Optimization of pyrazolo[1,5-a]pyrimidine based compounds with pyridine scaffold: Synthesis, biological evaluation and molecular modeling study

Abstract

Background: Pyrazolopyrimidine heterocycle and its isosteres represent the main scaffold for many pharmacologically active drugs including anti-inflammatory agents. The COX-2 inhibitors are the principal gate for the design of new safe and potent anti-inflammatory agents. Methods: Novel derivatives of pyrazolo[1,5-a] pyrimidines were synthesized and screened in vivo and in vitro for their anti-inflammatory potential. Results: Within the constructed compounds, compound 11 was the most active compound on IL-6 and TNF-α (percentage inhibition = 80 and 89%, respectively). In addition, compound 12 displayed the most inhibitory effect towards COX-2 (IC50 = 1.11 µM), whereas compound 11 recorded the highest COX-2 selectivity (S.I = 8.97). The target derivatives 11–14 displayed good edema inhibitory potential (46–68%) and compound 11 was the most potent candidate (ED50 = 35 mg/kg). Additionally, the most potent sPLA2-V inhibitors were compounds 11 and 13 (IC50 = 1 and 1.7 µM respectively). Regarding activity towards 15-LOX, derivative 12 was the most active compound with IC50 = 5.6 µM revealing higher inhibitory activity than nor-dihydroguaiaretic acid (IC50 = 8.5 µM). To confirm the anti-inflammatory potential of the target derivatives, molecular modeling was performed inside COX-2 and 15-LOX active sites. Conclusion: Display discoveries increment the plausibility that these pyrazolo[1,5-a]pyrimidines might act as a beginning point for the improvement of anti-inflammatory agents.

Keywords

• Pyrazolo[1,5-a]pyrimidines
• Molecular modeling
• Cyclooxygenase
• Pro-inflammatory cytokines
• TNF-α