Synthesis and biological evaluation of pyrazolopyrimidines as potential antibacterial agents

Abstract The fragment FOL7185 ( compound17 ) was found to be a hit against IspD and IspE enzymes isolated from bacteria, and a series of analogs containing the pyrazolopyrimidinecore were synthesized. The majority of these compoundsinhibited the growth of Burkholderia thailandensis( Bt ) and Pseudomonas aeruginosa ( Pa ) in the Kirby–Bauer disk diffusion susceptibility test. Compound29 shows inhibitory activity at 0.1 mM (32.2 μg/mL), which is comparable to the control compound kanamycin(48.5 μg/mL). Compound29 also shows inhibitory activity at 0.5 mM against kanamycinresistant P. aeruginosa . Saturation transfer difference NMR (STD-NMR) screening of these compoundsagainst Bt IspD and Bt IspE indicated that most of these compoundssignificantly interact with Bt IspE, suggesting that the compoundsmay inhibit the growth of Bt by disrupting isoprenoid biosynthesis. Ligand epitope mappingof compound29 with Bt IspE indicated that hydrogens on 2,4-dichlorophenyl group have higher proximity to the surface of the enzyme than hydrogens on the pyrazolopyrimidinering.