Synthesis and Antioxidant Activity of Some New Coumarinyl-1,3-Thiazolidine-4-ones

A series of Schiff’s bases (E)-N-2-aryliden-2-(4-methyl-2-oxo-2H-chromen-7-yloxy)acetohydrazides 2a-l and N-(2-(substituted phenyl)-4-oxo-thiazolidin-3-yl)-2-(4-methyl-2-oxo-2H-chromen-7-yloxy)acetamides 3a-l were synthesized and evaluated for their antioxidant activity by the phosphomolybdenum method. Most of the Schiff’s bases and thiazolidine-4-ones bearing two hydroxyl groups on the phenyl ring showed excellent antioxidant activity in comparison with ascorbic acid. Preliminary investigation on cytotoxic and antifungal activity was done on some representative samples.


Introduction
The structural and therapeutic diversity of small heterocyclic molecules coupled with their commercial viability has long fascinated organic and medicinal chemists. Heterocycles containing the coumarin ring system include some novel pharmacologically active compounds such as dicumarol, warfarin, mercumatilin and novobiocin. Natural coumarins affect the formation and scavenging of ROS and influence free radical-mediated oxidative damage [1].
In recent years, 4-thiazolidinones and 2,4-thiazolidinediones have been among the most extensively investigated classes of organic compounds. Thiazolidine derivatives are reported to show a variety of biological activities. The presence of a thiazolidine ring in penicillin and related derivatives was the first recognition of its occurrence in nature [15]. Thiazolidine-4-one represents a prevalent scaffold in drug discovery [16]. Literature surveys show that thiazolinylhydrazones exhibit antitubercular and antimicrobial activities [15], and their pronounced antioxidant [17] and antifungal [18] activity has also been reported. Thiazolidine-4-ones have many interesting activity profiles, namely COX-1 inhibitors [19], inhibitors of the bacterial enzyme MurB, which was a precursor acting during the biosynthesis of peptidoglycan [20], non-nucleoside inhibitors of HIV-RT [21] and anti-histaminic agents [22]. Depending on the substituents, 4-oxothiazolidine ring can induce different pharmacological properties such as antibacterial [23], antimycobacterial [24], anticonvulsant [25] or anti-inflammatory activity [26] and it has been reported that the introduction of arylidene moieties at different positions of the thiazolidinone ring enhanced biological activity [27][28][29]. Some authors examined the ability of this ligand structure to form complexes with some radionuclides for potential use in nuclear medicine [30]. Thus, coumarins containing a Schiff's base and a thiazolidinone moiety are expected to have enhanced biological activities.

Antioxidant activity
Data in Figure 1. show that substituents on the phenyl ring have a great influence on antioxidant activity. In descending order the effects of the various substituents on the phenyl ring of the Schiff's bases were found to be: 2,5(OH) 2 (2g) > 2,3-(OH) 2 (2d) > 3-Cl (2c) > 2,4-(OH) 2 3,4-(OH) 2 (2f). Among the Schiff's compounds 2g and 2d have better antioxidant activities than ascorbic acid (1.54 and 1.34 times better, respectively). Both of these compounds have two electron donating OH groups on phenyl ring, one of them being in ortho position in both cases. They also posses another electron donating group, the presence of which obviously contributes to increased antioxidant activity, as the compound 2a with only one OH group in the ortho position did not show relevant antioxidant activity.  The effects of various substituents on phenyl ring of 1,3-thiazolidine-4-ones in descending order were found to be: 2,5-(OH) 2 . Among the series of 1,3-thiazolidine-4-ones, compounds 3g, 3d and 3e have better antioxidant activity than ascorbic acid (1.48, 1.41 and 1.40 times better, respectively). All of these compounds also have two electron donating OH groups on the phenyl ring, one of them being in an ortho position. Presence of another OH group, no matter the position on the phenyl ring, obviously contributes to increased antioxidant activity, like in the series of Schiff's bases.
Observing the overall data for antioxidant activity, it is clear that the presence of two hydroxyl groups has a great influence on radical scavenging activity. Schiff's base 2g shows the greatest antioxidant activity of all investigated compounds, followed by the 1,3-thiazolidine-4-one 3g, both having 2,5-(OH) 2 substituents on phenyl ring, which is in accordance with the results of Lin et al. [32] who reported correlation of radical-scavenging effects of coumarins with the number of hydroxyl groups.

General
The melting points were taken on an Electrothermal capillary melting point apparatus and are uncorrected. Thin-layer chromatographies were performed using HF 254 fluorescent silica gel plates (Merck), which were examined under UV 254 and 365 nm light. Silica gel (230-400 mesh) was used for flash chromatography separations. The elemental analysis for C, H and N were done on a Perkin-Elmer Analyzer 2440. Infrared spectra (ν/cm -1 ) were recorded on a Beckmann FT-IR 3303 instrument, using KBr disks. 1 H-and 13 C-NMR spectra were recorded on JEOL EX-270 MHz NMR Spectrometer at 293 K in DMSO-d 6 . Spectra were internally referenced to TMS. Peaks are reported in ppm downfield of TMS. The absorbance was measured on a Helios γ UV visible spectrophotometer (Thermo Spectronic, Cambridge, UK).

Conclusions
In this study a series of Schiff's bases (E)-N-2-aryliden-2-(4-methyl-2-oxo-2H-chromen-7yloxy)acetohydrazides 2a-l and novel N-(2-(substituted phenyl)-4-oxo-thiazolidin-3-yl)-2-(4-methyl-2oxo-2H-chromen-7-yloxy)acetamides 3a-l were synthesized and evaluated for their antioxidant activity by phosphomolybdenum method. The 1,3-thiazolidine-4-one derivatives containing the coumarin moiety were synthesized by cyclocondensation of the Schiff's bases and mercaptoacetic acid. Compounds which are indicated as already known are resynthetized and the analytical data obtained for these compounds were comparable, but slightly different from those of other authors. For all the novel compounds structures were elucidated by the means of various spectral methods. Two of the Schiff's bases (2g, 2d) and three of 1,3-thiazolidine-4-ones (3g, 3d, 3e) proved to have better antioxidant activity in comparison with ascorbic acid. In conclusion, it is evident that the substituents on the phenyl ring have a great influence on antioxidant activity.