and (2) modified at the central ring ether groups. Structures 4a-b incorporating an oxidized methylene bridge showed a decrease in activity, while slightly larger alkyl groups (CH2CH3 vs CH3) on the central ring oxygen atoms (R-2 and R-3) had a minimal impact on the inhibition. Comparison of the potency data for previously reported RAB1 and BN-53 with the most potent of the new derivatives (19b and 20a-b) showed similar values for inhibition of cellular growth and direct enzymatic inhibition (MICs 0.5-2 mu g/mL). Compounds 29-34 with larger ester and ether groups containing substituted aromatic rings at R-3 exhibited slightly reduced activity (MICs 2-16 mu g/mL). One explanation for this attenuated activity could be encroachment of the extended R-3 into the neighboring NADPH co-factor. These results indicate that modest additions to the central ring oxygen atoms are well tolerated, while larger modifications have the potential to act as dual-site inhibitors of dihydrofolate reductase (DHFR). (C) 2014 Elsevier Ltd. All rights reserved.
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