Effects of anti-cyclooxygenases (COX-1 and COX-2), structure activity relationship, molecular docking and in silico ADMET of some synthesized chalcones (original) (raw)
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Biomedical journal of scientific & technical research, 2024
Nine derivatives of chalcones were successfully synthesized using the Claisen-Schmidt condensation reaction between different derivatives of benzaldehyde and acetophenone at low temperature in the presence of potassium hydroxide (KOH) and ethanol. The compounds were obtained in high yield. The percentage yield ranges from 90.38-27.68%, with sample B having the highest yield while sample I gave lowest yield. Also, the infra-red and nuclear magnetic resonance (FTIR and NMR) spectroscopic analysis shows distinct spectrum across all molecules, indicating the presence of unique functional groups and chemical environments. All the synthesized chalcones derivatives showed appreciable protein binding affinity against the COX-1 and COX-2 enzymes. The synthesized compounds had higher binding affinity against the COX-1 protein, compared to diclofenac and celecoxib that were used as standards. Sample A showed the highest affinity (-7.24 kcal/mol), while E showed the lowest affinity at-6.11 kcal/mol, higher than diclofenac (-5.46 kcal/mol) and comparable to celecoxib (-6.19 kcal/mol). For COX-2, Celecoxib (selective COX-2 blocker) showed highest binding affinity of-10.55 kcal/mol, while the test compounds B had-8.84 (highest among the test samples) and I (-8.69 kcal/mol (lowest affinity), with diclofenac having-8.49 kcal/mol respectively. Compounds E (4-methoxy-4,6-diphenyl-2-thiopyrimidine) and B (para-chlorochalcone) from previous studies, displayed remarkable anti-inflammatory in an in-vivo animal model analysis. B showed the highest affinity against COX-2 and very high affinity towards COX-1 protein compared to the standard molecules. This shows that with adequate physiochemical and structural modifications, these compounds could serve as potential lead compounds in analgesic and anti-inflammatory pharmacology.
Synthesis and evaluation of chalcone analogues and pyrimidines as cyclooxygenase (COX) inhibitors
African Journal of …, 2012
A series of chalcone analogues was synthesized and used as precursor for the synthesis of novel series of pyrimidines. Both groups have been evaluated for their effects on the cyclooxygenases (COXs) that are imperative enzymes in the genesis of prostaglandin H2, which is an antecedent for the biosynthesis of prostaglandins, thromboxanes and prostacyclins. The results depicted that chalcones and pyrimidines are very active inhibitors according to the pattern of substitution. Compounds C4, C5, P4 and P5 with methoxylation and nitro substitutions showed best results to inhibit COX-2.
Drug Design, Development and Therapy, 2014
Arachidonic acid metabolism leads to the generation of key lipid mediators which play a fundamental role during inflammation. The inhibition of enzymes involved in arachidonic acid metabolism has been considered as a synergistic anti-inflammatory effect with enhanced spectrum of activity. A series of 1,3-diphenyl-2-propen-1-one derivatives were investigated for anti-inflammatory related activities involving inhibition of secretory phospholipase A 2 , cyclooxygenases, soybean lipoxygenase, and lipopolysaccharides-induced secretion of interleukin-6 and tumor necrosis factor-alpha in mouse RAW264.7 macrophages. The results from the above mentioned assays exhibited that the synthesized compounds were effective inhibitors of proinflammatory enzymes and cytokines. The results also revealed that the chalcone derivatives with 4-methlyamino ethanol substitution seem to be significant for inhibition of enzymes and cytokines. Molecular docking experiments were carried out to elucidate the molecular aspects of the observed inhibitory activities of the investigated compounds. Present findings increase the possibility that these chalcone derivatives might serve as a beneficial starting point for the design and development of improved anti-inflammatory agents.
CHALCONES AS INOS AND COX-2 INHIBITORS; INSIGHTS FROM MOLECULAR DOCKING STUDIES
In the present study, a series of ring substituted chalcones were docked into the binding sites of COX-2 and iNOS enzymes. These enzymes exhibit similarities in terms of pathophysiological activities and are mostly co-expressed in cancer tissues. Dual inhibition of these enzymes has been proposed as a promising therapeutic tool in the treatment of various types of diseases, especially for antiiniflammatory and antinociceptive drug development. Results of docking experiments revealed that these structurally simple molecules have good binding affinity for the enzymes and electronic effects have profound influence on the binding interactions. Trifluoro methyl substituted chalcone, (C12) was found to have highest binding affinity among the chalcones studied, indicating the importance of strong electron withdrawing effect at this position. Predicted molecular properties of these compounds demonstrated good oral bioavailability and CNS permeability.
Journal of Medicinal Chemistry, 2010
Following our previous research on anti-inflammatory drugs (NSAIDs), we report on the design and synthesis of 4-(aryloyl)phenyl methyl sulfones. These substances were characterized for their capacity to inhibit cyclooxygenase (COX-1 and COX-2) isoenzymes. Molecular modeling studies showed that the methylsulfone group of these compounds was inserted deep in the pocket of the human COX-2 binding site, in an orientation that precludes hydrogen bonding with Arg120, Ser353, and Tyr355 through their oxygen atoms. The N-arylindole 33 was the most potent inhibitor of COX-2 and also the most selective (COX-1/COX-2 IC 50 ratio was 262). The indole derivative 33 was further tested in vivo for its anti-inflammatory activity in rats. This compound showed greater inhibitory activity than ibuprofen. Other compounds (20, 26, 9, and 30) showed strong activity against carrageenan-induced inflammation. The latter compounds showed a weak capacity to inhibit the proliferation of human cell lines K562, NCI-H460, and HT-29 in vitro. anti-inflammatory drugs; PG, prostaglandin; PGH 2 , prostaglandin G 2 ; MTT, 3(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide; SAR, structure-activity relationship; QSAR, quantitative structure-activity relationship.
International Journal of Research in Pharmaceutical Sciences, 2019
A novel series of chalcone bearing pyrazoline moieties were (P1 to P7) synthesized and characterized by various analytical techniques. The anti-inflammatory studies showed the compounds P1, P2, P5, and P6 have produced the noteworthy inhibition on protein denaturation (81.39 - 96.57 %) when compared to standard 98.17% whereas, the antiproteinase activity was in the range of 84.55- 90.44 % when compared to the standard, 95.95 %. The compounds, P1, P2, P5 (2-Cl, 4- Cl & -NO2 substituent) bearing electron-withdrawing groups and the compounds P3 & P6 (4-N(CH3)2 & -OH substituent) possessing electron-donating group in its phenyl ring system exhibited the prominent activity. Further, to explore the molecular mechanism, the in-silico docking study against COX-2 enzyme was performed. The compounds were also screened for their antibacterial activities. Among them, the compounds P1, P2, P3, P5 and P6 showed the significant antibacterial activity against both gram-positive and gram-negative p...
Drug Discovery of New Anti-Inflammatory Compounds by Targeting Cyclooxygenases
Pharmaceuticals, 2022
The goal of achieving anti-inflammatory efficacy with the fewest possible adverse effects through selective COX-2 inhibition is still being investigated in order to develop drugs with safe profiles. This work shows the efficacy and safety profile of two novel benzimidazole piperidine and phenoxy pyridine derivatives in reaching this goal, which would be considered a major achievement in inflammatory therapy. The compounds were evaluated by virtual screening campaign, in vitro cyclooxygenase 1 and 2 (COX-1 and COX-2) inhibition, in vivo carrageenan-induced rat paw edema assay, cytotoxicity against Raw264.7 cells, and histopathological examination of rat paw and stomach. Two new compounds, compound 1 ([(2-{[3-(4-methyl-1H-benzimidazol-2-yl)piperidin-1-yl]carbonyl}phenyl)amino]acetic acid) and compound 2 (ethyl 1-(5-cyano-2-hydroxyphenyl)-4-oxo-5-phenoxy-1,4-dihydropyridine-3-carboxylate) showed high selectivity against COX-2, favourable drug-likeness and ADME descriptors, a lack of cy...
In this study, two series of 35 new chalcone derivatives containing aryl-piperazine or aryl-sulfonyl-piper-azine fragment were synthesized and their structures were characterized by 1 H, 13 C and ESI-MS. The in vivo and in vitro anti-inflammatory activities of target compounds were evaluated by using classical para-xylene-induced mice ear-swelling model and ELISA assays. Furthermore, docking studies were performed in COX-2 (4PH9). The in vivo anti-inflammatory assays indicated that most of the target compounds showed significant anti-inflammatory activities. Docking results revealed that the anti-inflamma-tory activities of compounds correlated with their docking results. Especially, compound 6o exhibited the most potent anti-inflammatory activity in vivo with the lowest docking score of À17.4 kcal/mol and could significantly inhibit the release of LPS-induced IL-6 and TNF-a in a dose-dependent manner in vitro.