Abstract
A new route to 3-(4-arylmethylamino)butyl-5-arylidene-2-thioxo-1,3-thiazolidine-4-one 9 was developed in six steps from commercial 1,4-diaminobutane 1 as starting material. The key step of this multi-step synthesis involved a solution phase “one-pot two-steps” approach assisted by microwave dielectric from N-(arylmethyl)butane-1,4-diamine hydrochloride 6a–f (as source of the first point diversity) and commercial bis-(carboxymethyl)-trithiocarbonate reagent 7 for construction of the rhodanine platform. This platform was immediately functionalized by Knoevenagel condensation under microwave irradiation with a series of aromatic aldehydes 3 as second point of diversity. These new compounds were prepared in moderate to good yields and the fourteen synthetic products 9a–n have been obtained with a Z-geometry about their exocyclic double bond. These new 5-arylidene rhodanines derivatives 9a–n were tested for their kinase inhibitory potencies against four protein kinases: Human cyclin-dependent kinase 5-p25, HsCDK5-p25; porcine Glycogen Synthase Kinase-3, GSK-3α/β; porcine Casein Kinase 1, SsCK1 and human HsHaspin. They have also been evaluated for their in vitro inhibition of cell proliferation (HuH7 D12, Caco 2, MDA-MB 231, HCT 116, PC3, NCI-H727, HaCat and fibroblasts). Among of all these compounds, 9j presented selective micromolar inhibition activity on SsCK1 and 9i exhibited antitumor activities in the HuH7 D12, MDA-MBD231 cell lines.
Highlights
During the last decades, the five-membered heterocycle rings (FMHRs) are considered “privileged scaffolds” in medicinal chemistry [1]
The crude reaction mixture is stirred vigorously for 16 h at room temperature until the disappearance of aromatic aldehyde 3 controlled by thin-layer chromatography on 0.2-mm precoated plates of silica gel 60 F-254 (Merck)
The resulting suspension was stirred at 50 °C for 24 h
Summary
The five-membered heterocycle rings (FMHRs) are considered “privileged scaffolds” in medicinal chemistry [1]. Among the five-membered heterocycle rings, the 5-arylidene-2thioxo-1,3-thiazolidine-4-ones or 5-arylidene rhodanine derivatives represented privileged moieties in drug discovery because they have an inherent tendency for biological activity [2], such as DDX3 inhibitor for HIV replication [3], as potent and selective inhibitors of the “atypical” dual-specificity phosphatase (DSP) family member-JNK-stimulating phosphatase-1 (JSP-1) [4], as pancreatic cholesterol esterase (CEase) inhibitor [5] with IC50 values ranging from 1.44 to 85 μM. Substituted 5-arylidene-2-thioxo-1,3-thiazolidine-4-ones were able to inhibit HIV replication in MT-4 cells at low micromolar concentration with an appreciable selectivity index and are good scaffolds for the development of novel HIV-1 integrase inhibitors [8]. A family of 5-arylalkylidene rhodanine derivatives presented antiviral activity against chikungunya virus (LR2006_OPY1) in Vero cell culture by cytopathic effect CPE reduction assay [9]. For Alzheimer’s disease, the FMHRs derived from 5-arylidene-2-thioxo-1,3-thiazolidine-4-ones have been described for amyloid polypeptide fibril formation [10], regulation of Cathepsin D immuno-reactivity in the senile plaques [11] and inhibition of tau aggregation [12]
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