Synthesis and biological activity of substituted 2,4-diaminopyrimidines that inhibit Bacillus anthracis.
A series of substituted 2,4-diaminopyrimidines 1 has been prepared and evaluated for activity against Bacillus anthracis using previously reported (±)-3-{5-[(2,4-diamino-5-pyrimidinyl)methyl]-2,3-dimethoxyphenyl}-1-(1-propyl-2(1H)-phthalazinyl)-2-propen-1-one (1a), with a minimum inhibitory concentration (MIC) value of 1-3 μg/mL, as the standard. In the current work, the corresponding isobutenyl (1e) and phenyl (1h) derivatives displayed the most significant activity in terms of the lowest MICs with values of 0.5 μg/mL and 0.375-1.5 μg/mL, respectively. It is likely that the S isomers of 1 will bind the substrate-binding pocket of dihydrofolate reductase (DHFR) as in B. anthracis was found for (S)-1a. The final step in the convergent synthesis of target systems 1 from (±)-1-(1-substituted-2(1H)-phthalazinyl)-2-propen-1-ones 6 with 2,4-diamino-5-(5-iodo-3,4-dimethoxybenzyl)pyrimidine (13) was accomplished via a novel Heck coupling reaction under sealed-tube conditions.
Department of Chemistry, Oklahoma State University, 107 Physical Sciences, Stillwater, OK 74078, USA.
Baskar
B
Nammalwar
Richard A
RA
Bunce
K Darrell
KD
Berlin
Christina R
CR
Bourne
Philip C
PC
Bourne
Esther W
EW
Barrow
William W
WW
Barrow
D000900:Anti-Bacterial Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D001408:Bacillus anthracis / Q000187:drug effects* / Q000201:enzymology; D060326:Chemistry Techniques, Synthetic; D005493:Folic Acid Antagonists / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D008958:Models, Molecular; D011487:Protein Conformation; D011743:Pyrimidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D013237:Stereoisomerism; D013762:Tetrahydrofolate Dehydrogenase / Q000737:chemistry / Q000378:metabolism
D000900:Anti-Bacterial Agents; D005493:Folic Acid Antagonists; D011743:Pyrimidines; C017205:2,4-diaminopyrimidine; D013762:Tetrahydrofolate Dehydrogenase