Synthesis and Evaluation of Some 2 – Aryl – 3 – [ substituted pyridin – 2 – yl ]-amino / methylamino thiazolidin-4-ones

A series of compounds incorporating thiazolidinone moiety has been synthesized and screened for their antifungal activity. 2-Aryl-3-[substituted pyridin-2-yl]-amino/methylamino thiazolidin4-ones have been synthesized by cyclocondensation of [substituted pyridin-2-yl]-araldehydehydrazone and N-Methyl [substituted pyridin-2-yl]-araldehydehydrazone with mercapto acetic acid in dioxane. The initial reactants required for the synthesis were obtained by refluxing 2-hydrazino substituted pyridine and 2-[N-methylhydrazino]-substituted pyridine with different substituted aldehydes. These newly synthesized compounds were then screened for their fungicidal activity against Rhizoctina solani and Fusarium oxysporum. Structures of all these compounds were confirmed by 1H NMR, IR and mass spectrum analysis. Some compounds exhibited excellent fungicidal properties.


INTRODUCTION
The pyridine ring is associated with diverse biological activities viz: antibacterial,herbicidal, fungicidal and plant growth regulators [1][2][3][4][5][6][7] .Union of pyridine ring with N-containing heterocycles provide compounds of enhanced herbicidal activity 8 .The investigations of new pyrazine and pyridine derivatives showing antimicrobial activities have been carried out.They appeared to be of elevated activity towards the aerobes 9 .At 100 mgL -1 , bioassays indicated that some multi-substituted pyridine derivatives have good herbicidal activity on the roots of oilseed rape and barnyard grass 10 .
The thiazolidine ring by virtue of presence of toxophoric -N=C-S linkage and a cyclic >C=O function in the five membered ring is associated with diverse biological activities [11][12][13][14][15][16] .Reports pertaining to the pesticidal activities to the ring have also been reported [17][18][19] .Coumarin, thiazole and their respective derivatives have been reported to exhibit significant biological activity and are used as pharmaceuticals 20,21 .They are capable of imparting antimicrobial properties 22 .Amino and urea substituted thiazoles exhibited in vivo activity on duckweed (Lemna paucicostata) 23 .Keeping all the above facts it was worth interesting to synthesize compounds by incorporating pyridine ring with thiazolidinone ring in view to obtain the compound of better bioactivity.

EXPERIMENTAL
All the chemicals used were of analytical grade either BDH or E. Merck or Fluka and were used as received.The solvents were used after distillation.Melting points were taken in open glass capillaries and were uncorrected.IR spectra were recorded in KBr on a Perkin Elmer 881 spectrophotometer.The synthesis of this compound involves two steps.In step-I substituted pyridine hydrazide reacts with different substituted benzaldehyde in equimolar ratio to form intermediate hydrazones (I) which in step-II undergoes cyclocondensation with mercapto acetic acid to obtain the desired product.(II).
Other compounds of this type were synthesized similarly by taking aldehydes of different R 1 .
The analytical data of these compounds are recorded in Table 1.

Yield
The analytical data of these compounds are recorded in Table 2.

2-Aryl-3-[substituted pyridine-2-yl] methylamino thiazolidin -4-ones
In the synthesis of this series of compounds two steps were involved.Step -I involves the reaction of substituted pyridine hydrazide with different substituted benzaldehydes in equimolar ratio to an intermediate hydrazone (III) which in step-II undergoes cyclocondensation with mercapto acetic acid to form the desired product (IV).

Step-I:Synthesis of N-Methyl-N-[substituted pyridine-2yl] araldehyde hydrazones (III)
The title compound was prepared by refluxing a mixture of 2-[N-methylhydrazino]-3-triflouromethylpyridine (1.91g; 0.01M) and Other compounds of this series were synthesized similarly using different substituents R and R' as given below: The analytical data are presented in Table 3.
Other compounds were prepared similarly using various substituents R and R'.The analytical data of these compounds are recorded in Table 4.The synthesis of compounds I, II, III and IV is given in Scheme 1.
Antifungal Screening: All the test chemicals were dissolved in acetone and subjected to the following assay.The standard malt agar medium was prepared by dissolving malt (20 g), dextrose (20 g) and agar (20 g) in 1 litre distilled water and sterilizing at 1.5 kg cm -2 for 20 minutes.After cooling it to about 40 0 C, a mixture of penicillium G and streptosulphate (5 mg each) was thoroughly mixed in order to prevent any bacterial contamination.The filter paper discs (5 mm diameter), Whatmann The percentage of inhibition calculated for selected compounds have been presented in Table 5.

Synthesis
All the synthesized compounds were obtained in good yield.The analytical data of the compounds listed in Tables 1

1 HSynthesis 2 -
NMR spectra were recorded on a Perkin-Elmer R-32 [90 MHz] spectrometer in CDCl 3 or DMSO-d6 .These analyses were carried out at RSIC, CDRI, Lucknow and at BHU Varanasi.The antifungal activities of the synthesized compound were evaluated against Rhizoctina solani and Fusarium oxysporum by filter paper disc method at 100ppm and 10ppm concentrations.The standard fungicide carbendazim was also tested under similar conditions for comparison.Aryl-3-[substituted pyridin-2-yl]-amino thiazolidin-4-one (II)

Yield: 2 .
Scheme 1 -4 are compatible with the composition of desired product.The spectroscopic results are further in support of the compounds.The IR spectra of the compounds demonstrated well resolved absorption bands for characteristic groups.The appearance of absorption bands at 3200 cm -1 and at 1620 cm -1 in the IR spectra of intermediate hydrazones are clearly assignable to -NH and C=N stretching vibration respectively.The absorption band at 1680-1720 cm -1 in the IR spectra of thiazolidinones is due to carbonyl function and the appearance of characteristic bands of C-S-N toxophore at 1250 cm -1 are in further conformity of the formation of thiazolidinones.Antifungal Activity All the tested compounds showed moderate to high fungicidal activity at 100 ppm concentration against the test fungi.The compounds II, IIc, IIm and IVb showed greater than 80% activity against Rhizoctina solani and Fusarium oxysporum.This high activity may be due to the presence of two or more chlorine atoms in the compound and/or due to the methoxy group at para position to the chlorine atom.Although, the compounds bearing hydroxy or carboxylic group also exhibit activity in between 70 to 75% against the fungi but it can be very reasonably concluded that the compounds having combination of -Cl and -OMe at para position exhibit much higher fungicidal activity than any other combination.It was further noticed that neither the replacement of substituent at N-group from -H to -CH 3 nor changing the position of -CF3 on pyridine ring from -5 to -3 made any remarkable effect on activity.Schematic presentation of synthesis of compounds I-IV is given in flow chart (Scheme 1).

Table 1 : Analytical data of synthesized compounds
(I a -Im)

Table 2 : Analytical data of synthesizedcompounds (IIa-IIm)
in methanol for two hours.The reaction mixture was cooled and poured into ice cold water.The resultant compound was filtered, washed, dried and recrystallized from aqueous ethanol.