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Journal of the Chilean Chemical Society

versión On-line ISSN 0717-9707

J. Chil. Chem. Soc. vol.61 no.1 Concepción mar. 2016

http://dx.doi.org/10.4067/S0717-97072016000100009 

SYNTHESIS AND ANTIMICROBIAL EVALUATION OF SOME NEW ASYMMETRICALLY SUBSTITUTED 4-ARYL- 2,6-DI(COUMARINYL) PYRIDINES

YOGITA L. CHOVATIYA, KAUSHIK N. KUNDALIYA, RAKESH R. GIRI and DINKER I. BRAHMBHATT*

Department of Chemistry, Sardar Patel University, Vallabh Vidyanagar 388120, Gujarat, India.

e-mail: drdib317@gmail.com


ABSTRACT

In the present work the synthesis of various 4-aryl-2-(coumarin-3-yl)-6-(4-methyl-3-phenyl coumarin-6-yl)pyridines (6a-i) and 4-aryl-2-(coumarin-3-yl)-6-(4-methyl-7-methoxy coumarin-8-yl)pyridines (7a-i) have been carried out by reacting 1-[2(H)-1-benzopyran-3-yl]-3-aryl-prop-2-en-1-ones (coumarinoyl chalcones) (3a-f) with appropriate coumarinoyl methyl pyridinium bromide salt 4 and 5 respectively. The target compounds were characterized by the IR,JH-NMR, 13C-APT and mass spectral analysis. Preliminary examination of target compounds as antimicrobial agents has been carried out using Broth dilutionmethod.

Keywords: Dicoumarinyl pyridines, Krohnke's reaction, antimicrobial activity, Broth dilution method.


INTRODUCTION

Over past few decades, resistance to antimicrobial agents among bacterial and fungal pathogens represent major global health problem in terms of morbidity and mortality1. Infections caused by resistant microorganisms of tenfail to respond to the standard treatment, resulting in prolonged illness, higherhealth care expenditures, and a greater risk of death. Thus, to conquer suchmultidrug resistant pathogens is challenging task in present era. Therefore, there is crucial need to discover and develop effective antimicrobial agentswith novel mechanisms of action and enhanced activity.

At present, coumarin represents one of the classes of versatile biodynamic agents, which are plentiful in plant kingdom and present as basic frame inpotent pharmaceutical compounds. The promising biological profile offeredby coumarin and its derivatives attributed to enormous diversity in substitutionpatterns on core scaffold. Coumarins play pivotal role in drug discoveryexhibiting various therapeutic actions such as anticoagulant2, antitumor3, anti-inflammatory4, hypolipidaemic5, vasorelaxant6, CNS depressant7, antioxidant8,anti-TB9 and antimalarial10 activities.

The interesting biological profiles of the coumarins make them adaptable targets in organic synthesis. Therefore, a detailed literature survey concerning the coumarins derivatives was carried out, through which we came across some3-(2-pyridyl) and 3-(3-pridyl)coumarins which are recognized for their usefulbioactivities viz. antifungal11, bactericidal12,fish toxicity13, moth proofing activity13and CNS depressant activity14. Encouraged from the significant biologicalessence of pyridine substituted coumarins, a series of new 3-(2-pyridyl)15,20,6-(2-pyridyl)21 and 8-(2-pyridyl)coumarins22 and their antimicrobial assessmentwere reported from our laboratory. Additionally, we also reported some newdicoumarinyl substituted pyridines23 in which synthesized coumarins adjoinedpyridine by 3rd position. Thus two cumarin moieties were having symmetricallinkage with pyridine moiety and the attachment was by (3,3) positions of coumarins as shown in figure 1.


Figure 1: Attachment of two coumarin moieties with pyridine by (3,3') linkage.

In glance of our previous study here in, we report the synthesis of dicoumarinyl substituted pyridine in which the coumarin moieties are attachedwith pyridine moiety by different positions i.e by (3,6) [A] and (3,8) [B] asshown in figure 2 respectively. Additionally, the synthesized compounds werealso evaluated for their antimicrobial potential.


Figure 2: Attachment of two coumarin moieties with pyridine by different positions i.e by (3,6') [A] and (3,8') [B].

RESULTS AND DISCUSSION

Chemistry

In the present work, various 4-aryl-2-(coumarin-3-yl)-6- (4-methyl-3-phenyl coumarin-6-yl)pyridines 6a-i and 4-aryl-2-(coumarin-3-yl)-6-(7-methoxy-4-methylcoumarin-8-yl) pyridines 7a-i have been synthesized by the reacting 1-[2(H)-1-benzopyran-3-yl]-3-aryl-prop-2-en-1-ones 3a-fwith 4-methyl-3-phenyl-6-coumarinoyl methyl pyridinium bromide salt 4 and 7-methoxy-4-methyl-8-coumarinoyl methyl pyridinium bromide salt 5 respectively in the presence of ammonium acetate and acetic acid underKrohnke's reaction condition24 as displayed in scheme 1.


Scheme 1: Synthetic pathway for the preparation of starting precursor 3a-f, target compounds 6a-1 and 7a-i.

The structures of all the synthesized compounds were confirmed on the basis of 1H-NMR; 13C-APT; IR; elemental analysis and representative massspectral data.

Amongst the compounds 6a-i, the IR spectrum of compound 6a exhibited the band at 3054 and 2924 cm-1 are due to aliphatic C-H and aromatic C-Hstretching vibrations. The characteristic strong and sharp band observed at1716 cm-1 for carbonyl stretching of δ-lactone ring of coumarin nucleus. Thebands observed at 1611 and 1457 cm-1 are due to aromatic C=C and C=Nstretching vibrations. A sharp and intense band observed at 761 cm-1 is due toC-H out of plane bending vibrations for mono substituted benzene ring. The 1H'NMR spectrum of compound 6a showed a singlet at 2.47 δ integrating forthree protons, which is due to methyl group protons. The signal for C''7-Happeared as doublet of doublet in the downfield region centered at 8.35 δ (J=8.8 and 1.6 Hz). The C3-H appeared as meta coupled doublet at 8.42 δ (J= 1.6Hz). A poorly resolved meta coupled doublet centered at 8.68 δ corresponds toproton attached to C3 of the pyridine ring. The C3-H of pyridine ring appearedin the downfield region due to peri effect of carbonyl group of 5-lactone. Thesignal for C'4 of the coumarin ring appeared in the most downfield region at 8.95 δ is due to peri effect of nitrogen Nr The remaining sixteen aromaticprotons appeared as a multiplet between 7.28-7.93 δ. The 13C-APT spectrum of compound 6a showed signals at 16.80 5 is due to methyl carbon. The signalappeared at 160.33 and 160.76 5 are due to carbonyl carbon of the δ-lactonering of two coumarin moieties. The signals for thirty non equivalent carbonspresent in the compound appeared between 116.46 δ to 156.00 δ. The massspectrum of compound 6a showed molecular ion peak at m/z 533.0 along withother fragments corresponding to molecular formula C36H23NO4.

Among the compounds 7a-i, the IR spectrum of compound 7a showed the band at 3057 and 2924 cm-1 are due to aliphatic C-H and aromatic C-Hstretching vibrations respectively. A strong band at 1724 cm-1 due to carbonylstretching of δ-lactone ring present in coumarin nucleus. The bands observedat 1611 and 1457 cm-1 are due to aromatic C=C and C=N stretching vibrations respectively. A sharp and intense band observed at 748 cm-1 is due to C-Hout of plane bending vibrations for mono substituted benzene ring. The1H-NMR spectrum of compound 7a showed a two singlet appeared at 2.69 and 3.90 δ integrating for three protons are of methyl group and methoxylgroup respectively. A singlet appeared at 6.21δ correspond to proton attachedto C3''-H. A meta coupled doublet observed at 8.59 δ (J= 1.6 Hz) is due to C3-Hproton of pyridine ring. A singlet appeared at 8.76 δ and integrating for oneproton is due to proton attached at C'4. The C'4 proton appears in the downfieldregion due to the peri effect of nitrogen. The remaining twelve aromaticprotons appeared as multiplet between 7.79-7.06 δ. The 13C-APT spectrum of compound 7a showed signals at 19.61 and 56.47 5 are due to methyl carbon and methoxyl carbon respectively. The signal appeared at 160.11 and 160.535 can be assigned to carbonyl carbon of the δ-lactone ring of two coumarinmoieties. The signals for the other aromatic carbons appeared between 108.33δ to 159.18 δ. The mass spectrum of compound 7a showed molecular ion peakat m/z 443.0 along with other fragments corresponding to molecular formulaC31H21NO4. The analytical data for the other derivatives were discussed inexperimental section.

The analytic and spectroscopic data of remaining synthesized compounds are given in the Supplementary Material to this paper.

Evaluation of Antimicrobial activity

All the synthesized compounds were screened for their in vitro antimicrobial activity by Broth dilution method25. All the newly synthesized compounds 6a-iand 7a-i exerted significant inhibitory activity against all the employed strains.Upon evaluating antimicrobial activity data in Table I, it was observed thatcompounds 7b and 7h (MIC= 62.5 μg/ml) exhibited superior activity compareto Ampicillin (MIC= 250 μg/ml) against gram positive bacteria S. aureus,while compounds 6e and 7g (MIC= 6.25 μg/ml) were found to be more potentthan Ampicillin (MIC= 250 μg/ml) against gram positive bacteria B. Subtilis.Against S. aureus, compounds 6d, 6h, 7a, 7e, 7g and 7i (MIC= 100 μg/ml) andagainst B. Subtilis compounds 6c, 7a and 7e (MIC= 100 μg/ml) demonstratedmore inhibition than Ampicillin (MIC= 250 μg/ml) and comparable activity toNorfloxacin (MIC= 100 μg/ml). Compounds 6a, 6c, 6e, 6g and 7f (MIC= 125 μg/ml) against S. aureus, while compounds 6a, 6b, 6f, 6g, 6h, 7b, 7d and 7i (MIC= 125 μg/ml) against B. Subtilis displayed better activity as compare toAmpicillin (MIC= 250 μg/ml). Moderate inhibition were shown by compounds6b, 6i, 7c and 7d (MIC= 200 μg/ml) against S. aureus than Ampicillin (MIC=250 μg/ml). Similarly, compound 6i (MIC= 200 μg/ml) displayed moderateactivity against B.subtilis. Compound 6f (MIC= 250 μg/ml) against S. aureusand compounds 7c, 7f and 7h (MIC= 250 μg/ml) against B. Subtilis showedcomparable activity to Ampicillin (MIC= 250 μg/ml).

In case of gram negative bacteria, compound 7b (MIC= 50 μg/ml) was displayed outstanding inhibitory effect against E. Coli compare to Ampicillin(MIC= 100 μg/ml) and comparable activity to Chloramphenicol (MIC= 50μg/ml). Against E. Coli, compounds 6d and 6i (MIC= 62.5 μg/ml) depictedremarkable activity compare to Ampicillin (MIC= 100 μg/ml). Compound 7h(MIC= 100 μg/ml) against E. Coli and compounds 6c, 6d and 7i (MIC= 100 μg/ml) against S. Typhi were found to equipotant to Ampicillin (MIC= 100 μg/ml).

Antifungal assessment data of target compounds revealed that Compounds 7e, 7h (MIC= 100 μg/ml) against A. Niger exhibited equal inhibition to Griseofulvin (MIC= 100 μg/ml) and Nystatin (MIC= 100 μg/ml). Compounds6d, 7b (MIC= 100 μg/ml) against C. Albicans exerted excellent inhibitioncompare to Griseofulvin (MIC= 500 μg/ml) and equal potency to Nystatin (MIC= 100 μg/ml). Against C. Albicans, compounds 6b and 6g (MIC= 200μg/ml); compounds 6h, 7d and 7i (MIC= 250 μg/ml) exhibited significant activity compare to Griseofulvin (MIC= 500 μg/ml).

Structure activity relationship established from the analysis of data reported in Table.1, lead to some general conclusions that mainly two structuralfeatures have influence on biological potential of synthesized compounds: 1)Substitution on phenyl ring. 2) Position of attachment of coumarin and pyridinemoieties to each other. Observations indicate that the compounds 6b, 6e, 6h,7b, 7e and 7h bearing weak electron releasing methyl group (R3=OCH3 showedoutstanding activity compare to parent targets. The increased efficiencyattributed to lipophilicity of methyl group. Introduction methoxyl group(R3=OCH3) exerted reduced activity compare to parent analogs. It is interestingto note that compounds 7a-i possess promising antimicrobial activity againstgram positive bacteria B. Subtilis and S. aureus, while compounds 6a-idemonstrate excellent activity against gram negative bacteria E. Coli and S.Typhi. We also noticed that among the compounds 6a-i and 7a-i, compoundsbearing 4-methyl-7-methoxycoumarin-8-yl moiety at 6th position of pyridinering, i.e. compounds 7a-i were more efficient compare to compounds 6a-i.


Table I. Antibacterial Activity MIC (μg/mL) of the compounds 6a-i and 7a-i.

 

EXPERIMENTAL SECTION

All the melting points were determined on p Thermocal 10 apparatus. All the IR spectra (KBr disc) were recorded on Shimadzu FT-IR 8400-S spectrometer. 1H-NMR and 13C-NMR spectra were recorded on BrukerAvance 400 spectrometer operating at 400 MHz for 1H-NMR and 100 MHzfor 13C-APT. The chemical shift (δ) is reported in ppm using chloroform-d asa solvent and calibrated standard solvent signal. Mass spectra were recordedon Shimadzu QP 2010 spectrometer. Elemental analysis was carried out onPerkin-Elmer 2400 C-H-N-S-O Analyzer Series-II.

1-[2(H)-1-benzopyran-3-yl]-3-aryl-prop-2-en-1-ones (coumarinoyl Chalcone) 3a-f3, 4-methyl-3-phenyl-6-coumarinoyl methyl pyridinium bromide salt 426 and 7-methoxy-4-methyl-8-coumarinoyl methyl pyridiniumbromide salt 527 were prepared according to literature procedure.

General procedure for the synthesis of 4-aryl-2-(coumarin-3-yr)-6-(4-methyl-3-phenyl coumarin-6-yl) pyridines compounds 6a-i:

A solution of 4-methyl-3-phenyl-6-coumarinoyl methyl pyridinium salt (4) (0.003 mol) in glacial acetic acid (15 mL) was charged in a roundbottom flask. Ammonium acetate (0.03 mol) and an appropriate 1-[2(H)-1-benzopyran-3-yl]-3-aryl-prop-2-en-1-ones (coumarinoyl Chalcone) 3a-f(0.003 mol) in glacial acetic acid (15 mL) were add to the solution in the flaskwith stirring . The reaction mixture was further stirred for 30 minutes and the nrefluxed for 8 hours. It was allowed to cool at room temperature. The reactionmixture was poured into ice-cold water and extracted with chloroform (3x30 ml). The organic layer was then washed with water and then dried overanhydrous sodium sulfate. The removal of chloroform under reduced pressuregave gummy material which was subjected to column chromatography usingsilica gel and chloroform- petroleum ether (60-80) (9:1) as an eluent to givecompounds 6a-i. The compounds were recrystallized from chloroform-hexane.

4-aryl-2-(coumarin-3-yl)-6-(4-methyl-3-phenyl coumarin-6-yl) pyridine (6a): White Solid, Yield 65%,; mp 282°C; Anal. Calcd. for C36H23NO4: C, 81.10; H, 4.38; N, 2.59%. Found: C, 81.04; H, 4.34; N, 2.63%;IR (KBr, υmax cm-1): 3054, 2924, 1716, 1611 and 1457; *H NMR (400 MHz,CDCl3): 5 2.47 (3H, s, CH3), 7.28-7.93 (16H, m, Ar-H), 8.35 (1H, dd, J =8.8 Hz and 1.6 Hz, C''7-H), 8.42 (1H, poorly resolved doublet, C''-H), 8.68(1H, poorly resolved doublet, C3-H ), 8.95 (1H, s, C'4-H ); 13C APT (100 MHz, CDCl3): 5 16.8 (CH3), 116.5(CH), 117.3(CH), 118.2(CH), 119.5(C),120.8(C), 123.7(CH), 124.7(CH), 125.3(C), 127.2(CH), 127.3(CH), 127.8(C),128.4(CH), 128.5(CH), 128.9(CH), 129.2(CH), 129.3(CH), 130.1(CH),130.2(CH), 132.3(CH), 134.4(C), 135.7(C), 138.4(C), 142.8(CH), 147.7(C),150.5(C), 151.7(C), 153.4(C), 154.0(C), 156.0(C), 160.3(CO) and 160.7 (CO).

General procedure for the synthesis of 4-aryl-2-(coumarin-3-yl)-6-(7-methoxy-4-methyl coumarin-8-yl)pyridines 7a-i:

A solution of 4-methyl-7-methoxy-8-coumarinoyl methyl pyridinium salt (5) (0.003 mol) in glacial acetic acid (15 mL) was charged in a round bottomflask. Ammonium acetate (0.03 mol) and an appropriate 1-[2(H)-1-benzopyran-3-yl]-3-aryl-prop-2-en-1-ones (coumarinoyl Chalcone) 3a-f (0.003 mol) inglacial acetic acid (15 mL) were add to the solution in the flask with stirring .The reaction mixture was further stirred for 30 minutes and then refluxed for12 hours. It was allowed to cool at room temperature. The reaction mixturewas poured into ice-cold water and extracted with chloroform (3x 30 ml).The organic layer was then washed with water and then dried over anhydroussodium sulfate. The removal of chloroform under reduced pressure gavegummy material which was subjected to column chromatography using silicagel and chloroform-petroleum ether (80-20) as an eluent to give compounds7a-i. The compounds were recrystallized from chloroform.

4-aryl-2-(coumarin-3-yl)-6-(4-methyl-7-methoxycoumarin-8-yl) pyridine (7 a):

White solid, Yield 60%; mp 280°C; Anal. Calcd. for C31H21NO4 C,78.90; H, 4.42; N, 3.01%. Found: C, 78.97; H, 4.49; N, 2.97%; IR (KBr, υmax cm-1):3057, 2923, 1724, 1611 and 1457; *H NMR (400 MHz, CDCl3): δ 2.69 (3H,s, CH3), 3.90 (3H, s, OCH3), 6.21 (1H, s, C3"-H), 7.79-7.06 (12H, m, Ar-H),8.59 (1H, d, J=2 Hz, C3-H), 8.76 (1H, s, C'4-H); 13C-APT (100 MHz, CDCl3): 519.61(CH3), 56.47 (OCH3), 108.33(CH), 110.34(C), 111.63(CH), 112.23(CH),114.31(C), 116.28(CH), 119.72(C), 121.36(CH), 124.09(CH), 124.50(CH),126.22(CH), 127.46(CH), 129.04(CH), 129.19(CH), 131.98(CH), 138.30(C),143.72(CH), 149.29(C), 150.81(C),150.88(C),151.48(C),152.21(C), 153.99(C), 157.10(C), 159.18(C), 160.11(CO), 160.53(CO).

Biological Assay

All the synthesized compounds were screened for their antimicrobial activity against two Gram-positive bacteria viz. Bacillus subtilis (MTCC441) and Staphylococcus aureus (MTCC 96), two Gram-negative bacteriaviz. Escherichia coli (MTCC 443) and Salmonella typhi (MTCC 98) and two fungi viz. Aspergillus niger (MTCC 282) and Candida albicans (MTCC 227).All MTCC cultures were collected from Institute of Microbial Technology,Chandigarh and tested against above mentioned standard drugs. MuellerHinton Broth was used as nutrient medium to grow and dilute the compoundsuspension for the test bacteria and Sabouraud Dextrose Broth was used forfungal nutrition. The size of the inoculum for the test strain was adjusted to108 colony forming unit (CFU) per milliliter by comparing the turbidity. In the present study, ampicillin and norfloxacin were used as standard antibacterialdrugs, whereas nystatin and griseofulvin were used as standard antifungal drugs.DMSO was used as a diluent to get the desired concentration of compounds totest upon standard bacterial strains. Each synthesized compound and standarddrugs were diluted obtaining 2000 μgmL-1 concentration, as a stock solution. Inprimary screening 1000, 500 and 250 μgmL-1 concentrations of the synthesizeddrugs were taken. The active synthesized compounds found in this primaryscreening were further diluted to obtain 200, 125, 100, 62.5, 50, 25, 12.5 and 6.250 μgmL-1 concentrations for secondary screening to test in a second set of dilution against all microorganisms. The lowest concentration, which showedno visible growth (turbidity) after spot subculture was considered as MIC foreach compound.

CONCLUSION

From present study, we summarized that employed synthetic strategy provide efficient route for the synthesis of asymmetrically substituted 4-aryl-2,6-di(coumarinyl) pyridines by Krohnke's protocol in good yield. Moreover the starting precursors were also easy to prepare from synthesis point of view.Antimicrobial study on target compounds concluded that the all the compoundsexerted promising activity against gram positive bacteria and gram negative.The target compounds showed feeble activity against fungal pathogens. Thecompounds 6d, 7b, 7g and 7h were most proficient members of the series.

Acknowledgements: The authors YLC, KNK and RRG are thankful to the Head, Department of Chemistry, Sardar Patel University for providing research facilities. Financial assistance to the authors from the University Grants Commission, New Delhi, India, is highly acknowledged.

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