Trimethyl‐4‐oxo‐4,5,6,7‐tetrahydroindazole‐1‐acetic Acid: A New Lead Compound with Selective COX‐2 Inhibitory Activity

Abstract

A novel series of 3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydroindazole-1-acetic acid derivatives was designed and synthesized by a new one-step pathway. Structure elucidation of the synthesized compounds was confirmed by various spectral and elemental analyses. The prepared compounds were evaluated for their ability to inhibit cyclooxygenase-2 (COX-2) and cyclooxygenase-1 (COX-1) enzymes in vitro. Among the synthesized compounds, the 2-(3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydroindazol-1-yl)acetic acid 4 emerged as the most potent COX-2 inhibitor (IC(50) value: 150 nM) with the highest selectivity index (COX-1/COX-2 inhibition ratio: 570.6). Docking studies of compound 4 in the active site of COX-2 recognized its potential binding mode to the enzyme. Based on the preliminary results, compound 4 was considered as a lead compound for further optimization.

Design, synthesis, and fungicidal activities of novel ethylenediamine bridged thiazole derivatives containing oxime ether or oxime ester moieties

“…A solution [24] of 7 (16 g, 72.02 mmol) in absolute ethyl alcohol (150 ml), ethylenediamine (20.27 g, 337.43 mmol) was added dropwise. Then the reaction mixture was heated at reflux.…”

“…A series of novel ethylenediamine bridged thiazole derivatives containing oxime ether or oxime ester moieties compounds 16a-16r were successfully prepared as reported previously [11][12][13][14][15][16][17][18][19][20][21][22][23][24][25][26][27][28][29] (Schemes 1 and 2). To study the effect of substituents on ethylenediamine on the fungicidal activity, a series of oxime ether derivatives containing different substituents on ethylenediamine were also synthesized.…”

“…13 A solution [23] of 15 (0.70 g, 1.57 mmol) and pyridine (0.16 g, 2.05 mmol) in n-hexane and dichloromethane mixed solvent (1:3) (40 ml), benzoyl chloride (0.31 g, 2.20 mmol) was added dropwise. When the starting material was completely consumed as indicated by thin-layer chromatography, the mixture was washed with water (3 Â 30 ml), dried over Na 2 SO 4 , and filtered; the filtrate was evaporated under reduced pressure and the residue was purified by silica column chromatography with 10:1 petroleum ether/ethyl acetate as the eluent to give 17a as a yellow solid (0.50 g, 58% yield), mp 77-79 C. 1 A solution [24] of 7 (16 g, 72.02 mmol) in absolute ethyl alcohol (150 ml), ethylenediamine (20.27 g, 337.43 mmol) was added dropwise. Then the reaction mixture was heated at reflux.…”

Crystal structure of 3,6,6-trimethyl-4-oxo-1-(pyridin-2-yl)-4,5,6,7-tetrahydro-1H-indazol-7-aminium chloride and its monohydrate

“…Heterocyclic compounds containing a tetrahydroindazole core have been researched as antiviral agents (Bassyouni et al, 2016) and compounds with antioxidant properties (Polo et al, 2016). With appropriate side-chain decorations, they also possess COX-2 inhibitory activity (Abdel-Rahman et al, 2012) and can inhibit bacterial type II topoisomerases (Wiener et al, 2007). The latter has led to the development of compounds with both antitumor and antimicrobial activity (Faidallah et al, 2013), including novel antituberculosis agents (Guo et al, 2010).…”

Synthesis and evaluation of tetrahydroindazole derivatives as sigma-2 receptor ligands

“…[47][48][49][50][51][52] It is interesting to note that some of the 4-(3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indazol-1-yl)benzamide analogs showed potent activities in inhibiting heat shock proteins, 50 and various kinases, 51,52 and thus possessing potent anti-cancer activity. Therefore, the tetrahydroindazole scaffold may possess some favorable abilities toward protein binding.…”