SYNTHESIS, CHARACTERIZATION AND BIOLOGICAL EVALUATION OF SUBSTITUTED 1,3,4-OXADIAZOLE DERIVATIVE: DERIVED FROM CIPROFLOXACIN

Objective: The purpose of this research is synthesized and evaluates different derivatives of oxadiazole. 
Methods: A novel series of substituted 1,3,4-oxadiazole derivative were synthesized by condensing different amine with 1-cyclopropyl-6-fluoro-7- (piperazin-1-yl)-3-(5-thioxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)quinolin-4(1H)-one (III) in the presence of formaldehyde. The structure of these novel synthesized compounds was characterized on the bases of physicochemical and spectral analysis. The title compounds (IVa-h) were screened for antibacterial activity by disc diffusion method. 
Results: Substituted 1,3,4-oxadiazole derivative was synthesized, characterized, and evaluated for antibacterial activity. Compounds IVa, IVd, IVe, IVf, and IV h showed enhance activities then ciprofloxacin against all Gram-positive and Gram-negative organisms. Compound IVe showed the highest activity against Staphylococcus aureus and compound IV showed the highest activity against Escherichia coli. 
Conclusion: The present study demonstrates the synthesis and characterization of 1,3,4-oxadiazole derivatives derived from ciprofloxacin. These compounds were evaluated for antibacterial activity against different Gram-positive and Gram-negative organism. In some cases, antibacterial activity is found to be enhanced as compared to standard drug ciprofloxacin.


INTRODUCTION
Chemical modification of bioactive components is one of the most common approaches in drug discovery and development with an improved therapeutic effect. As resistance to antimicrobial drugs is widespread, there is an increasing need for the identification of novel structure leads that may be of use in designing new, potent, and less toxic antimicrobial agents.
In this paper, we have focused on the incorporation of 1,3,4-oxadiazole with ciprofloxacin in one framework. Oxadiazole ring was introduced to the carboxylic side chain and different amines were attached to oxadiazole. In some cases, antibacterial activity is found to be enhanced as compared to standard drug ciprofloxacin.
Ciprofloxacin is the first widely used quinolone with advanced systemic activity, marketed in 1987. The second-generation antibiotics, now called fluoroquinolones, have excellent activity against many Gram-negative bacteria. Fluoroquinolones constituted a significant advancement in the management of infectious diseases [16]. Ciprofloxacin is used for the treatment of urinary tract infection [17], prostatitis [18], continuous ambulatory peritoneal dialysis infection [19], antitumor activity [20], etc.
Ciprofloxacin is found to be an important antibacterial agent. Keeping this in view, it was thought worthwhile to design the synthesis of title compounds, wherein the biological activity of ciprofloxacin is enhanced by 1,3,4-oxadiazole.

METHODS
Chemicals used in this synthetic work were purchased from S.D. Fine-Chem Ltd., Mumbai, and Sigma-Aldrich, India (Merck). Solvents except laboratory reagent grade were dried and purified according to the literature when necessary. The purity of the compounds was checked on thin-layer chromatography (TLC) plates using silica gel G as stationary phase and iodine vapors as a visualizing agent. Melting points of synthesized compounds were determined using Thermonik melting point apparatus and are uncorrected; IR spectra were recorded on Thermo Nicolet Spectrophotometer using KBr pellets. The proton nuclear magnetic resonance ( 1 H NMR) was recorded on Bruker Avance II NMR 500 MHz instruments using appropriated solvent and TMS as internal standard, chemical shifts are expressed as δ values (ppm).

Synthesis and spectral studies
The title compounds were synthesized as given in Scheme 1.

General procedure for the synthesis of derivatives (IVa-h)
To a solution of III (0.01 mol) in ethanol, a mixture of formaldehyde (0.015 mol) and a secondary amine (0.01 mol) in ethanol was added with stirring. After complete addition, the stirring was continued overnight at room temperature. The precipitated solids were filtered, washed with water, and recrystallized from methanol.
The result was compared with ciprofloxacin against seven different Gram-positive and Gram-negative organisms, i.e., Staphylococcus aureus, Bacillus subtilis, Staphylococcus pneumonia, Escherichia coli, Pseudomonas aeruginosa, Klebsiella pneumonia, and Salmonella typhi.
The result of antibacterial activity is collected in Table 2. The antibacterial activity of all newly synthesized derivatives was performed by disc diffusion method. The result was compared with ciprofloxacin against seven different Gram-positive and Gram-negative organisms and observed that compounds IVa, IVd, IVe, IVf, and IVh showed enhance activities then ciprofloxacin against all Gram-positive and Gramnegative organism. Compound IVg showed less potent activity than ciprofloxacin against all Gram-positive and Gram-negative organisms. Compounds IVb and IVc showed similar activity as ciprofloxacin against Gram-positive and Gram-negative organism. Compound IVe showed the highest activity against S. aureus and compound IV showed the highest activity against E. coli. Compounds IVb and IVc showed less active against S. typhi. In general, we can say that a total of five derivatives showed enhanced activities out of eight derivatives.
It was observed that when oxadiazole ring was introduced to the carboxylic side chain, significant enhancement of potency against the organism attached to ciprofloxacin.

CONCLUSION
A series of substituted 1,3,4-oxadiazole were synthesized according to Scheme 1 and the identity of the compounds was confirmed based on their melting point, TLC, IR, and 1H-NMR data. Antibacterial activity was carried out for all the synthesized compounds using disc diffusion method against various Gram-positive and Gram-negative organisms and ciprofloxacin was used as standard. Compounds IVa, IVd, IVe, IVf, and IV h showed enhance activities then ciprofloxacin against all Gram-positive and Gram-negative organisms. A total of five derivatives showed enhanced activities out of eight derivatives.