Screening of curcumin‐derived isoxazole, pyrazoles, and pyrimidines for their anti‐inflammatory, antinociceptive, and cyclooxygenase‐2 inhibition

Abstract

Curcumin has shown pharmacological properties against different phenotypes of various disease models. Different synthetic routes have been employed to develop its numerous derivatives for diverse and improved therapeutic roles. In this study, we have synthesized curcumin derivatives containing isoxazole, pyrazoles, and pyrimidines and then the synthesized molecules were evaluated for their anti-inflammatory and antinociceptive activities in experimental animal models. Acute toxicity of synthesized molecules was evaluated in albino mice by oral administration. Any behavioral and neurological changes were observed at dose of 10 mg/kg body weight.Additionally, cyclooxygenase-2 (COX-2) enzyme inhibition studies were performed through in vitro assays. In vivo anti-inflammatory studies showed that curcumin with pyrimidines was the most potent anti-inflammatory agent which inhibited induced edema from 74.7% to 75.9%. Compounds 7, 9, and 12 exhibited relatively higher prevention of writhing episodes than any other compound with antinociceptive activity of 73.2%, 74.9%, and 71.8%, respectively. This was better than diclofenac sodium (reference drug, 67.1% inhibition). Similarly, COX-2 in vitro inhibition assays results revealed that compound 12 (75.3% inhibition) was the most potent compound.Molecular docking studies of 10, 11, and 12 compounds in human COX-2 binding site revealed the similar binding modes as that of other COX-2-selective inhibitors. K E Y W O R D Santi-inflammatory, COX-2 inhibition, curcumin derivatives, molecular modeling Chemically curcumin is diferuloylmethane which has attracted much attention of medicinal chemists for various diseases and therapeutic agents development. It has shown its pharmacological safety and wide range of biological activities such as antibacterial to anticancer agent [1][2][3][4] . Currently, curcumin is acclaimed to be one of the most widely researched naturally occurring chemopreventive agent which is cytoprotective to healthy human cells [5][6][7] . In spite of important therapeutic application, limited therapeutic utility concerns are associated with curcumin because of its poor absorption and fast metabolism under physiological conditions [8] . Active methylene and keto moiety are believed to be responsible for its rapid metabolism. In order to circumvent the problem of rapid metabolism and to improve its pharmacokinetics profile, several synthetic modifications have been studied on carbonyl and active methylene moiety [9] . In present study, isoxazole, N-substituted pyrazoles, and pyrimidine ring were incorporated in this focused segment of curcumin. Nitrogen heterocyclic moieties such as pyrazoles and pyrimidines containing derivatives gained considerable attention in medicinal chemistry for

Recent Updates in Curcumin Pyrazole and Isoxazole Derivatives: Synthesis and Biological Application

“…[47] A series of pyrazole, pyridopyrazoltriazine, pyrazolotriazine, isoxazole and pyridine-containing products were prepared as a new class of antioxidant agents starting with curcumin and appropriate chemical reagents. [69] 3. Also, pyrazole and isoxazole derivatives were obtained upon treatment of curcumin with hydrazines or hydroxylamine hydrochloride.…”

“…[49] Curcumin derived isoxazoles, pyrazoles and pyrimidines were screened for anti-inflammatory and antinociceptive activities. [69]…”

Curcuminoids versus Pyrazole‐Modified Analogues: Synthesis and Cytotoxicity against HepG2 Cancer Cell Line

“…The observations are similar to the reported results in previous works, in which pyrazole-based analogues showed better cytotoxicity profiles due to their improved solubility and stability. [6,15,16,[18][19][20] Labbozzetta et al reported that curcuminoids sensitize the human hepatic cancer cells to apoptotic effects while pyrazole curcuminoids lacked the interaction with cell -SH groups and glutathione. [13] In other words, the detoxification mechanism is not required for an increased anticancer potency of pyrazole candidates, in which, the pyrazole fragments prevent a Michael addition with thiol nucleophile.…”

“…Experimental and computational studies on curcumin structure demonstrated that the aromatic ring/substituents on it and β-diketone moieties are crucial for biological responses and kinetic stability. [1][2][3][4][5][6][7][8][9][10][11][12] Several synthetic curcumin analogues have been developed through chemical modifications on its pharmacophores such as pyrazole, [6,[13][14][15][16][17][18][19][20] 1,4-thiazepane, [7] monocarbonyl, [8] aza-aromatic, [9] N-alkyl β-enaminone curcuminoids. [10][11][12] to circumvent the limitations of curcumin.…”

“…Replacing the β-diketone by pyrazole ring may increase anticancer activities, [6,[13][14][15][16][17] water solubility and delay degradation of curcumin. [6,15,16,[18][19][20] In order to prepare pyrazole-modified analogues of curcumin, the amount of curcumin substrate needs to be large enough for semi-synthetic processes. However, the isolation of natural curcumin from the Curcuma longa rhizome is a costly and timeconsuming procedure.…”