Three-component regioselective synthesis and antibacterial evaluation of new arene-linked bis(pyrazolo[1,5-a]pyrimidine) hybrids

Abstract

In the current study, a three-component protocol was adopted to efficiently synthesize butane-linked bis(pyrazolo[1,5-a]pyrimidines) 1 attached to arene units in 74–81% yields. The one-pot reaction involved reacting bis(aldehyde) with the respective 1H-pyrazole-3,5-diamines and acetophenones in ethanol at 80 °C in the presence of potassium hydroxide for 6 h. Using a similar protocol, another series of regioisomeric bis(pyrazolo[1,5-a]pyrimidines) 2 was prepared, in 77–87% yields, utilizing the appropriate synthons bis(acetyl) and benzaldehydes. The new products showed a wide spectrum of antibacterial activity against six different ATCC strains. In general, products attached to 3-(4-methoxybenzyl) units exceeded their analogues attached to 3-(4-chlorobenzyl) units in antibacterial activity. Moreover, hybrids which are linked to arene units with para-electron releasing substituents demonstrated improved antibacterial activity. The hybrid 2h, 3-(4-methoxybenzyl) and 7-(4-methoxyphenyl) units, had the best antibacterial activity against all strains tested. It demonstrated more effective activity than ciprofloxacin with MIC/MBC values up to 2.0/4.0 µM.

Graphical Abstract

Keywords:

• 3(5)-Aminopyrazoles
• in vitro antibacterial activity
• Pyrazolo[1,5-a]pyrimidine
• regioselective reaction
• tandem protocol