The use of 4-thiazolidinone as chemical fertilizers to increase the yield of crops and pesticides to eliminate all kinds of parasites able to attack the cultivation is becoming more and more important because of the great problem facing the world to provide food to an increasing population [1] . Recently, 4-thiazolidinones derivatives exhibited a wide spectrum of biological medicinal and pharmacological properties such as antibacterial, antioxidant, and hypoglycemic activity [2] . Most of 4-thiazolidinones synthesized exhibited antifungal and antibacterial activity [3] [4] [5] . 4-Amino-antipyrine showed various important properties as an anti-inflammatory [6] , antimicrobial [7] and as an inhibitor of mild steel corrosion in HCl solution [8] . Also, it’s used to eliminate some metal ions as an antifungal agent [9] . Its interest that Schiff’s base analogs of 4-amino-antipyrine exhibited antibacterial and cytotoxic activities [10] . Because of these important results and variables observations, the present work prompted us to synthesize some new Schiff’s bases derived from condensation of 4-amino-antipyrine with aromatic aldehydes followed by cycloaddition with thioacetic acid to obtain the thiazolidin-4-ones in view of their an enzymatic as inhibition of purine metabolism enzymes caused by E. coli. It is known that E. coli strains do not cause disease, but virulent strains can cause gastroenteritis, urinary tract infections, neonatal meningitis, hemorrhagic colitis, and Crohn’s disease. Common signs and symptoms include severe abdominal cramps, diarrhea, hemorrhagic colitis, vomiting, and sometimes fever. Some strains of E. coli, for example, O157:H7, can produce Shiga toxin (classified as a bioterrorism agent). This toxin causes premature destruction of the red blood cells, which then clog the body’s filtering system, the kidneys, causing hemolytic-uremic syndrome (HUS). For these reasons, we focused on synthesize some compounds act as inhibitors for E. coli [11] .

The Schiff’s base of 4-amino-antipyrine is a group of systems showed a wide range of biological activities having the azomethine (-N=CH-) active pharmacophore, which plays major roles in their bio-active properties [10] . Also, the presence of cyclic (NCS-C=O) group in thiazolidin-4-ones often enhances those biological and pharmacological properties [12] [13] [14] [15] . Similarly, condensation of 4-aminoantipyrine (1) with selective halogenated aromatic aldehydes and/or heteroaldehydes in refluxing EtOH, yielded the Schiff’s base 2a-f (Scheme 1).

The main aim of the present work is to synthesize of new 4-thiazolidinone bearing antipyrine moiety. Thus, cycloaddition reaction of mercaptoacetic acid with a Schiff’s bases 2a,e,f in refluxing with non-polar solvent as dioxane produced 3-(1'-phenyl-2',3'-dimethyl-5'-oxo-pyrazol-4'-yl) thiazolidin-4-ones (3) (Scheme 1).

Due to the order of nucleophilicity as S > O > N > C, the formation of compounds 3 may be by attack of S⁻ on a more electrophilic carbon of Schiff’s bases 2 followed by elimination of one molecule of H₂O (Figure 1).

On other hand, condensation of 4-aminoantipyrine (1) with 1,4-terphthaldehyde (2:1 by mole) in refluxed EtOH, afforded 4,4'-((1,4-phenylenebis (methaneylylidene))bis(azaneylylidene))bis(1,5-dimethyl-2-phenyl-1,2-dihydro-3H-pyrazol-3-one) (4) (Scheme 2).

Similarly, cycloaddition reaction of bis compound 4 with mercaptoacetic acid in refluxing dioxane furnished 2,2'-(1,4-phenylene)bis(3-(1,5-dimethyl-3-oxo-2-phenyl-2,3 -dihydro-1H-pyrazol-4-yl)thiazolidin-4-one) (5) (Scheme 2). Compound 5 also obtained from refluxing of compound 1 with 1,4-terphthaldehyde (2:1 by mole) in excess mercaptoacetic acid in abs. EtOH with a few drops of piperidine for a long time (Scheme 2).

Formation of compound 5 may be as a nucleophilic attack of S⁻ on a more electrophilic center of Schiff base 4 to give the thioacetic acid derivative, which upon refluxing gave the 4-thiazolidinone via losing of H₂O (Figure 2).

Former structure of the new compounds 2-5 established from corrected elemental analysis and their spectral data. The UV spectrum of compound 2a recorded the absorption band at λ_max 395 nm, indicated the formation of bio-conjugated systems (N=CH-). FT-IR spectra of Schiff bases 2 exhibited ῡ at 3175 - 3040 & 3035 - 3025 cm⁻¹ for stretching of aromatic CH, with an intense band at ῡ 1680 cm⁻¹ for C=O.

Scheme 1. Synthesis of compounds 2a-f and 3a,e,f.

Scheme 2. Synthesis of compounds 4 and 5.

Besides, presence of ῡ at 1590 - 1575 cm⁻¹ for C=N and 2980-2915 cm⁻¹ (stretching modes) with the deformation of aliphatic CH₃ at ῡ 1480 - 1440 cm⁻¹.

¹H NMR spectra of compound 2a display mainly of two sharp signals at δ 2.25 and 3.0 ppm for N-Me & C-Me protons. Also, it showed δ at 6.80 - 7.90 ppm, 8.2 - 8.5 ppm for aromatic protons with d,d of F-adjacent aromatic protons, besides, δ at 9.4 and 6.3 ppm attribute for CH=N protons. Moreover, mass fragmentation pattern of compound 3a recorded a molecular ion peak with the base peak at m/z 95 attribute to C₆H₄F ion (Figure 3).

UV absorption spectra of compounds 3 showed λ_max 275 nm, lower than the corresponding Schiff’s bases 2. IR spectra of both the compounds 3&5 showed the absorption bands at ῡ at 1720, 1680 cm⁻¹ for true C=O, with lacks of NH groups and or CH=N. ¹H NMR spectra of both the compounds 3&5 exhibited a new resonated signal at δ 4 - 3.5 ppm for the presence of CH₂ of 4-thiazolidinone with lacks of δ at 9.5 ppm of CH=N, which confirm that structures.

A ¹³C NMR spectrum of compound 4 recorded a different type of carbons which confirm that structure which gives us a good indication about that structure (Figure 4).

Also, mass fragmentation pattern of compound 4 showed the molecular ion peak at m/e 505 with the base peak at m/z 187 attribute to antipyrine ion (Figure 5 & Figure 6).

In addition, ¹³C NMR spectrum of compound 5 recorded mainly resonated signals at δ 119 - 118 ppm for cyclic C-S-C with δ at 70 and 170 ppm for CH₂ and C=O carbons.

Finally, mass fragmentation pattern of compound 5 recorded the molecular ion peak with the base peak at 187 m/z attribute to 1,5-dimethyl-3-oxo-2-phenylpyrazol ion (Figure 7 & Figure 8).

It is interest that, UV-absorption spectral study showed that λ_max of compound 4 is higher than λ_max of compound 5, which attribute to inhibition of the conjugated system formed of 4 to an isolated thiazolidinone moiety.

All the synthesized compounds evaluated as enzymatic inhibitors towards purine metabolic by bacteria. The antibacterial effects can be deduced through one of five fundamental mechanisms 1) inhibition of cell-wall synthesis 2) interference with the function of the cytoplasmic membrane 3) inhibition of protein synthesis and 4) interference with cytoplasmic metabolism and final 5) inhibition of nucleic acid fission. A possible mechanism of action is the formation of a type of complexes between different centers, one from the positive microorganisms and the other from the negative drug [16] . According to these finding, the present work aimed to synthesize some new Schiff’s bases and the corresponding thiazolidin-4-ones bearing antipyrine moiety and evaluate their enzymatic properties towards purine metabolic enzymes by bacteria. The new compounds tested at concentrations 32 and 131 μM in the case of E. coli (PNP) and 45 - 65 μM in the case of XAO [17] . Since the analogs Schiff’s base and the corresponding thiazolidin-4-ones, e.q. Allopurinol has therapeutic applications as known as potent inhibitors of the xanthine oxidase (XAO) Enzyme [18] . The IC₅₀ values are given in (Table 1), were insensitive to the concentration of the m⁷ Guo substrate, indicating a non-competitive type of the inhibition. Enzymatic phosphorolysis of m⁷ Guo assayed in 50 μM phosphate pH 7.0.

From the results obtained, we can be concluded that the tested compounds have indirect effects on the role of the tested organism. The high IC₅₀ values indicated that the good inhibition toward organism and vice versa low IC₅₀ values give good to moderate inhibition for purine metabolism enzymes.

The order of the inhibitionactivity is as 3a > 4 > 2a > 5 > 3f > 3e. A higher activity of compound 3a may attribute to the presence of F-atom and NCS of thiazolidin-4-one. Also, both compounds 4 and 5 refer to the presence of two thiazolidin-4-ones and two Schiff bases units.

The melting point recorded on Stuart scientific SMP3 (Bibby, UK) melting point apparatus and reported as uncorrected. A Perkin Elmer (Lambda EZ-2101) double beam spectrophotometer (190 - 1100 nm) used for recording the electronic spectra. A Perkin Elmer model RXI-FT-IR 55,529 cm⁻¹ used for recording the FT-IR spectra. A Brucker advance DPX 400 MHz using TMS as an internal standard for recording the ¹H/¹³C NMR spectra in CDCl₃ (δ in ppm). AGC-MS-QP 1000 Ex model used for recording the mass spectra. Elemental analysis performed on Micro Analytical Center of National Reaches Center-Dokki, Cairo, Egypt.

Some new 4-thiazolidinones and bis-compounds have been synthesized and derived from condensation of 4-aminoantipyrine with aromatic aldehyde followed by cycloaddition of thioglycolic acid in a non-polar solvent. Fluorine substituted thiazolidin-4-one moiety bearing antipyrine nucleus enhanced the enzymatic effects of the bacteria, which agreed with last results published [19] [20] [21] .

Many thanks for King Abdulaziz University, Jeddah, SA.

The authors declare no conflicts of interest regarding the publication of this paper.

Rahman, R.M.A., Alharbi, A.S. and Alshammari, N.A. (2019) Synthesis of Novel 4-Thiazolidinone and Bis-Thiazalidin-4-One Derivatives Derived from 4-Amino-Antipyrine and Evaluated as Inhibition of Purine Metabolism Enzymes by Bacteria. International Journal of Organic Chemistry, 9, 85-95. https://doi.org/10.4236/ijoc.2019.92008