Synthesis and Anticancer Activity of Isatin‐Based Pyrazolines and Thiazolidines Conjugates

Abstract

The synthesis and antitumor activity screening of novel isatin based conjugates with thiazolidine and pyrazoline moieties were performed. Reaction of 3,5-diaryl-4,5-dihydropyrazoles with chloroacetyl chloride yielded starting 2-chloro-1-(3,5-diaryl-4,5-dihydropyrazol-1-yl)-ethanones which were utilized in alkylation of isatin and 5-bromoisatin. Thus, corresponding 1-[2-(3,5-diaryl-4,5-dihydropyrazol-1-yl)-2-oxoethyl]-1H-indole-2,3-diones (1a-1d) have been obtained. The compounds 1a-1d have been used in Knoevenagel condensation with 4-thiazolidinones for obtaining a series of 5-ylidenederivatives 2a-2f and 3a-3d. The synthesized compounds were tested for their anticancer activity in NCI60 cell lines. Among the tested compounds, 5-bromo-1-{2-[5-(4-chlorophenyl)-3-(4-methoxyphenyl)-4,5-dihydropyrazol-1-yl]-2-oxoethyl}-1H-indole-2,3-dione (1d) was found to be the most active candidate with selective influence on leukemia subpanel tumor cell lines with GI(50) values range of 0.69-3.35 µM.

3-Hydroxy-3-(2-oxo-2,3-dihydro-1H-indol-3-yl)-2,3-dihydro-1H-indol-2-one

“…Recently, isatin derivatives have attracted strong interest in organic and medicinal chemistry due to their potent biological and pharmacological activities including antitumor (Premanathan et al, 2012;Havrylyuk et al, 2011), antimicrobial (Singh et al, 2010;Ali & Alam, 1994;Pandeya et al, 1999b), anti-inflammatory and analgesic (Abele et al, 2003;Mondal, et al, 2010), antimycobacterial (Aboul-Fadl et al, 2010;Sriram et al, 2006), anticonvulsant (Malawska, 2005), antiviral (Selvam et al, 2006;Selvam et al, 2008;Abbas et al, 2013), anthelmintic (Suresh et al, 2011), anti-HIV applications (Pandeya et al, 1999a) and anti-oxidant (Andreani et al, 2010;Kiran et al 2013). In this context, the present study reports the synthesis and crystal structure determination of the title bis-indole derivative.…”

Synthesis and Anticancer Activity of Isatin, Oxadiazole and 4-Thiazolidinone Based Conjugates

“…Synthesis of new 4-thiazolidinones with oxadiazole moiety in N3 position (2a-c) was performed based on the alkylation reaction of 2,4-thiazolidinedione potassium salt, generated in situ, and 2-chloro-N-(5-aryl-1,3,4-oxadiazol-2-yl)-acedamides 1a-c. Considering the fact, that the presence and nature of the moiety in thiazolidinone C5 position are critical for realization and character of the pharmacological effects [2,11,27], the following modification was directed to the methylene group of synthesized compounds 2a-c. Thus, the synthesis of new non-condensed systems with 4-thiazolidinone, 1,3,4-oxadiazole, and indoline moieties 3a-g were performed, using standard Knoevenagel reaction procedure (medium -acetic acid, catalyst -fused sodium acetate).…”

“…It is known that the combination of different bioactive fragments with complementary pharmacophoric functions or with different mechanisms of the action often showed synergistic effects. Thus, among isatin based conjugates with thiazolidinone [10][11][12][13][14], oxadiazole [15] or benzothiazole [16,17] the promising anticancer agents were identified.…”

Recent Highlights in the Development of Isatin-Based Anticancer Agents

“…These observations led Lesyk and colleagues to synthesise new isatin-pyrazoline hybrids (75a-d, Fig. (23)) with the aim of discovering new active and selective compounds that elicit synergistic anticancer activity [165]. The further conjugation of isatin-pyrazoline hybrids with 4-thiazolidinones to from isatin-based hybrids with three distinct bioactive drug components (76a-d)…”