Synthesis and biological evaluation of pyrazolone analogues as potential anti‐inflammatory agents targeting cyclooxygenases and 5‐lipoxygenase

Abstract

New pyrazolone derivatives structurally related to celecoxib and FPL 62064 were synthesized and biologically evaluated for their inhibitory activity against cyclooxygenases (COXs) and 5‐lipoxygenase (5‐LOX) and their selectivity indices were calculated. The results showed that compounds 3f, 3h, 3l, and 3p have an excellent COX‐2 selectivity index. Moreover, they showed potent 5‐LOX inhibitory activity relative to celecoxib and zileuton, as positive controls. These promising candidates were further investigated for anti‐inflammatory activity using the carrageenan‐induced rat paw edema method and ulcerogenic liability. The results showed no ulceration, which implies their gastric safety profile. Moreover, these compounds were evaluated for prostaglandin (PGE2) production in rat serum. Molecular docking in the COX‐2 and 5‐LOX active sites was performed to rationalize their anti‐inflammatory activities. Strong binding interactions and effective docking scores were identified. The results indicated that these derivatives are good leads for dual‐acting COX‐2/5‐LOX inhibitors to be used as potent and safe anti‐inflammatory agents.

Development of pyrazole derivatives in the management of inflammation

“…The pyrazole derivative–enzyme interaction has been evaluated using molecular docking. The result of this assessment provides the affinity of designed compounds and contributes to the detection of acceptable inhibitors of COX‐2 ( 15 ; 17 ; 23–32 ; 34–37 ; 39 ; 51 ; 58 ; 60 ; 61 ; 69–72 ; 74 ; 85–87 ) [18,26,27–34,35–39] and 5‐LOX ( 46 ; 63 ; 82–84 ) [40–42] catalytic activity. The energy score of docked derivatives appears related to the degree of enzyme inhibition and selectivity.…”

“…Similarly, the higher 5‐LOX docking scores of pyrazole derivatives implicate the involvement of different amino acid residues. In addition to the metal complex (Fe) and H‐bond interactions with the active site of 5‐LOX, the compound 63 shown another type of docking, the arene–cation interaction with the Phe177 amino acid residue that improves the energy score in comparison with standard drug zileuton ( E score = –7.20 and –6.30 Kcal/mol) [40]. The interaction with varying or additional amino acids seems to enhance the docking score and inhibitory activity of compound 46 (Leu368, Leu414, Ile415, Phe421, Tyr181, and Asn425) and compounds 82–84 (Phe177, Gln413, Val671, Ala672, Gln363, Leu368, and others) as compared with known NSAIDs—meclofenamic acid [41] and celecoxib [42].…”

“…In a previous study, the anti‐inflammatory activity of pyrazolyltriazoles ( 20 ; 21 ), curcumin analogs without β‐diketone ( 92–96 ), and pyrazole‐5‐carbonitrile derivatives was assessed using the methods of protein denaturation and membrane‐stabilizing property of red blood cells [17,40,44]. The functional groups with promising anti‐inflammatory and/or analgesic activity were detected in molecular and electrophysiological trials.…”

“…The diaryl pyrazoles ( 10 ; 11 ) inhibited COX‐2 and 15‐LOX, while others ( 15 ; 16–19 ; 46 ; 82–84 ) inhibited COX‐2 and 5‐LOX [16,18,38,41,42] in an immunoassay. The pleural exudate ( 44 ) [46], cerebrospinal fluid ( 77 ) [44], blood samples ( 49 ; 63–66 ) [40,52], or cell culture of RAW 264.7 macrophages ( 56 ; 59 ) revealed that some compounds were able to reduce PGE 2 levels [51,59]. As reported for derivative 49 [52], the decrease of cytosolic and microsomal PGE 2 synthase concentration can also be measured to elucidate if compounds were able to block the prostaglandin production beyond the COX‐2 inhibition.…”

“…The anti‐inflammatory or antinociceptive potential of some derivatives ( 22 ; 38–40 ; 43 ; 44 ; 46 ; 68 ; 77 ; 82–96 ; 98 ; 99 ; 103–109 ) was demonstrated in a nonspecific abdominal writhing test [29,31,41,42,44,45,61,63–65,71–76]. The anti‐inflammatory activity of several compounds ( 10–14 ; 16–19 ; 22–24 ; 27–33 ; 38 ; 40–44 ; 46 ; 49 ; 51 ; 54 ; 55 ; 57 ; 58 ; 60–67 ; 73 ; 74 ; 76 ; 79–87 ; 89–91 ) was assessed in carrageenan‐induced paw edema [16,18,26,27–29,31,32,35,36,37–42,46–49,52–55,61,71,77–79]. Furthermore, the antiedematogenic effect of some derivatives ( 15 ; 34–37 ; 50 ; 109 ) has been evaluated with formalin [30,34,38,76,80] and histamine‐induced paw edema ( 52 ) [81], in addition to xylene ( 48 ) [66] and croton oil‐induced ear edema ( 77 ; 109 ) [44,76].…”