Design and synthesis of ciprofloxacin-sulfonamide hybrids to manipulate ciprofloxacin pharmacological qualities: Potency and side effects

https://doi.org/10.1016/j.ejmech.2021.114021Get rights and content

Highlights

  • Synthesis of fluoroquinolone-sulfonamide hybrids involving triazene/amide linkers.

  • Structure modification on N of C7 substituent of ciprofloxacin with sulfonamides.

  • Topoisomerase IV and gyrase inhibitory activities of new hybrids were evaluated.

  • New hybrids showed lower CNS side effects and GABA expression than ciprofloxacin.

Abstract

Fluoroquinolones are a class of antibacterial agents used clinically to treat a wide array of bacterial infections. Although being potent, susceptibility to CNS side effects limits their use. It was observed that improvements in absorption, activity and side effects were achieved via modifications at the N atom of the C7 of the side chain. To meet the increasing demand for development of new antibacterial agents, nineteen novel ciprofloxacin-sulfonamide hybrid molecules were designed, synthesized and characterized by IR, 1H NMR and 13C NMR as potential antibacterial agents with dual DNA gyrase/topoisomerase IV inhibitory activity. Most of the synthesized compounds showed significant antibacterial activity that was revealed by testing their inhibitory activity against DNA gyrase, DNA topoisomerase IV as well as their minimum inhibitory concentration against Staphylococcus aureus. Six ciprofloxacin-sulfonamide hybrids (3f, 5d, 7a, 7d, 7e and 9b) showed potent inhibitory activity against DNA topoisomerase IV, compared to ciprofloxacin (IC50: 0.55 μM), with IC50 range: 0.23–0.44 μM. DNA gyrase was also efficiently inhibited by five ciprofloxacin-sulfonamide hybrids (3f, 5d, 5e, 7a and 7d) with IC50 range: 0.43–1.1 μM (IC50 of ciprofloxacin: 0.83 μM). Compounds 3a and 3b showed a marked improvement in the antibacterial activity over ciprofloxacin against both Gram-positive and Gram-negative pathogens, namely, Staphylococcus aureus Newman and Escherichia coli ATCC8739, with MIC = 0.324 and 0.422 μM, respectively, that is 4.2-fold and 3.2-fold lower than ciprofloxacin (MIC = 1.359 μM) against the Gram-positive Staphylococcus aureus, and MIC = 0.025 and 0.013 μM, respectively, that is 10.2-fold and 19.6-fold lower than ciprofloxacin (MIC = 0.255 μM) against the Gram-negative Escherichia coli ATCC8739. Also, the most active compounds showed lower CNS and convulsive side effects compared to ciprofloxacin with a concomitant decrease in GABA expression.

Introduction

Nowadays, the world faces a global crisis due to the emergence of multiple drug resistant bacterial strains which represent a serious threat to public health. This resistance gives rise to microbes that can overcome the prophylaxis or therapy longer than any other form. Diseases caused by infectious resistant bacteria, viruses and fungi remain a pressing problem worldwide that unless it is solved, we will reach 10 million deaths annually in 2050 [1,2].

In order to solve or slow down the emergence of resistance, combination therapy was one of the approaches that achieved some clinical success [3]. It depends on the combination of two or more antibiotics, inder the condition that they have different mechanisms of action, which will lessen the cell's ability to develop resistance [4]. However, the therapeutic effects in vivo will not necessarily correlate to in vitro results as the pharmacokinetic properties of drugs in combination are much likely to be varied [5,6].

Another winning strategy that was introduced in order to overcome the drawbacks of combination therapy is the design of hybrid antibacterial agents, it is based on the combination of two or more active structure units of antibiotics with different bacterial targets in a single molecular framework by one or more chemical bonds thus producing a potential weapon that will reduce their expected side effects. Also, hybrid strategies are popular for their effective role in preventing bacterial resistance with improved affinity, and efficacy compared with the parent drugs [2,[7], [8], [9]]. Since a single hybrid molecule targets bacterial cells through several modes of action, they are considered as new leads with complementary activities and/or multiple pharmacological targets. The newly designed hybrid molecule increases the opportunity to improve drugs' pharmacokinetic properties, toxicity profiles and to increase their retention [10,11]. Additionally, rationally designed linkers that connect two bioactive moieties may increase the chance to get better inhibition of both drug targets with decreased incidence of new resistance mutations, and may even overcome existing resistance mechanisms to individual drugs [12].

Fluoroquinolones (FQs) are one of the most prominent widely used classes of synthetic antibacterial agents in the treatment of several infectious diseases. This is because they offer many of the attributes of an ideal antibacterial combining high potency, broad spectrum of activity, good bioavailability, oral and intravenous formulations, high serum levels and a large volume of distribution indicating good concentrations in different tissues [13,14]. They play a key role in the treatment of urinary tract infections (UTI), upper and lower respiratory tract infections (RTI) and sexually transmitted diseases (STD). Beside their effects in curing skin, soft tissue, gastrointestinal, bones and joints infections [15,16]. They exert their bactericidal activity by targeting bacterial DNA gyrase and topoisomerase IV (Topo IV), where they bind to complexes that are formed between DNA and DNA gyrase or Topo IV forming DNA-enzyme-quinolone ternary complex. The produced complexes inhibit DNA replication and cell growth and are responsible for the antibacterial activity of fluoroquinolones [17].

In 1987, Ciprofloxacin which is considered one of the most popular drugs among the fluoroquinolones class was approved for clinical use. Recently, other related derivatives have been designed and synthesized. One approach, to generate new potent ciprofloxacin derivatives is by modifying N atom of the C-7 side chain through addition of a functional moiety [15]. This position acts as the most promising area for regulating drug characters and thus changes at this position can be introduced to upgrade potency, spectrum, absorption and safety of the parent drug [18,19]. Studies reported the importance of lipophilicity, which can be increased by adding substituents at this position, to ciprofloxacin antibacterial activity [20].

Unfortunately, quinolone therapy was correlated with frequent central nervous system (CNS) adverse effects including headache, dizziness, sleep disorders, agitation and scarcely convulsions. These effects are due to direct CNS interaction through binding of quinolones to ᵞ-aminobutyric acid (GABA) receptors in the brain, hence preventing normal binding of GABA, and thus resulting in decreased GABA inhibitory activity and increased CNS stimulation. Studies revealed that the substituent at position 7 has a prominent effect on the direct CNS interaction, where it was reported that the degree of GABA inhibition was high in ciprofloxacin and norfloxacin having unsubstituted piperazine at the 7 position, whereas substituting NH of piperazine with methyl as in ofloxacin markedly decreased the degree of GABA inhibition [21,22].

In the last 20 years, literature reported the synthesis of many fluoroquinolone hybrids. Roche developed Ro 23–9424, which is a hybrid of cephalosporin and quinolone. Ro 23–9424 showed broad and potent in vitro and in vivo antibacterial activities. As a result of this, new hybrids are produced like MCB3837 (oxaquin) and CBR-2092, these hybrids have been entered in human clinical trials, and may be used in clinical practice to struggle against various upcoming diseases [23] (Fig. 1).

Sulfonamides are synthetic antimicrobial agents that are popular for their use in the treatment of bacterial infections as well as fungal ones. Their stability, bioavailability, broad spectrum of activity, beside their ease of preparation nominate them to be incorporated in massive number of drugs and encourage their continuous study. Sulfonamides inhibit the bacterial enzyme dihydropteroate synthetase (DPS) in the folic acid pathway [24]. Many hybrid drugs incorporating a sulfonamide moiety with different antibacterial agents including fluoroquinolone were reported in the literature [[25], [26], [27], [28], [29]]. In 2000, Alovero et al. reported the synthesis of benzylsulfonamide-ciprofloxacin hybrids through direct coupling of the benzenesulfonylamido group to the C7 piperazinyl ring. The prepared compounds were 10-fold more active than ciprofloxacin against Staphylococcus aureus and Staphylococcus pneumoniae and showed much potent inhibitory activity against gyrase enzyme [28]. In view of the aforementioned findings and in our attempt to search for effective antibacterial agents with fewer side effects, herein we report the design and synthesis of new ciprofloxacin- sulfonamide hybrids using different linkers (3a-f, 5a-e, 7a-e and 9a-c) with the prime aim of improving ciprofloxacin qualities as increasing potency and lipophilicity, as well as decreasing its CNS side effects and decreasing the incidence of new resistance mutations Fig. 2. All the synthesized compounds were tested for their inhibitory activities toward DNA gyrase, DNA topoisomerase IV, minimum inhibitory concentration against Staphylococcus Aureus and Escherichia coli. Besides, the most active compounds were tested for CNS side effects mainly convulsive activity and GABA expression and compared to the ciprofloxacin as the reference drug. Molecular docking studies were performed at DNA gyrase and DNA topoisomerase IV active sites to study the binding modes of our target compounds.

Section snippets

Chemistry

In this paper, we aimed to synthesize four series of ciprofloxacin-sulfonamide hybrids through four different linkers. The synthetic pathways employed to prepare the target hybrids (3a-g, 5a-e, 7a-e and 9a-c) are depicted in Scheme 1, Scheme 2.

The first series 1-cyclopropyl-6-fluoro-4-oxo-7-(4-((4-(un)substituted sulfamoylphenyl) diazenyl)piperazin-1-yl)-1,4-dihydroquinoline-3-carboxylic acid 3a-f involved a diazenyl linker and was prepared through the reaction of ciprofloxacin with the

Conclusion

The current study describes the synthesis of nineteen ciprofloxacin-sulfonamide hybrid molecules 3a-f, 5a-e, 7a-e and 9a-c based on six sulfonamides (sulfanilamide, sulfadiazine, sulfaquinoxaline, sulfamethoxazole, sulfaclozine and sulfaguanidine). They were evaluated for their in vitro inhibitory activity against DNA topoisomerase IV and DNA gyrase. Against DNA topoisomerase IV, six ciprofloxacin-sulfonamide hybrids (3f, 5d, 7a, 7d, 7e and 9b) showed potent inhibitory activity with IC50 range:

General methods

All reagents are purchased from Sigma-Aldrich or Alfa Aesar and used without further purification. The starting material 1-cyclopropyl-6-fluoro-4-oxo-7-(piperazin-1-yl)-1,4-dihydroquinoline-3-carboxylic acid (Ciprofloxacin) was purchased from Memphis pharmaceuticals and used without further purification. Melting points are uncorrected and were carried out by open capillary tube method using Stuart SMP3 melting point apparatus (United Kingdom). IR spectra were recorded using Shimadzu Infrared

Declaration of competing interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

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