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 concentr...

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Bibliographic Details
Published in:	European journal of medicinal chemistry 2012-08, Vol.54, p.387-396
Main Authors:	Nammalwar, Baskar, Bunce, Richard A., Berlin, K. Darrell, Bourne, Christina R., Bourne, Philip C., Barrow, Esther W., Barrow, William W.
Format:	Article
Language:	eng
Subjects:	2,4-Diaminopyrimidine Anti-Bacterial Agents - chemical synthesis Anti-Bacterial Agents - chemistry Anti-Bacterial Agents - pharmacology Antibiotic Bacillus anthracis - drug effects Bacillus anthracis - enzymology Biological and medical sciences Chemistry Techniques, Synthetic DHFR inhibitor Folic Acid Antagonists - chemical synthesis Folic Acid Antagonists - chemistry Folic Acid Antagonists - pharmacology Heck coupling Medical sciences Miscellaneous Models, Molecular Pharmacology. Drug treatments Protein Conformation Pyrimidines - chemical synthesis Pyrimidines - chemistry Pyrimidines - pharmacology Sealed-tube reaction Stereoisomerism Tetrahydrofolate Dehydrogenase - chemistry Tetrahydrofolate Dehydrogenase - metabolism
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Summary:	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. A series of substituted 2,4-diaminopyrimidines exhibited MIC values in the range of 0.5–16 μg/mL with respect to inhibition of Bacillus anthracis. The lead compound, where R was –CHC(CH3)2, had a MIC value of ≤0.5 μg/mL. [Display omitted] ► An improved synthesis of 2,4-diaminopyrimidine-based antibiotics is reported. ► Antibiotic synthesis includes a novel sealed-tube Heck reaction. ► The agents synthesized show activity in the μg/mL range. ► The size and planarity of the phthalazine C-1 substituent influences the activity. ► Steric and electronic factors affect the binding of the agents to DHFR.
ISSN:	0223-5234 1768-3254