Synthesis of new bis(pyrazolo[1,5-a]pyrimidines) linked to different spacers with potential MurB inhibitory activity utilizing 1H-pyrazole-3,5-diamines

Abstract

Recently, there has been an increased interest in developing new antibacterial agents that target the MurB inhibition, which is necessary for bacterial survival. We developed a two-step tandem protocol to synthesize 15 new bis(pyrazolo[1,5-a]pyrimidines), which are attached to alkane cores by amide linkages. The protocol involved reacting the appropriate bis(2-cyanoacetamides) with dimethylformamide-dimethylacetal in toluene at 80 °C for 3-4 h. The crude bis(2-cyano-3-(dimethylamino)acrylamides) was collected, then reacted with 3,5-diamino-1H-pyrazoles. The reaction gave the desired products in 82-92% yields after 5-6 h of heating at reflux in pyridine. Bis(2,7-diamino-3-(4-methoxybenzyl)pyrazolo[1,5-a]pyrimidine-6-carboxamides) demonstrated comparable efficacy to ciprofloxacin. Their MIC and MBC ranged from 2.8-3.0 and 5.7-6.0 µM, respectively, against S. aureus and E. coli. Moreover, these products displayed promising MurB inhibitory activity with IC₅₀ ranging from 7.8 to 8.0 µM.