Optimization of Pyrazolo[1,5-A]pyrimidine Based Compounds with Pyridine Scaffold: Synthesis, Biological Evaluation and Molecular Modeling Study

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-a (percentage inhibition = 80 and 89%, respectively). In addition, compound 12 displayed the most inhibitory effect towards COX-2 (IC50 = 1.11 mu M), 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 mu M respectively). Regarding activity towards 15-LOX, derivative 12 was the most active compound with IC50 = 5.6 mu M revealing higher inhibitory activity than nor-dihydroguaiaretic acid (IC50 = 8.5 mu M). 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.(c) 2022 The Author(s). Published by Elsevier B.V. on behalf of King Saud University. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).