Optimized Synthesis of Novel Pyrazole Based Thiazole Derivatives and their Antimicrobial Evaluation

. A series of nitro pyrazole based thiazole derivatives compounds were synthesized by using solid base catalyst. The process was further optimized by setting up the solvent and catalyst ratio. The structures of these compounds were elucidated by spectral (IR, 1 H NMR, 13 C NMR, mass spectra) analysis. Synthesized compounds were screened for their in vitro antibacterial activity against the representative panel of Gram-positive ( Staphylococcus aureus, Streptococcus pyogenes ) and Gram-negative ( Escherichia coli, Pseudomonas aeruginosa ) bacteria. These compounds were tested for their inhibitory action against strains of fungi ( Candida albicans, Aspergillus niger, Aspergillus clavatus ).


Introduction
As rate of microbial infections is increasing and microorganisms are resisting the known antimicrobial agents, designing novel, potent and broad spectrum antimicrobial agents are still remained a major challenge for medicinal chemists.

Chemistry
To compare the efficienty of the catalyst, we had carried out a set of experiments by varying the reaction time, amounts of the catalysts and various solvents. The optimized conditions to prepare compound (3a-o) was achieved with 20 mmol catalyst and dry methanol as solvent. The details are given below in Table 1 and Table 2. The final compounds (5a-o) can be synthesized in three main reaction steps. According to Scheme 1, the key chalcone derivatives (3a-o) are used as precursors for the synthesis of title compounds (5a-o). These chalcone derivatives were prepared from 1 (3-(4-nitrophenyl)-1-phenyl-1H-pyrazole-4-carbaldehyde) and derivatives of acetophenone (2a-o). This reaction is modified Claisen Schmidt reaction which was further optimized. In second step, these chalcones (3a-o) were cyclise with thiosemicarbazide to get pyrazoline compounds (4ao). In the last step, compounds (4a-o) were further cyclised using ethyl bromoacetate in order to get targeted compounds (5a-o).

Spectral characterization of synthesized compound (5a-o)
IR spectrum of the compound 5a showed stretching vibrations at 3068, 3042 cm -1 due to the C-H stretching of aromatic ring. Aromatic carbon having C-H stretching of methylene group appeared at 2860 cm -1 .>C=O stretching of thiazolidinone ring appeared at 1690 cm -1 . Stretching vibration at 1578 cm -1 revealed the presence of >C=N-group in the compound 5a. >C=C-stretching of aromatic ring appeared at 1532 cm -1 . Asymmetric and symmetric stretching appeared at 1485 cm -1 and 1351 cm -1 is due to the -NO 2 group. 1 H NMR spectra of compound 5a showed a singlet at δ = 8.32 ppm which is the proof of =CH-N<proton in pyrazoline ring. Aromatic proton expressed multiplet values between δ=6.86-8.21 ppm. Functional group =CH-N< of pyrazoline ring appeared as doublet of doublet at δ=6.09 ppm. Protons of -S-CH 2 -gave a sharp singlet at δ=4.11 ppm. Lastly-CH 2 -protons of pyrazoline ring appeared as two different doublet of doublet signals at δ=3.91 ppm and at δ=3.42 ppm.   3-(4-nitrophenyl)-1-phenyl-1H-pyrazole-4-carbaldehyde (0.75 mol) and acetophenone (0.75 mol). b. All reactions were refluxed in ethanol till completion as indicated by TLC.

Scheme 1 Synthetic route for preparation of title compounds (5a-o)
International Letters of Chemistry, Physics and Astronomy Vol. 66

Antibacterial activity
From the Table 3 it has been clearly seen that synthesized compounds (5a-o) showed significant activity against bacterial strains along with MIC values of reference compounds ciprofloxacin. Compound containing electron donating groups at para position (compound 5j, 5m and 5o) had shown optimum activity against the bacterial strains. When para position is replaced by electron withdrawing group (compound 5e and 5h) the activity was slightly decreased.

Antifungal activity
In comparison of the antifungal activity the case was altered. Compound containing electron withdrawing group at para position (compound 5e) had expressed excellent overall activity as compared to the standard drug nystatin. While compound 5m containing electron donating group at para position found to be a bit less active then compound 5e. The remaining compounds of the series possessed feeble antimicrobial activity.

Materials and method
The essential chemicals were purchased from E. Merck. Melting points were recorded on Gallenkamp apparatus and were left uncorrected. The completion of reaction was checked on aluminum-coated TLC plates 60, F 245 (E. Merck) using various solvent systems as mobile phase and visualized under ultraviolet (UV) light, or iodine vapor. Elemental analysis (% C, H, N) was carried out by a Perkin-Elmer 2400 CHN analyzer. IR spectra were also recorded on Perkin Elmer FT-IR L1280002 spectrophotometer. 1 H NMR and spectra were recorded on Varian Gemini 400 MHz and 13 C NMR spectra on Varian Mercury-400, 100 MHz in DMSO-d 6 as a solvent and tetramethylsilane (TMS) as an internal standard. Mass spectra were scanned on a Shimadzu LCMS 2010 spectrometer.

Synthesis of
were prepared according to the literature method [34].