Design and Microwave Synthesis of New (5Z) 5-Arylidene-2-thioxo-1,3-thiazolinidin-4-one and (5Z) 2-Amino-5-arylidene-1,3-thiazol-4(5H)-one as New Inhibitors of Protein Kinase DYRK1A

Abstract

Here, we report on the synthesis of libraries of new 5-arylidene-2-thioxo-1,3-thiazolidin-4-ones 3 (twenty-two compounds) and new 2-amino-5-arylidene-1,3-thiazol-4(5H)-ones 5 (twenty-four compounds) with stereo controlled Z-geometry under microwave irradiation. The 46 designed final compounds were tested in order to determine their activity against four representative protein kinases (DYR1A, CK1, CDK5/p25, and GSK3α/β). Among these 1,3-thiazolidin-4-ones, the molecules (5Z) 5-(4-hydroxybenzylidene)-2-thioxo-1,3-thiazolidin-4-one 3e (IC50 0.028 μM) and (5Z)-5-benzo[1,3]dioxol-5-ylmethylene-2-(pyridin-2-yl)amino-1,3-thiazol-4(5H)-one 5s (IC50 0.033 μM) were identified as lead compounds and as new nanomolar DYRK1A inhibitors. Some of these compounds in the two libraries have been also evaluated for their in vitro inhibition of cell proliferation (Huh7 D12, Caco2, MDA-MB 231, HCT 116, PC3, and NCI-H2 tumor cell lines). These results will enable us to use the 1,3-thiazolidin-4-one core as pharmacophores to develop potent treatment for neurological or oncological disorders in which DYRK1A is fully involved.

Synthesis of (Z)-3-Allyl-5-(4-nitrobenzylidene)-2-sulfanylidene-1,3-thiazolidin-4-one and Determination of Its Crystal Structure

“…The 1 H-NMR recorded in d 6 -DMSO (Figure 2) reveals the aryl signals as doublets at δ 7.91 and 8.36 ppm. The chemical shift in the vinyl proton at δ 7.93 indicates that the exocyclic double bond has a Z-configuration, as already observed for other 5-arylidene rhodanines described in the literature [6]. Its signal appears at a lower field than that of the E-isomer due to the stronger deshielding effect of the carbonyl group compared to the sulfur atom [36].…”

“…Molbank 2024, 2024, x FOR PEER REVIEW 3 of 10 other 5-arylidene rhodanines described in the literature [6]. Its signal appears at a lower field than that of the E-isomer due to the stronger deshielding effect of the carbonyl group compared to the sulfur atom [36].…”

“…The five-membered heterocyclic compound rhodanine, also called 2-thioxo-4-thiazolidinone (see Figure 1) and its derivatives [1] not only play a role in organic chemistry as building blocks for further transformations but have also found application in various therapeutic areas [2,3] due to their broad spectrum of biological and pharmacological activities. These include antidiabetic activity [4], protein kinase inhibitors [5,6], topoisomerase II inhibition potency [7,8], anticancer activity against MCF-7 breast cancer [9,10] and potential cholinesterase inhibitors [11,12]. After approval of the N-substituted rhodanine Epalrestat [13] by the Food and Drug Administration (FDA) as an inhibitor drug for the treatment of diabetic neuropathy [14], several arylidene N-substituted rhodanine derivatives have also been identified as potential inhibitors of essential therapeutic targets such as PTP1B [15], α-amylase [16] and α-glucosidase [17] for the clinical management of Type 2 diabetes mellitus (T2DM) (Figure 1).…”

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

“…According to recent literature, DYRK1A occurs due to its involvement in different diseases, including Alzheimer's disease (AD), Down syndrome (DS) [97], and cancer [98][99][100]. Bourahla et al [101] designed a series of novel compounds, including (5Z) 5-arylidene-2-thioxo-1,3-thiazolidin-4-one derivatives prepared under microwave irradiation from various aromatic aldehydes and respective 2-thioxo-1,3-thiazolidin-4-ones, and some valuable results for structures 62, 63, 64, 65, 66, and 67 were obtained (Figure 36). Compound 62, with a hydroxyl group at the C-4 position of the exocyclic phenyl moiety, exhibited a sub-micromolar inhibitory effect towards DYRK1A (IC 50 = 0.028 µM).…”

N-Benzylated 5-Hydroxybenzothiophene-2-carboxamides as Multi-Targeted Clk/Dyrk Inhibitors and Potential Anticancer Agents

“…Furthermore, macrocyclic inhibitors, which were reported as potent Dyrk1A inhibitors, also exhibited antiproliferative effects and decreased colony formation in head and neck squamous cell carcinoma [ 26 ]. Similarly, some thiazolidines derivatives revealed antitumor activity against colorectal carcinoma cell lines [ 27 ].…”