Design, synthesis, and biological evaluation of new pyrazoloquinazoline derivatives as dual COX‐2/5‐LOX inhibitors

Abstract

A new series of pyrazoloquinazoline derivatives equipped with different chalcones was designed, synthesized, and identified through 1 H nuclear magnetic resonance (NMR), 13 C NMR, and infrared spectroscopic techniques. Our design strategy of the quinazolinone-privileged scaffold as a new scaffold was based on merging pharmacophores previously reported to exhibit cyclooxygenase-2 (COX-2)/5lipoxygenase (5-LOX) inhibitory activity. All the newly synthesized derivatives were biologically evaluated for COX and 5-LOX inhibitory activity and COX-2 selectivity, using celecoxib and zileuton as reference drugs, as they exhibited promising antiinflammatory activity. Compound 3j was found to be the most promising derivative, with IC 50 values of 667 and 47 nM against COX-1 and COX-2, respectively, which are superior to that of celecoxib (IC 50 value against COX-2 = 95 nM), showing an SI of 14.2 that was much better than celecoxib. Compounds 3f and 3h exhibited COX-1 inhibition, with IC 50 values of 1,485 and 684 nM, respectively. The synthesized compounds showed a significant inhibitory activity against 5-LOX, with IC 50 values ranging from 0.6 to 4.3 µM, where compounds 3f and 3h were found to be the most potent derivatives, with IC 50 values of 0.6 and 1.0 µM, respectively, in comparison with that of zileuton (IC 50 = 0.8 µM). These promising derivatives, 3f, 3h, and 3j, were further investigated in vivo for anti-inflammatory, gastric ulcerogenic effects, and prostaglandin production (PGE2) in rat serum. The molecular docking studies concerning the binding sites of COX-2 and 5-LOX revealed similar orientation, compared with reported inhibitors, which encouraged us to design new leads targeting COX-2 and 5-LOX as dual inhibitors, as a new avenue in anti-inflammatory therapy.

Non-steroidal anti-inflammatory drugs: recent advances in the use of synthetic COX-2 inhibitors

“…27. 97 A series of fused-ring derivatives incorporating a thienopyridine moiety were reported by Sanad et al 98 to be COX-2 inhibitors with significant antibacterial activity (Fig. 26).…”

“…Pyrazoloquinazoline derivatives (30) reported by Shaaban et al 97 to be dual COX-2 and 5-LOX inhibitors with moderate anti-inflammatory activities are depicted in Fig. 26 .…”

Structural Insights into Pyrazoles as Agents against Anti‐inflammatory and Related Disorders

“…This reveals that the electron donating groups like methoxy at the phenyl ring attached to the pyrazole moiety exhibited potent COX‐2 inhibitory activity which is 7.17 fold more selective than celecoxib, because of the increase in size allowing the molecule to fit into the larger pocket of COX‐2 active site. Whereas electron withdrawing groups showed low inhibitory and selectivity against COX‐2 enzyme [150] (Figure 10).…”

Computational analysis of eugenol inhibitory activity in lipoxygenase and cyclooxygenase pathways

“…In π-π T-shaped interaction π-electron cloud between the aromatic groups of amino acid fragments and non-chlorinated aromatic ring on diclofenac in a T-shaped manner, i.e., sidewise electron cloud of the ring and head on electron cloud of other ring, these bonds/interactions are necessary to have temporary interactions, especially for the drug action to be accomplished in a system, in addition interactions involving aromatic rings are major contributors to protein-ligand recognition and concomitantly to drug design. Dual COX-2/5-LOX inhibitors had demonstrated excellent analgesic and anti-inflammatory activities with lower gastric irritation, bleeding and ulcerogenic side effects, and are an interesting alternative to provide safer NSAIDs 30,37,43,[97][98][99] . The development of drugs with dual inhibitory activity for COX-2/5-LOX enzymatic pathways offers new options for the development of more effective anti-inflammatory agents with an improved safety profile.…”