Chinese Chemical Letters  2014, Vol.25 Issue (07):1073-1076   PDF    
Synthesis of N-arylquinolone derivatives bearing 2-thiophenoxyquinolines and their antimicrobial evaluation
Mehul B. Kanani, Manish P. Patel     
Department of Chemistry, Sardar Patel University, Vallabh Vidyanagar 388120, India
Abstract: A new series of 2-thiophenoxyquinolines based trifluoromethyl substituted N-aryl quinolone derivatives 8a-f and 9a-f have been synthesized via a one-pot multicomponent reaction. In vitro antimicrobial activity of the synthesized compounds was investigated against a representative panel of pathogenic strains. Compounds 8c, 9c and 9e exhibited comparable antimicrobial activity to first line drugs.
Key words: 2-Thiophenoxyquinoline     Trifluoromethyl     N-Aryl quinolone     Antimicrobial activity    
1. Introduction

Recently,multicomponent reactions (MCRs) have been shown to provide an efficient access to highly complex products in a single step. They have proven to be fast,convergent,atom-efficient reactions and often required effortless purifications through give generally high yields of products [1]. These reactions have emerged as a valuable tool in the synthesis of drug libraries because they have greater advantages over conventional strategies to synthesize biologically active compounds with significant structural diversity [2]. Consequently, designing novel MCRs to generate of diverse ‘‘drug-like’’ molecules has been the focus of many medicinal chemists.

Since the discovery of norfloxacin by Kogaet al. in the early 1980s [3],fluoroquinolones have been used extensively in clinic because of their extremely potent activity,rapid bactericidal effects,and low incidence of resistance development [4]. These antibiotics exhibit properties like excellent bioavailability and a relatively low incidence of adverse and toxic effects [5]. Also a large number of fluoroquinolone derivatives have been designed and synthesized,and structure activity relationship (SAR) has been accumulated. Cyclopropyl (Ciprofloxacin) and mono/difluorophenyl (Difloxacin or Temafloxacin) groups are generally considered the most favorable substituents at the N-1 position of the 4-quinolones [6, 7].

Over the past few years,we have been principally engrossed in the synthesis of quinolone-containing structures for biological evaluations [8, 9, 10, 11] on the fact that the quinoline moiety is found in a large variety of naturally occurring compounds diverse bioactivities such as antibiotic [12],antimalarial [13],antituberculosis [14],anti-HIV [15],anticancer [16],antihypertensive properties [17]. Additionally,some known fluoroquinolones antibiotics such as Ciprofloxacin,Delafloxacin,Sparfloxacin, Temafloxacin,Difloxacin and Norfloxacin are well known drugs. One of the best known drugs with a trifluoromethyl-quinoline nucleus,the antimalarial drug mefloquine is still being used today [18]. Also,a 5-quinolone derivative,2-(benzylthio)-7,7-dimethyl-5-oxo-5,6,7,8-tetrahydroquinoline-3-carbonitrile act as mGlur1 Modulator [19] (Fig. 1).

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Fig. 1. Example of biologically active quinoline derivatives.

In this study,we introduce substituted 2-thiophenoxyquinolines at the C-4 position and lipophilic groups,trifluoromethyl substituted aromatic ring at theN-1 position on 5-quinolone to probe biological activity. The synthesis ofN-aryl quinolone bearing 2-thiophenoxyquinolines derivatives was based on the assumption that the incorporation of more than one bioactive moiety into a single scaffold may produce novel heterocycles with good antimicrobial activity. 2. Experimental

All the reagents were obtained commercially and used without further purification. Solvents used were of analytical grade. All melting points were taken in open capillaries and were uncorrected.Thin-layer chromatography (TLC,on aluminum plates coated with silica gel 60 F254,0.25 mm thickness) (Merck,Darmstadt,Germany) was used for monitoring the progress of all reactions,purity and homogeneity of the synthesized compounds. UV radiation and/or iodine were used as the visualizing agents. Elemental analysis (% C, H,N) was carried out using a Perkin-Elmer 2400 series-II elemental analyzer (Perkin-Elmer,USA) and all compounds are within±0.4% of theoretical values. The IR spectra were recorded in KBr on a PerkinElmer Spectrum GX FT-IR Spectrophotometer (Perkin-Elmer,USA) and only the characteristic peaks are reported in cm-1. 1H NMR and 13C NMR spectra were recorded in DMSO-d6 on a Bruker Avance 400F (MHz) spectrometer (Bruker Scientific Corporation Ltd.,Switzerland) using solvent peak as an internal standard at 400 MHz and 100 MHz respectively. Chemical shifts are reported in parts per million (ppm). Mass spectra were scanned on a Shimadzu LCMS 2010 spectrometer (Shimadzu,Tokyo,Japan).

The synthetic approach adopted to obtain 6-(un)substituted-2-((4-(un)substituted phenyl)thio)quinoline-3-carbaldehydes 4a-f is shown in Scheme 1. The starting material 2-chloro-3-formyl quinolines 2a-b were prepared by the Vilsmeier-Haack reaction [20] from acetanilides1a-band were conveniently converted into 4a-f by nucleophilic displacement of chloro group at C-2 in1a-d with 4-(un)substituted thiophenols 3a-c in the presence of anhydrous k2CO3in DMF at 120°C for 2 h.

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Scheme 1. General synthetic route for the title compounds 8a-f and 9a-f.

The required &bate;-enaminones 5 were prepared by the reaction of 5,5-dimethylcyclohexane-1,3-dione with trifluorinated aromatic amines according to the literature procedures [10]. Subsequently, the one-pot three-component cyclocondensation of a series of 4a- f, &bate;-enaminones 5 and malononitrile 6 or isopropyl cyanoacetate 7 in ethanol containing a catalytic amount of piperidine afforded the targeted compounds 8a-f and 9a-f in good to excellent yields.

A plausible mechanism for the reaction is provided in Scheme 2. The heterylidenenitrile,containing an electron-poor C55C double bond is produced,from the Knoevenagel condensation between 4a-f and malononitrile 6 or isopropyl cyanoacetate 7 followed by dehydration. Michael addition of &bate;-enaminone 5 to the ylidenic bond forms an acyclic intermediate,which cyclizes by nucleophilic attack of the NH group on the cyano carbon. The subsequent tautomerisation gives the final products 8a-f and 9a-f .

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Scheme 2. Plausible mechanistic pathway for the synthesis of 8a-f and 9a-f biquinoline.

The MICs of synthesized compounds 2'-amino-7',7'-dimethyl-5'-oxo-2-((4-sub)phenylthio)-1'-(3-(trifluoromethyl)phenyl)-1',4',5',6',7',8'-hexahydro-[3,4'-biquinoline]-3'-carbonitrile 8a-f and isopropyl 2'-amino-7',7'-dimethyl-5'-oxo-2-((4-sub)phenylthio)-1'-(3-(trifluoromethyl)phenyl)-1',4',5',6',7',8'-hexahydro-[3,4'-biquinoline]-3'-carboxylate 9a-f against three Gram-positive and three Gram-negative bacteria as well as two fungi were carried out by the broth microdilution method according to National Committee for Clinical Laboratory Standards (NCCLS) [21]. 3. Results and discussion

The values of the MIC against microorganisms showed that these compounds have significant inhibitory effects. The antibacterial data indicate that the synthesized compounds are more effective against Gram-positive strains. It shows that lipophilic character of the molecules plays an important role in their antimicrobial effect. Among them compound 9c was found to be more active than the comparator against Gram-positive bacterium S. pneumoniae. Compounds 8a,8c,8d and 8d showed promising activity againstB. subtilis. Compounds 8b and 9d showed moderate activity against S. pneumoniae. Compounds 8a exhibited good activity towardC. tetani. Compound 8c,9e and 9f were found to be equipotent against Gram-negative bacterium S. typhi. Except compounds 8b and 9b(R1= H and R2 =CH3),all the compounds displayed good to excellent inhibitory effects againstC. tetani. Also, compounds 8c and 9e exhibited significant potency against Gram negative bacterium E. coli as benchmarked by ampicillin (MIC = 100ug/mL).

In vitro antifungal activity of the synthesized quinolyl-quinolone derivatives are summarized in Table 1. Compound 9d was endowed promising activity,while the compounds 8b and 9f showed moderate activity against A. fumigatus. Unfortunately, none of the synthesized compounds were found sufficiently potent in inhibiting fungal pathogen C. albicans.

Table 1
Antimicrobial activity results of compounds 8a-f and 9a-f against various microorganisms (MIC,mg/mL).
4. Conclusion

In conclusion,the aim of the present investigation was to design and synthesis of 5-quinolone derivatives by introducing substituted 2-thiophenoxyquinolines at the C-4 position and diversely trifluoromethyl substituted phenyl ring at N-1 position to probe antimicrobial activity. Modification of substituents on both 2-thiophenoxyquinolines ring and N-aryl quinolone ring with various electron donatig and electron withdrawing groups improved the activity. Compounds 8c,9c and 9e exhibited excellent antimicrobial activity. Finally,these compounds represent new scaffolds that could be further optimized to produce more potent and selective antimicrobial agents. Acknowledgments

The authors are thankful to Prof. H. S. Patel,Head,Department of Chemistry,Sardar Patel University for providing 1H NMR,13C NMR spectroscopy and research facilities. We are also thankful to PURSE central facility for mass spectrometry sponsored by DST, New Delhi,Vaibhav Laboratories,Ahmedabad,Gujarat,India for the FT-IR,SICART,Vallabh Vidyanagar,for elemental analysis and Dhanji P. Rajani,Microcare Laboratory,Surat,Gujarat,India for antimicrobial and antituberculosis screening of the compounds reported herein. One of the authors (M.B. Kanani) is grateful to UGC,New Delhi for Research Fellowship in Sciences for Meritorious Students.

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