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 (la), with a minimum inhibitory concentration (MIC) value of 1-3 mu g/mL, as the standard. In the current work, the corresponding iso-butenyl (le) and phenyl (1h) derivatives displayed the most significant activity in terms of the lowest MICs with values of 0.5 mu g/mL and 0.375-1.5 mu g/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)la. 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. (C) 2012 Elsevier Masson SAS. All rights reserved.