title: Modified 2,4-diaminopyrimidine-based dihydrofolate reductase inhibitors as potential drug scaffolds against Bacillus anthracis.
abstract: 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 (19 b and 20a-b) showed similar values for inhibition of cellular growth and direct enzymatic inhibition (MICs 0.5-2 μg/mL). Compounds 29-34 with larger ester and ether groups containing substituted aromatic rings at R(3) exhibited slightly reduced activity (MICs 2-16 μg/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).
authors.affiliation: Department of Chemistry, Oklahoma State University, 107 Physical Sciences, Stillwater, OK 74078, USA.
authors.forename: Baskar
authors.initials: B
authors.lastname: Nammalwar
authors.affiliation: Department of Veterinary Pathobiology, Oklahoma State University, 250 McElroy Hall, Stillwater, OK 74078, USA.
authors.forename: Christina R
authors.initials: CR
authors.lastname: Bourne
authors.affiliation: Department of Veterinary Pathobiology, Oklahoma State University, 250 McElroy Hall, Stillwater, OK 74078, USA.
authors.forename: Nancy
authors.initials: N
authors.lastname: Wakeham
authors.affiliation: Department of Veterinary Pathobiology, Oklahoma State University, 250 McElroy Hall, Stillwater, OK 74078, USA.
authors.forename: Philip C
authors.initials: PC
authors.lastname: Bourne
authors.affiliation: Department of Veterinary Pathobiology, Oklahoma State University, 250 McElroy Hall, Stillwater, OK 74078, USA.
authors.forename: Esther W
authors.initials: EW
authors.lastname: Barrow
authors.affiliation: Department of Chemistry, Oklahoma State University, 107 Physical Sciences, Stillwater, OK 74078, USA.
authors.forename: N Prasad
authors.initials: NP
authors.lastname: Muddala
authors.affiliation: Department of Chemistry, Oklahoma State University, 107 Physical Sciences, Stillwater, OK 74078, USA. Electronic address: rab@okstate.edu.
authors.forename: Richard A
authors.initials: RA
authors.lastname: Bunce
authors.affiliation: Department of Chemistry, Oklahoma State University, 107 Physical Sciences, Stillwater, OK 74078, USA.
authors.forename: K Darrell
authors.initials: KD
authors.lastname: Berlin
authors.affiliation: Department of Veterinary Pathobiology, Oklahoma State University, 250 McElroy Hall, Stillwater, OK 74078, USA.
authors.forename: William W
authors.initials: WW
authors.lastname: Barrow
mesh_terms: D000900:Anti-Bacterial Agents / Q000737:chemistry* / Q000494:pharmacology; D001408:Bacillus anthracis / Q000201:enzymology*; D005493:Folic Acid Antagonists / Q000737:chemistry* / Q000494:pharmacology; D008958:Models, Molecular; D011485:Protein Binding; D011743:Pyrimidines / Q000737:chemistry* / Q000494:pharmacology; D013329:Structure-Activity Relationship
chemical_list: D000900:Anti-Bacterial Agents; D005493:Folic Acid Antagonists; D011743:Pyrimidines; C017205:2,4-diaminopyrimidine
keywords: Antibiotics; Antifolates; Antimicrobial agents; Bacillus anthracis inhibition; Dihydrofolate reductase