Optimization of pyrazolo[1,5-a]pyrimidine based compounds with pyridine scaffold: Synthesis, biological evaluation and molecular modeling study
Mohamed A. Abdelgawad, Nadia A. A. Elkanzi, Arafa Musa, Mohammed M. Ghoneim, Waqas Ahmad, Mohammed Elmowafy, Ahmed Mahmoud Abdelhaleem Ali, Ahmed H. Abdelazeem, Syed Nasir Abbas Bukhari, Mohamed El-Sherbiny, Mohammed A. S. Abourehab, Rania B. Bakr
Abstract
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. Novel derivatives of pyrazolo[1,5-a] pyrimidines were synthesized and screened in vivo and in vitro for their anti-inflammatory potential. 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. 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.