Quinoline Derivatives as Potential Antimicrobial Agents
Article in ChemistrySelect · April 2020
DOI: 10.1002/slct.201904455
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z Medicinal Chemistry & Drug Discovery
Synthesis and Biological Evaluation of New 1,2,3-Triazolyl- Pyrazolyl-Quinoline Derivatives as Potential Antimicrobial Agents
Prashant P. Thakare,
[a]Abhijit D. Shinde,
[a]Abhijit P. Chavan,*
[a]Narendra V. Nyayanit,
[b]Vivek D. Bobade,
[c]and Pravin C. Mhaske*
[a]A new series of 4-{1-phenyl-4-[(4-phenyl-1,2,3-triazol-1-yl)meth- yl]pyrazol-3-yl}quinoline (7a-l) have been synthesized by a click reaction of 4-(4-(azidomethyl)-1-phenyl-1H-pyrazol-3-yl) quinoline (5a-d) with a substituted ethynylbenzene. The newly synthesized 1,2,3-triazolyl-pyrazolyl-quinoline derivatives were evaluated for biological activity against Escherichia coli (NCIM 2574), Proteus mirabilis (NCIM 2388), (Gram negative strains), Bacillus subtilis(NCIM 2063),Staphylococcus albus(NCIM 2178) (Gram positive strains) and in vitro antifungal activity against Candida albicans(NCIM 3100) andAspergillus niger(ATCC 504).
Five 1,2,3-triazolyl-pyrazolyl-quinoline derivatives, 7d, 7 g, 7 h, 7k and 7 l exhibited good antifungal activity against A. niger with MIC 62.5μg/mL. The compounds 7 h, 7k and 7 l were further evaluated for ergosterol inhibition assay againstA. niger cell sample at 62.5μg/mL concentration. Upon analysis of the sterol inhibition assay, it was revealed that, the ergosterol biosynthesis has decreased in the fungal samples treated with the 1,2,3-triazolyl-pyrazolyl-quinoline derivatives. Thus antimi- crobial activity suggested that, these compounds could aid and assist in the development of lead compounds to treat microbial infections.
1. Introduction
Antimicrobial resistance has become one of the major issues which confront global health, food security, and development in the last few decades. Resistance to microorganisms, threaten
the efficient prevention and treatment of infections caused by bacteria, fungi, parasites and viruses. In the future, medical treatments like major surgery, organ transplantation, cancer chemotherapy and diabetes management can become high risk without the efficient use of antimicrobial drugs.[1,2]
The hybrid structure, including two and more bioactive pharmacophore scaffolds, is one of the leading tools used in the discovery of a new drug.[3]Pyrazole and its derivatives are potent medicinal scaffolds, and they exhibit a large spectrum of biological activities[4,5] against infectious diseases. They showed antibacterial and antifungal,[6–9] antitubercular,[10]
anticancer,[11] antioxidant,[12] anti-inflammatory and antipyretic[13] activities. Quinoline tethered azole hybrids are important pharmacophores that possess a wide range of biological activities.[14–24] The 1,2,3-triazole nucleus containing compounds are important pharmacophore for drug development[25,26] as they also exhibit significant biological activities.[27–35]
Pyrazole clubbed with other heterocycles have received much attention in recent years due to their importance in medicinal chemistry.[36] The bound quinoline-pyrazole, pyrazole-triazole and quinoline-triazole scaffolds containing heterocyclic compounds have received attention due to their potential antimicrobial activity (Figure 1). Quinoline clubbed with pyrazole has been reported for antibacterial,[37]
antifungal,[38] antitubercular,[39]anticancer,[40]activities. Pyrazol- yl-triazole were reported for antibacterial,[41]antifungal,[42,43]and anticancer[44] activities. Quinoline-triazole compounds were reported for antimicrobial[45,46] antitubercular[47] and antimalarial[48] activities. The biological importance and struc- tural modification of quinoline, pyrazole and 1,2,3-triazole have made them significant targets for new antimicrobial agents.
(Figure 1)
Owing to the significant biological activities of quinoline, pyrazole and 1,2,3-triazole derivatives and in continuation with our search for new pyrazole and 1,2,3-triazole as anti-infection agents,[49,50]we report herein the synthesis of 4-{1-phenyl-4-[(4- phenyl-1,2,3-triazol-1-yl)methyl]pyrazol-3-yl}quinoline deriva- tives as potential antimicrobial agents.
[a] P. P. Thakare, A. D. Shinde, Dr. A. P. Chavan, Dr. P. C. Mhaske
Post-Graduate Department of Chemistry, S. P. Mandali’s Sir Parashur- ambhau College, Tilak Road, Pune, India 411 030, (Affiliated to Savitribai Phule Pune University).
Fax: 91-Mumbai, 020-24332479 Tel: 91–020-24331978 E-mail: [email protected]
[email protected] [b] N. V. Nyayanit
Department of Zoology, S. P. Mandali’s Sir Parashurambhau College, Tilak Road, Pune, India 411 030, (Affiliated to Savitribai Phule Pune University).
[c] Prof. V. D. Bobade
Post-Graduate Department of Chemistry H. P. T. Arts and R. Y. K. Science College, Nashik India 422005 (Affiliated to Savitribai Phule Pune University).
Supporting information for this article is available on the WWW under https://doi.org/10.1002/slct.201904455
2. Results and Discussion
2.1. Chemistry
The retrosynthetic analysis (Figure 2) of the target compounds 7 a-l suggests that 1,4-disubstituted triazole ring can be achieved by the copper catalysed azide-alkyne cyclization reaction. The azide could be achieved by nucleophilic sub- stitution reaction on alcohol. While the methyl alcohol derivative can be obtained by reduction of the aldehyde group which can be easily generated on the pyrazole ring at 4- position by Vilsmeyer Haack reaction. The pyrazole ring could be easily obtained from 4-Acetyl quinoline upon reaction with phenyl hydrazine.
Following this retrosynthetic analysis, the synthetic route for 4-{1-phenyl-4-[(4-phenyl-1,2,3-triazol-1-yl)methyl]pyrazol-3- yl}quinoline derivatives7 a-lis presented in Scheme 1. 4-Acetyl quinoline1 a-eupon reaction with phenyl hydrazine cyclizes to form the pyrazole ring. Vilsmeyer Haack reaction with DMF/
POCl3 gave 1-phenyl-3-(quinolin-4-yl)-1H-pyrazole-4-carbalde- hyde 2 a-d. Aldehyde 2 a-d was subsequently reduced with sodium borohydride in methanol to yield (1-phenyl-3-(quinolin- 4-yl)-1H-pyrazol-4-yl)methanol 3 a-d. This quinoline-pyrazolyl alcohol 3 a-d was converted to a good leaving group on reaction with methyl sulphonyl chloride and triethyl amine in DCM which gave (1-phenyl-3-(quinolin-4-yl)-1H-pyrazol-4-yl) methyl methanesulfonate 4 a-d. Nucleophilic substitution of
the mesityl group with sodium azide in DMSO gave 4-(4- (azidomethyl)-1-phenyl-1H-pyrazol-3-yl)quinoline, 5 a-d. Azido derivatives, 5 a-d on copper catalyzed click reaction with aryl alkyne 6 a-c in the presence of Na-ascorbate, CuSO4.5H2O in DMF:Water (3 : 1) gave exclusively 1,4-disubstituted triazole ring and thus resulted in the target compounds of 4-{1-phenyl-4-[(4- phenyl-1,2,3-triazol-1-yl)methyl]pyrazol-3-yl}quinoline deriva- tives7 a-l. The structure of the newly synthesized 1,2,3-triazolyl- pyrazolyl-quinoline derivatives was predictable by spectral analysis. The yield and physical constant of compounds 7 a-l are presented in Table 1.
The 1H NMR spectrum of 4-(4-{[4-(4-methoxyphenyl)-1,2,3- triazol-1-yl]methyl}-1-phenylpyrazol-3-yl)quinoline, (7 c) showed signals at δ 3.74 and 5.36 that corresponds to –OCH3 and triazole-CH2-pyrazole group, respectively that confirmed the formation of 1,2,3-triazole. There were two singlets, which resonated atδ7.23 and 8.13 due to triazole and pyrazole ring protons, respectively. The aryl and quinoline protons appeared at δ6.83 to 8.95. The structure of compound7 c was further confirmed by 13C NMR analysis, appearance of signals in the aliphatic and aromatic region confirmed the formation 1,2,3- triazolyl-pyrazolyl-quinoline. The signals of a methoxy and a methylene carbon appeared at δ 54.28 (-OCH3) and 43.33 (pyrazole-CH2-triazole), respectively. The quinoline, pyrazole and triazole carbons resonated at δ 113.18 to 158.63 and confirmed the formation of compound 7 c. The structure of Figure 1.Representative biologically active pyrazole-triazole, quinoline-triazole, quinoline-pyrazole and new proposed analogues (7 a-l).
Figure 2.Retrosynthetic analysis of 1,2,3-triazolyl-pyrazolyl-quinoline analogues (7 a-l).
compound 7 c was further confirmed by HRMS data analysis, which showed a peak at m/z=459.1935 (M+H)+. The structure of the newly synthesized 1,2,3-triazolyl-pyrazolyl-quinoline derivatives was thus established accordingly.
2.2. Biological Evaluation 2.2.1. Antimicrobial activity
The newly synthesized 4-{1-phenyl-4-[(4-phenyl-1,2,3-triazol-1- yl)methyl]pyrazol-3-yl}quinoline derivatives,7 a-lwere screened for antibacterial activity against Gram-negative bacteriaE. coli and P. mirabilis and Gram-positive bacteria B. subtilis and S.
albususing the well diffusion method.[51–52] The standard drug Streptomycin was used as the reference and DMSO was used as the negative control. Also, in vitro antifungal activity[51,52]was performed against A. Candida and A. niger using the well diffusion method. The antifungal drugs, Fluconazole and
Ravuconazole were used for reference. All the test solutions were prepared in DMSO at 1000μg/mL concentrations and the wells were filled with 80μL (80μg) of the samples. The plates were incubated for a period of 24–48 hrs. at 37°C for bacterial strains and 48–72 hrs at 30°C for fungal strains, respectively.
After the incubation period, the antimicrobial activity was evaluated by measuring the zone of inhibition in mm using a measuring scale and the average was calculated. The experi- ments were carried out in 4 replicates. The result of antimicro- bial activity in the zone of inhibition (mm) was presented in Table 2 indicates some lead compounds having zone of inhibition is 14 mm and more.
The antimicrobial activity result analysis of 4-{1-phenyl-4- [(4-phenyl-1,2,3-triazol-1-yl)methyl]pyrazol-3-yl}quinoline deriv- atives revealed that, most of the synthesized compounds showed moderate to good activities againstP. mirabilisandB.
subtilis bacterial strains. They also showed good antifungal activity againstC. albicans andA. niger. To further investigate, Scheme 1.Synthetic route of compounds7 a-l
Table 1. Yield and physical constants of compound 7a-l
Compd. R R1 Yield[a]% M.p.°C Compd. R R1 Yield[a]% M.p.°C
7a H H 78 128-130 7 g 4-Cl H 84 116-118
7b H 4-F 75 140-142 7 h 4-Cl 4-F 80 120-122
7c H 4-OCH3 70 172-174 7i 4-Cl 4-OCH3 72 134-136
7d 4-Br H 84 162-164 7j 4-F H 72 210-212
7e 4-Br 4-F 76 168-170 7k 4-F 4-F 76 160-162
7f 4-Br 4-OCH3 78 138-140 7 l 4-F 4-OCH3 68 152-154
[a] Isolated yield.
compounds 7 a-l was screened for the determination of the minimum inhibitory concentration (MIC) with concentrations ranging from 500 to 3.90μg/mL. The in vitro antimicrobial MIC screening results of synthesized compounds 7 a-l has been presented in Table 3.
The antimicrobial analysis of 7 a-l revealed that the compounds 7 g, 7 i and 7 l showed good activity and com- pound 7 a showed moderate activity against P. mirabilis.
Compound7 gshowed moderate activity againstB. subtilisand compounds 7 c and 7 j showed moderate activity against S.
albus. All the tested compounds were found to be inactive againstE. coli.
The result of antifungal activity presented in Table 3 provides some lead compounds that showed good activity against A. niger.Notably, the compounds 7 d,7 g,7 h,7 kand 7 lrecorded two fold less activity againstA. nigerwith respect to the standard drug Ravuconazole.
Structure activity relationship analysis revealed that, amongst the 4-{1-phenyl-4-[(4-substituted phenyl-1,2,3-triazol-
1-yl)methyl]pyrazol-3-yl}quinoline, (7 a-c), compound7 a(R=H, R1=H) showed moderate activity against P. mirabilis, and compound7 b(R=H, R1=F) showed moderate activity against A. candida whilst compound 7 c showed moderate activity against S. albus. From compounds 6-bromo-4-{1-phenyl-4-[(4- substituted phenyl-1,2,3-triazol-1-yl)methyl]pyrazol-3-yl}
quinoline (7 d-f), the compound 7 d (R=Br, R1=H) showed good activity againstA. nigerwith MIC 62.5μg/mL, whereas it was less active against other tested strains. Compounds7 eand 7 f were found less active against all tested strains. Amongst the 6-chloro-4-{1-phenyl-4-[(4-substituted phenyl-1,2,3-triazol- 1-yl)methyl]pyrazol-3-yl}quinoline, (7 g-i), compound7 g(R=Cl, R1=H), reported good activity againstP. mirabilis, A. candida andA. nigerwith MIC 62.5μg/mL and moderate activity against B. subtilis. Compound7 h (R=Cl, R1=F) showed good activity against A. niger with MIC 62.5μg/mL. Compound 7 i (R=Cl, R1=OCH3) showed good activity against P. mirabilis and moderate activity against A. niger. From the compounds 6- fluoro-4-{1-phenyl-4-[(4-phenyl-1,2,3-triazol-1-yl)methyl]pyrazol- Table 2. Antimicrobial activity in zone of inhibition (mm) of compounds7 a-y
Comp. R R1 E. coli P. mirabilis B. subtilis S albus A. Candida A. niger
7 a H H 11.75 14.6 13.2 9.8 13.4 13.2
7 b H F 10.25 11.5 10.8 10.4 15 11.8
7 c H OCH3 10 13 13.4 16.5 14 12.2
7 d Br H 10.2 13.6 12.2 10.4 12.2 13.2
7 e Br F 10.4 12.8 11.4 9.2 12.8 13.2
7 f Br OCH3 9.4 13 11.2 9.2 11.6 10
7 g Cl H 9.8 16.6 14.8 10.6 18.6 17
7 h Cl F 8.8 12.6 13.4 11.6 12 16.4
7 i Cl OCH3 10.25 14 14 9 10.8 14.6
7 j F H 9.6 13.6 13 13.4 11.4 12.8
7 k F F 9.8 13 12 10.2 12.6 17.2
7 l F OCH3 9 14 13.8 10.2 11.8 15.4
Streptomycin 25.0 18.52 21.6 21.6 NA NA
Fluconazole NA NA NA NA 20.25 18.35
Ravuconazole NA NA NA NA 28.64 20.18
[a] The concentration of test compounds and reference=80μg/well NA=Not Applicable.
Table 3. Antimicrobial activity in MIC (μg/mL) of compounds7 a-l
Comp. R R1 E. coli P. mirabilis B. subtilis S. albus A. Candida A. niger
7 a H H >250 125 >250 >250 >250 >250
7 b H F >250 >250 >250 >250 125 >250
7 c H OCH3 >250 >250 250 125 >250 >250
7 d Br H >250 >250 >250 >250 >250 62.5
7 e Br F >250 >250 >250 >250 >250 >250
7 f Br OCH3 >250 >250 >250 >250 >250 >250
7 g Cl H >250 62.5 125 >250 62.5 62.5
7 h Cl F >250 >250 >250 >250 >250 62.5
7 i Cl OCH3 >250 62.5 250 >250 >250 125
7 j F H >250 >250 >250 125 >250 >250
7 k F F >250 >250 >250 >250 >250 62.5
7 l F OCH3 >250 62.5 250 >250 >250 62.5
Streptomycin 7.81 7.81 7.81 7.81 NA NA
Fluconazole NA NA NA NA 7.81 7.81
Ravuconazole NA NA NA NA 7.81 31.25
NA=Not Applicable
3-yl}quinoline (7 j-k), compounds 7 j (R=F, R1=H) showed moderate activity against S. albus, 7 k (R=F, R1=F) showed good activity against A. niger, compound 7 l showed good activity againstP. mirabilisandA. nigerwith MIC 62.5μg/mL.
It is worth mentioning that, amongst the twelve derivatives of 1,2,3-triazolyl-pyrazolyl-quinoline (7 a-l), five compounds7 d, 7 g,7 h, 7 kand 7 l were found to be two fold less active, as compared to Ravuconazole against A. niger. It was observed that derivatives having halogen atoms (Br, Cl and F) in the quinoline nucleus showed better activity than the unsubsti- tuted quinolone ring. This may be due to effective binding of these halogens with the receptor site. It was also noted that the fluoro and methoxy substitution in the phenyl ring has very little or no effect on the activity againstA. niger.
2.2.2. Ergosterol inhibition activity
Ergosterol is the major component of the fungal plasma membrane which maintains the functionality of a cell. The azole derivatives are known for the inhibition of fungal cytochrome P450 enzymes, responsible for the synthesis of ergosterol from lanosterol. The compound which disrupts ergosterol biosynthesis has the potential of antifungal activity.[53] Quantitative estimation of ergosterol biosynthesis inhibition along with MIC in a confirmatory way of determining antifungal activity. To find the probable mode of action of the synthesized 1,2,3-triazolyl-pyrazolyl-quinoline derivatives, com- pounds 7 h,7 k and 7 l were evaluated for the inhibition of ergosterol biosynthesis activity. A. nigerwas grown on potato dextrose broth with and without a compound at MIC concentration for 72 hrs. As described by Arthington-Skaggs et al.[54]and Breivik and Owades[55]ergosterol was isolated from the fungal cells by saponification, followed by the extraction of nonsaponifiable lipids with heptane. Ergosterol was identified by its unique spectrophotometric absorbance profile between 240 and 300 nm.
The spectrophotometric absorbance profiles between 240 and 300 nm (Figure 3) give the characteristic peaks of ergoster- ol at 265, 274 and 282 nm in control. These peaks were in agreement with absorption maxima of ergosterol.[56]In case of compound 7 h, no peaks were observed in comparison to
characteristics peaks of ergosterol in control. This suggests that ergosterol biosynthesis might be inhibited in fungal sample treated with7 h. In fungal samples treated with compounds7 l and7 k, there is decrease in absorbance at characteristic peak wavelength suggested the decrease in synthesis of ergosterol as compared to control. The reduction in ergosterol biosyn- thesis and disruption of sterol biosynthetic pathway was observed in the fungal samples treated with compounds7 l,7 k and7 hrespectively.
Conclusions
In this study, a series of 4-{1-phenyl-4-[(4-substituted phenyl- 1,2,3-triazol-1-yl)methyl]pyrazol-3-yl}quinoline derivatives (7 a-l) have been synthesized and evaluated for antibacterial and antifungal activities. The compounds 7 d, 7 g, 7 h, 7 k and 7 l exhibited good antifungal activity against A. niger. The plausible mode of action studies revealed that the antifungal action of the azole compounds was through inhibition of ergosterol biosynthesis pathways. It is concluded that, 6-chloro- 4-{1-phenyl-4-[(4-phenyl-1,2,3-triazol-1-yl)methyl]pyrazol-3-yl}
quinoline, 7 g was found to be more effective upon a broad spectrum of activity against P. mirabilis,B. subtilis,A. Candida andA. nigerstrains and need further confirmatory studies.
Supporting Information Summary
The supporting information contains detailed experimental procedures, characterization data and1H and13C NMR spectra.
Acknowledgements
The authors are thankful to the Central Instrumentation Facility, Savitribai Phule Pune University, Pune for the spectral analysis. A D Shinde is grateful to CSIR-India for award of SRF, Award No08/
319(000 4)/2017-EMR-1. Shikshana Prasaraka Mandali’s Bhide Foundation, Pune is also acknowledged for lending support with their biological activities.
Conflict of Interest
The authors declare no conflict of interest.
Keywords: Pyrazole · 1 · 2 · 3-Triazole · Quinoline · Click reaction·Antimicrobial activity.
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Submitted: November 22, 2019 Accepted: April 8, 2020
