Synthesis and in vitro antimicrobial activity of 3-(5-((2-oxo-2 H -chromen-4-yl)thio)-4-phenyl-thiazol-2-yl)-2-substitutedphenyl

. An array of 3-(5-((2-oxo-2 H -chromen-4-yl)thio)-4-phenyl


INTRODUCTION
Thiazolidinone is a well-known saturated form of thiazole. The carbonyl group of thiazolidine-4-ones is highly un-reactive, and substitution is possible at 2 nd , 3 rd and 5 th position. Thiazolidine-4-one are the derivatives of thiazolidine, which belongs to important groups of heterocyclic compounds containing sulfur and nitrogen in a five member ring. Thiazolidine-4-ones are ordinarily solids, often melting with decomposition but the attachment of an alkyl group to the nitrogen lowers the melting point. In the structure of thiazolidinone (Figure 1), carbonyl group is present on fourth carbon. A lot of research work on thiazolidinones, with a carbonyl group at position 2, 4, or 5, has been done in the recent decades [1][2][3]. Moreover, thiazolidinone is recognized as a magic moiety, because it shows almost all types of remarkable biological activities [1].
These compounds showed good activity against particular bacterial including E. coli, P. aeruginosa, S. aureus, & S. pyogenes respectively, as well as antifungal activity against C. albicans, A. niger, and A. clavatus. The structure of all newly synthesized derivatives were confirmed by IR, 1 H-NMR, 13 C NMR, mass spectra as well as elemental analysis.

Material and methods
All the chemicals and solvents used for the synthesis work acquired from commercial sources, were of analytical grade, and used without further purification. Melting points were determined by using open capillary tubes and are uncorrected. TLC was checked on E-Merck pre-coated 60 F254 plates and the spots were rendered visible by exposing to UV light or iodine. IR spectra were recorded on SHIMADZU HYPER IR. NMR spectra were recorded on 400 MHz BRUKER

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ILCPA Volume 51 AVANCE instrument using TMS as internal standard (Chemical Shift in δ, ppm) and DMSO-d6 as a solvent. Spectra were taken with a resonant frequency of 400 MHz for 1 H NMR and 100 MHz for 13 C NMR. The splitting patterns are designated as follows; s, singlet; d, doublet; dd, doublet of doublets; and m, multiplet. Elemental analysis was done on "Haraeus Rapid Analyser". The mass spectra were recorded on JOEL SX-102 (EI) model with 60 eV ionizing energy.

Synthesis of 4-phenylthiazol-2-amine
The mixture of thiourea (12.61 g, 0.166 mole) and iodine (10.41 g, 0.041 mole) were added to a stirring solution of the acetophenone (10 g, 0.083 mole) in absolute ethanol (50 mL). The mixture was heated at 80 °C for 2-3 h. Progress of the reaction was monitored by TLC using ehtylacetate: hexane (2:8) as eluent. After the completion of reaction, the pH of the solution was adjusted to 7.0 by drop wise addition of NH 4 OH solution. The crude generated was filtered and extracted with ether (4x10mL). It was then recrystallized from hot water to get the title compound. Yield: 85%

Synthesis of 5-bromo-4-phenylthiazol-2-amine
To an ice-cold solution of 4-phenylthiazol-2-amine (7.0 g, 0.040 mole) in glacial acetic acid (30 mL), a solution of bromine (5.0 mL, 0.039 mol) in acetic acid (10 mL) was added drop wise at 5-10 °C during 30 min. The mixture was further stirred at room temperature for 2 h. Progress of the reaction was monitored by TLC using ethyl acetate: hexane (2:8) as eluent. After the completion of reaction it was dumped in to water. The precipitated solid was collected by filtration, washed with ice-cold acetic acid (5.0 mL) and water, neutralized by NH 4 OH solution and recrystallized from aqueous ethanol to get a brown solid product. Yield: 80%

Synthesis of N-arylidene-5-bromo-4-phenyl thiazol-2-amine
A mixture of 5-bromo-4-phenyl thiazol-2-amine (3.5 g, 0.01 mol) and benzaldehyde (0.01 mol, 1.06 mL) in ethanol (15 mL), and acetic acid (0.5 mL) was refluxed for 6 hrs. Progress of the reaction was monitored by TLC using ethyl acetate: hexane (1:9) as eluent. The solvent was removed and the residue was added to crushed ice. The solid precipitates obtained were collected by filtration and purified by recrystallization from ethanol to get pale yellow solid product. Yield: 78%. Other anils were synthesized by the same method as described above.

General procedure for the synthesis of compounds 7a-j
A mixture of 4-((2-(arylidine amino)-4-phenyl thiazol-5-yl)thio)-2H-chromen-2-one (0.0045 mol) and thioglycolic acid (0.63 mL, 0.0090 mol) in DMF (N,N-dimethylformamide) was refluxed for 12 hrs. Water formed azeotropically, was removed by Dean-stark apparatus, Progress of the reaction was monitored by TLC using ehtylacetate: hexane (1:9) as eluent. After the completion of reaction it was poured into cold water, and treated with 10% NaHCO 3 to remove unreacted acid. The solid obtained was filtered, dried, and recrystallized from alcohol to get the title compound. Similarly, other thiazolidinones were prepared by the same method and their analytical data are given in Table-1. International Letters of Chemistry, Physics and Astronomy Vol. 51

In vitro antibacterial activity
In this series, we have synthesized a series of compounds containing thiazolidinyl-thiazole fused motif with coumarin through sulphur bridge. Functionalization has been done on phenyl nucleus of thiazolidinone ring to get various compounds. It has been observed that the test compounds (7a-j) exhibited interesting antibacterial activity ( Table 2), however with a degree of variation. The chloro group containing final compounds i.e. 7b and 7d showed very good potency against specific bacterial strain. The final derivatives containing electron withdrawing nitro group i.e. 7h and 7j exhibited superior inhibition profile for the selected bacterial strains. On the other hand significant deviation of activity has been observed against Gram-negative strains where the unsubstituted phenyl ring containing thiazolidinone compounds i.e. 7a exhibited higher inhibition against the bacterial strain P. aeruginosa. Rest of the compounds exhibited moderate to poor activity.

In vitro antifungal activity
Antifungal activity data ( Table. 3) showed that the final compound 7a exhibited virtuous inhibition against the fungal strain A. clavatus. Also compounds 7b, 7c, 7i, and 7j showed good inhibition against C. albicans, A. niger and A. clavatus. Rest of the compounds appeared with moderate to poor activity profile.
International Letters of Chemistry, Physics and Astronomy Vol. 51