Novel N -4-Piperazinyl Ciprofloxacin-Ester Hybrids: Synthesis, Biological Evaluation, and Molecular Docking Studies
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ovel N-4-Piperazinyl Ciprofloxacin-Ester Hybrids: Synthesis, Biological Evaluation, and Molecular Docking Studies A. Shahbazia, H. Mostafavia,*, G. Zarrinib, and M. Mahdavib a
Department of Organic Chemistry and Biochemistry, University of Tabriz, Tabriz, 5166614766 Iran of Animal Biology, Faculty of Natural Science, University of Tabriz, Tabriz, 5166614766 Iran *e-mail: [email protected]
b Department
Received May 29, 2020; revised July 30, 2020; accepted August 6, 2020
Abstract—A series of novel N-4-piperazinyl ciprofloxacin-ester hybrids has been synthesized and the structures confirmed by 1H and 13C NMR, FT-IR spectral data, and elemental analysis. The products have been tested in vitro for their antibacterial activity against six bacterial strains (MRSA, Staphylococcus epidermidis, Bacillus subtilis, Escherichia coli, Salmonella enterica, and Klebsiella pneumoniae) and have demonstrated good antibacterial activity with MIC values range 6.25–200 μg/mL. Antifungal and cytotoxic activities of the products have been tested against Candida kefyr and human leukemia K562 cell line, respectively. All compounds inhibit growth of K562 cells more efficiently than the parent ciprofoxacin in a dose- and duration-dependent way. Molecular dokking studies performed for the compound 3i indicates that similarly to ciprofloxacin it can act as an inhibitor of S. aureus DNA gyrase. Keywords: antibacterial, anticancer, molecular docking, quinolone, ciprofloxacin
DOI: 10.1134/S1070363220080265 INTRODUCTION Ciprofloxacin is a second-generation fluoroquinolone antibiotic that is widely used for treatment of a variety of infections. The widespread use and misuse of fluoroquinolones have resulted in development of bacterial resistance to those which made it necessary to produce novel drugs with the broad-spectrum of antibiotic activity, high potency and few side effects [1]. Modification of the structures of existing fluoroquinolone agents is a fruitful strategy to overcome the resistance effect and increase their potency [2]. Nature of substituents in position C7 of fluoroquinolones has a considerable impact on their antibacterial potency, spectral characteristics, solubility, pharmacokinetics, bioavailability, safety, and the preferred target of those [3, 4]. Physicochemical properties of fluoroquinolones, such as charge, lipophilicity and molecular mass play a significant role in their penetration into the bacterial cell [5, 6]. Introduction of carboxymethyl in N4 position of the piperazine ring of ciprofloxacin can lead to its increased antibacterial activity [7]. Based on the above and in development of our ongoing research program of creating drug agents with high potency and broad-spectrum of antibiotic activity, we have synthesized various esters of N-4-carboxymethyl
ciprofloxacin and evaluated their biological properties. Various types of aromatic, heteroaromatic and monoterpene alcohols that demonstrated antibacterial or anticancer properties [8–12] have been used in the synthesis. Also the target compounds were test
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