Research Articles

2019  |  Vol: 5(3)  |  Issue: 3 (May- June)  |  https://doi.org/10.31024/ajpp.2019.5.3.12
Synthesis, characterisation and biological evaluation of 1, 4 disubstituted 1, 2, 3 triazoles

Anis Ahmed Shaikh, Mohamad Asif, Prashant Netankar, Sayyad Sultan Kasim*

Post Graduate and Research Centre , Maulana Azad College, Aurangabad 431001 Maharashtra, India

*Address for Corresponding Author

Sayyad Sultan Kasim

Post Graduate and Research Centre, Maulana Azad College, Aurangabad 431001 Maharashtra, India


Abstract

Objective: The main objective of this research work was to synthesis the triazoles compounds by Click reaction and evaluated their antibacterial activities against gram positive and gram negative bacteria. Material and Methods: In this work 1,4-disubstituted 1,2,3-triazole  compounds (3a-3i) were  synthesized by Azide Alkyne Cycloaddition reaction  and characterized by IR,1H NMR and Mass spectroscopy. Further these compounds were evaluated for antibacterial activity against Bacillus substilusStaphylococcus aureus and Escherichia coli by using Ciprofloxacin as standard compound with various concentrations. Results: Among all the compounds (3a-3i) which were screened for antibacterial activity, the compounds 3c, 3d, 3e and 3i were found to be excellent antibacterial agents. Conclusion: The presence of electron donating, electron withdrawing and halogen groups plays an important role of biological activity of compounds.

Keywords: Alkyne, antibacterial activity, azide, click reaction, triazole


Introduction

Triazoles are important five membered nitrogen heterocycles having three nitrogen atoms and two carbon atoms in ring. 1,2,4 triazole moiety containing drugs are now a days available in market due to their excellent biological activity, it includes Fluconazole, hexaconazole, rizatriptan as shown in figure.

Figure 1. Bioactive 1,2,4 Triazole Compounds: (a) Fluconazole as Antimycotics, (b) Hexaconazole as Antifungal, (c) Rizatriptan as Antimigrane

Similarly 1,2,3 triazoles moiety containing drugs are excellent antimicrobial   (Phillips et al., 2009), antitubercular (Patpi et al., 2012), antiallergic (Buckle et al., 1984), antrifungal  (Ferreira et al., 2015), antiHIV  (Mohammed et al., 2016), anti-inflammatory  (Shafi et al., 2012), anticancer (Grana et al., 2006; Zhang et al., 2008 ) antiplatelet  (Palhegan et al., 2001), anti-Alzheimer (Monceaux et al., 2011) and antiviral (Joan et al., 1998) agents. The biologically important drugs containing 1,2,3 triazole moieties are shown in figure 2.

Figure 2. Examples of drugs containing 1,2,3 triazole moiety

 

In spite of biologically significant, the 1,2,3 triazoles are also found to have wide range of  agricultural (Gisi et al., 2002) and industrial (Kim et al., 2010)  applications. Due to simple structure and versatile applications of triazoles, several methods have been introduced for synthesis of 1,4 and 1,5 substituted triazoles compounds. The Husgen 1,3 dipolar cycloaddition reaction (Rostovtsev et al., 2002) is well known which produced 1,4 substituted triazole in presence of copper. The literature survey revealed (Holla et al., 2005) that 1,4 disubstituted 1,2,3 triazoles compounds  with electron donating, withdrawing and  halogens substituents plays an important role in bioactivity.   Therefore the  biological importance of 1,4 disubstituted 1,2,3 triazole with various  substituents on ring  inspired us to synthesis the substituted triazole  and evaluate their biological activity. By taking the factors like presence of haloges, electron donating and withdrawing groups, position of substituent we have performed the reaction between alkyne (1a-i) with azides (2a-i) catalysed by copper to give the 1,4 disubstituted 1,2,3 triazoles (3a-i) as shown in scheme 1. The resulting triazoles (3a-i) were then screened for antibacterial activity against Bacillus substilius, Staphylococcus aureus and Escherichia coli. The results obtained are presented in table 1.

Scheme 1. Synthesis of 1,4 disubstituted 1,2,3 Triazoles

 

Where

1a :  R1=H, R2=NO2        2a : R3=H,R4=H,R5=COCH3        3a :    R1=H, R2=NO2,

                                                                                                         R3=H,R4=H,R5=COCH3

1b :  R1=H, R2=OCH3     2b : R3=H,R4=H,R5=COCH3         3b :   R1=H, R2= OCH3

                                                                                                         R3=H,R4=H,R5=COCH3  

1c : R1= NO2, R2=H        2c : R3=H,R4=H,R5=COCH3         3c :    R1=NO2, R2= H

                                                                                                         R3=H,R4=H,R5=COCH3  

1d :  R1=H, R2=NO2       2d : R3=H,R4=H,R5= NO2,               3d :    R1=H, R2=NO2,

                                                                                                         R3=H,R4=H,R5= NO2,

1e :  R1= NO2 , R2=H      2e : R3=H,R4=H,R5= NO2,              3e  :    R1= NO2 , R2=H

                                                                                                         R3=H,R4=H,R5= NO2,

1f :  R1=H, R2=NO2        2f : R3= COCH3,R4=H,R5= H,         3f :     R1=H, R2=NO2,

                                                                                                         R3= COCH3,R4=H,R5= H

1g :  R1= NO2 , R2=H      2g : R3= COCH3,R4=H,R5= H,     3g :     R1= NO2 , R2=H

                                                                                                         R3= COCH3,R4=H,R5= H

1h :  R1=H, R2=NO2       2h : R3= NO2,R4= NO2,R5= H      3h :     R1=H, R2=NO2

                                                                                                         R3= NO2,R4= NO2,R5= H

1i :  R1= NO2 , R2=H      2i : R3= NO2,R4= NO2,R5= H       3i :      R1= NO2 , R2=H

                                                                                                         R3= NO2,R4= NO2,R5= H

Material and methods

The SD-Fine brand chemicals were used for this work. Melting points were determined in an open capillary by micro controller based melting point apparatus of Chemline company and are uncorrected. 1H NMR spectra were recorded on Bruker 400 MHz spectrometer by TMS as standard. Mass Spectra were recorded using Thermo Fischer mass spectrometer. IR Spectra were determined.

Synthesis of 1, 4 disubstituted 1,2,3-triazoles (3a-3i)

In a round bottom flask alkyne 1a-i (3 mmol) and azide 2a-i (3.5 mmol) were added in 1:1 mixture of ter-butyl alcohol and water (40 ml).Sodium Ascorbate (60 mg, 0.3 mmol, 1 ml of freshly prepared 3M solution in water) was added, followed by copper sulphate pentahydrate (7.5 mg, 0.03 mmol, 1 ml of 0.3 M solution in water). The resulting mixture was stirred at room temperature for 24 hrs the completion of reaction was confirmed by TLC. Then the reaction mixture was diluted with water, extracted with CH2Cl2, dried over Na2SO4, filtered and concentrated in vacuum to give a crude product, which was purified by column chromatography on silica gel to obtain pure product. The structures of desired products were confirmed by 1HNMR, Mass and IR Spectroscopy. 

Antibacterial evaluation

The stock solution of all the synthesised compound (3a-i) were prepared by dissolving them in DMSO. The antibacterial activity of compounds 3a-i and Ciprofloxacin was performed by close disc method (Bhalodia et.al, 2011). All the cultures were placed for maintenance on nutrient agar and incubated at 40 0 C overnight. After centrifugation and sterilisation 0.1 ml of bacterial culture solution was spread on nutrient agar plate. During the process Ciprofloxacin antibiotic disc was used as controller. The disc was then kept on nutrient agar plate and then incubated for 24 hours at 400C and zone of inhibition were measured in millimetre.  

Results and discussion

1,4 disubstituted 1,2,3-triazoles (3a-i) were successfully synthesised by click reaction and their characterisation results showed the acceptable results. The synthesized compounds were evaluated for their antibacterial activity and found that all the compounds showed good to moderate antibacterial activity. The compounds 3c, 3d, 3e and 3i were found to be excellent antibacterial agents (Table 1).

Table 1. Antibacterial activity of 1, 4 disubstitiuted 1,2,3 triazoles (3a-3i) (Zone of inhibition in millimetre at 300 μg/ml concentration)

Compounds

Concentration (μg/ml)

Bacillus subtillus

Staphylococcus aureus

Escherichia coli

3a

300

17

19

18

3b

300

16

15

-

3c

300

11

12

14

3d

300

14

15

14

3e

300

10

11

13

3f

300

19

16

19

3g

300

14

16

-

3h

300

-

17

15

3i

300

11

10

11

Ciprofloxacin

30 (μg/disc)

23

21

22

Compound 3a (1-{4-[1-(4-Nitro-phenyl)-1H- 1,2,3-triazol-4-ylmethoxy]-phenyl}-ethanone):

Yield 73 %, m.f. C17H14N4O4 , M.Pt.178-183 0 C. 1H NMR (CDCl3, 400 MHz): δ 2.5 (s, 3H), 5.3 (s, 2H), 7.9 (s, 1H), 7.1 (d, 2H), 7.9 (d, 2H), 8.4 (d, 2H) 9.0 (d, 2H),  LC–MS: m/z: 339.31 (M+ 1)+ , IR KBr cm-1  2915(CH3),1713(C=O),1597(NO2)1257(OCH2)

Compound 3b (1-{4-[1-(4-Methoxyphenyl)-1H- 1,2,3-triazol-4-ylmethoxy]-phenyl}-ethanone):

 Yield 91 %, m.f. C18H17N3O3 , M.Pt. 121 -127 0 C. 1H NMR (CDCl3, 400 MHz): δ 2.5 (s, 3H), 3.8 (s, 2H),5.3 (s,2H), 7.0 (d, 2H), 7.1 (d, 2H), 7.6(s, 1H), 7.7 (d, 2H) 7.9 (d, 2H),  LC–MS: m/z: 324.34 (M+ 1)+ , ,IR KBr cm-1  2920(CH3),1719(C=O),1250(OCH2)

 Compound 3c (1-{4-[1-(Nitro-phenyl)-1H- 1,2,3-triazol-4-ylmethoxy]-phenyl}-ethanone):

Yield 89 %, m.f. C17H14N4O4, M.Pt.155-161 0 C 1H NMR (CDCl3, 400 MHz): δ 2.5 (s, 3H), 5.4 (s, 2H), 7.1 (d, 2H), 7.6 (d, 2H),7.7 (s,1H),8.1(d 1H), 8.2(d,2H),8.3 (m, 1H), 8.6 (s, 1H),  LC–MS: m/z: 339.31 (M+ 1)+ , IR KBr cm-1  2931(CH3),1775(C=O),1696(CH=CH)

Compound 3d (1-(4-Nitro-phenoxymethyl)-1-(4-nitro-phenyl)-1H-1,2,3 triazole):

Yield 69 %, m.f. C15H11N5O5, M.Pt.210-216 0 C 1H NMR (CDCl3, 400 MHz): δ 5.4 (s, 2H), 7.1 (d, 2H),7.5 (d,2H), 7.8 (s, 1H), 7.9 (d, 2H), 8.4(d, 2H), LC–MS: m/z: 342.18 (M+ 1)+ , IR KBr cm-1   1720,(CH=CH),1590(NO2),1255(OCH2)

Compound 3e (1-(3-Nitro-phenoxymethyl)-1-(4-nitro-phenyl)-1H-1,2,3 triazole):

Yield 81 %, m.f. C15H11N5O5, M.Pt.163-167 0 C 1H NMR (CDCl3, 400 MHz): δ 5.4 (s, 2H), 7.1-7.6 (m, 4H), 7.8 (d, 2H),7.7(s,1H), 8.3(d, 2H), LC–MS: m/z: 342.18 (M+ 1)+ , IR KBr cm-1    1713(CH=CH),1574(NO2)1260(OCH2)

Compound 3f (1-{2-[1-(4-Nitro-phenyl)-1H- 1,2,3-triazol-4-ylmethoxy]-phenyl}-ethanone):

Yield 73 %, m.f. C17H14N4O4, M.Pt.127-131 0 C 1H NMR (CDCl3, 400 MHz): δ 2.6 (s, 3H), 5.4 (s,2H),7.0-7.5 (m,4H), 7.4(d,2H),7.7(s,1H), 8.4(d, 2H), LC–MS: m/z: 339.31 (M+ 1)+ , IR KBr cm-1  2913(CH3),1725(C=O),1305(N-O)

Compound 3g (1-{2-[1-(3-Nitro-phenyl)-1H- 1,2,3-triazol-4-ylmethoxy]-phenyl}-ethanone):

Yield 82 %, m.f. C17H14N4O4, M.Pt.137-143 0 C 1H NMR (CDCl3, 400 MHz): δ 2.6 (s, 3H), 5.4 (s,2H),7.0-7.7 (m,4H), 8.1-8.6(m,3H),7.7(s,1H), 8.6(s, 1H), LC–MS: m/z: 339.31 (M+ 1)+ , IR KBr cm-1  2940(CH3),1712(C=O),1561(NO2)

Compound 3h (4-(2,3-Dinitro-phenoxymethyl)-1-(4-nitro-phenyl)-1H-1,2,3-trizole):

Yield 63 %, m.f. C15H10N6O7, M.Pt.171-175 0 C 1H NMR (CDCl3, 400 MHz): δ 5.6 (s,2H),7.8 (d,2H), 8.1-8.4(m,3H),8.9(d,2H), LC–MS: m/z: 387.16 (M+ 1)+, IR KBr cm-11696(CH=CH),1539(NO2 ),1261(OCH2)

Compound 3i (4-(2,3-Dinitro-phenoxymethyl)-1-(3-nitro-phenyl)-1H-1,2,3-triazole):

Yield 63 %, m.f. C15H10N6O7 ,M.Pt.153-157 0 C 1H NMR (CDCl3, 400 MHz): δ 5.6 (s,2H),7.2 (s,1H), 7.5-8.4(m,3H),8.7(s,1H),7.7-8.7(m,3H) LC–MS: m/z: 387.16 (M+ 1)+ , IR KBr cm-1  1708(CH=CH),1570(NO2 ),1211(OCH2)

Conclusion

In conclusion we have synthesised the 1,4 disubstituted 1,2,3 triazoles by well known Click reaction and evaluate their antibacterial activities against Bacillus subtilus, Staphylococcus aureus and Escherichia coli and found that these are good antibacterial agents. Out of which, the compounds 3c, 3d, 3e and 3i showed excellent antibacterial activity, it is due to presence of nitro and carbonyl groups at different positions of ring which enhance the activity of these compounds as compared to other compounds.

Conflicts of interest

The author declares that there is no conflict of interest.

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