Synthesis and evaluation of biological activity of rhodanine-pyrazoline hybrid molecules with 2-(2,6-dichlorophenylamino)-phenylacetamide fragment

Abstract

Synthesis of new rhodanine-pyrazoline hybrid molecules with a diclofenac fragment in position 3 using the reactions of heterocyclization and aminolysis with potential antitumor and antitrypanosomal activities. Methods. Organic synthesis, NMR spectroscopy, pharmacological screening. Results. The reaction between 2-(2,6-dichloro-phenyl-amino)-phenylacetic acid hydrazide and thiocarbonyl-bis-thioglycolic acid in ethanol medium providing rhodanine derivative with fragment of the anti-inflammatory drug diclofenac in position 3 was performed. The presence of an active methylene group in position 5 and its subsequent modification providing 5-ethoxymethylenerhodanine and further aminolysis reaction with various 3,5-diaryl-4,5-dihydro-1H-pyrazoles allowed to produce of a series of 5-(3,5-diaryl-4,5-dihydropyrazol-1-ylmethylene)-2-thioxothiazolidin-4-ones. The antitumor activity screening allowed to identify a highly active compound 9 with a mean GI 50 = 0.71/1.09 and TGI = 82.95/28.46 μM towards 60 cancer lines (DTP NCI program). The synthesized pyrazoline-thiazolidine hybrid molecules with the diclofenac fragment in the structure did not show significant antitrypanosomal activity against Trypanosoma brucei brucei (Tbb). Conclusions. The synthesized 5-(3,5-diaryl-4,5-dihydropyrazol-1-ylmethylene)-2-thioxothiazolidin-4-ones with a diclofenac fragment in the structure are a promising molecular platform for creation of new highly active potential drugs with a low toxicity.

Anticancer Profile of Rhodanines: Structure–Activity Relationship (SAR) and Molecular Targets—A Review

“…Based on this form of furochromone, khellin with a lipophilic rhodanine structure, the discovery of even more active molecules slowing down the progression of the tumor cells could be carried out, mainly for novel anti-breast cancer agents. New 5-(3,5-diaryl-4,5-dihydropyrazol-1-ylmethylene)-2-thioxothiazolidin-4-ones with a diclofenac moiety, namely compound 30 and 31 (Figure 15), have been synthesized and evaluated for their antitumor activities [10]…”

“…These rhodanine-pyrazoline hybrid molecules, with a diclofenac moiety after some further modifications on pharmacophore, could potentially serve as a base for designing novel anticancer drugs. New 5-(3,5-diaryl-4,5-dihydropyrazol-1-ylmethylene)-2-thioxothiazolidin-4-ones with a diclofenac moiety, namely compound 30 and 31 (Figure 15), have been synthesized and evaluated for their antitumor activities [10]…”

“…The rhodanine derivatives are small compounds with a broad spectrum of biological activities; they are used as antimicrobial [5], antiviral [6], antitubercular [7], antiinflammatory [8], antidiabetic [9], and antitumor agents [10][11][12][13].…”

Design, Synthesis, and Antiproliferative Activity of Novel Neocryptolepine–Rhodanine Hybrids

“…The rationale behind introducing the amino side chains into the core of neocryptolepine was justified due to their indispensable role in antiproliferative activity. On the other hand, rhodanine, 2-thioxo-4-thiazolidone C, and its analogs ( Figure 2 ) have a wide range of biological activities such as antidiabetic [ 21 ], antiviral [ 22 , 23 ], anti-inflammatory [ 24 ], antimicrobial [ 25 ], antimalarial [ 26 ], antifungal [ 27 , 28 ], anti-HIV [ 29 ], and anticancer agents [ 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 ].…”

The Bioactivity of Thiazolidin-4-Ones: A Short Review of the Most Recent Studies

“…Among the all-tested compounds, only Derivatives 54a-54c and 55 (Figure 23) showed % of growth inhibition more than 50% at concentration 10 µM against Dami cell line. The study conducted by Shepeta et al showed that rhodanine-pyrazoline hybrid with diclofenac moiety (56) had high effectiveness against 60 cancer cell lines (NCI DTP protocol) with a mean of GI50 = 0.71/1.09 µM and TGI = 82.95/28.46 µM [57]. Tilekar et al described series of 5-(naphtha-2-ylidene)thiazolidine-2,4-dione derivatives as simultaneously target PPARγ and HDAC (Figure 24).…”