Research Article

 

Synthesis, Characterization and Antibacterial Activity of Some Novel 1,2,3-Triazole-Chalcone Derivatives from N-Acetyl-5H-Dibenzo [b,f] Azepine-5-Carboxamide

 

Ruaa Wassim Adam 1*, Hutham Mahmood Yousif Al-Labban 1, Ahmed Abduljabbar Jaloob Aljanaby 2, Nadheema Abed Abbas 2 

 

1 University of Kufa, Faculty of Sciences, Department of Chemistry, Iraq.

2 University of Kufa, Faculty of Sciences, Department of Biology, Iraq.

 

* Corresponding authors. E-mail: abdulfadhil@uokufa.edu.iq  

 

Received: Jun. 6, 2018; Accepted: Feb. 5, 2019; Published: Apr. 8, 2019

 

Citation: Ruaa Wassim Adam, Hutham Mahmood Yousif Al-Labban, Ahmed Abduljabbar Jaloob Aljanaby, and Nadheema Abed Abbas, Synthesis, Characterization and Antibacterial Activity of Some Novel 1,2,3-Triazol-Chalcone Derivatives from N-Acetyl-5H-Dibenzo [b,f] Azepine-5-Carboxamide. Nano Biomed. Eng., 2019, 11(2): 99-110.

DOI: 10.5101/nbe.v11i1.p99-110.

 

Abstract

This work involves preparation of a series of 1,2,3-triazole derivatives. In the first step, the reaction of N- acetyl-5H-dibenzo [b,f] carboxamide with different benzaldehyde derivatives  to yield chalcone compounds A-D was carried out. In the second step, compounds A-D reacted with 4,4’ sulfonylbis(azidobenzene) (G) to produce  1,2,3-triazole derivatives A1-D1. All the prepared compounds were characterized by Fourier-transform infrared spectroscopy (FTIR) and melting point, some of them were characterized by proton nuclear magnetic resonance (1H-NMR), spectroscopy analysis. Biological activity test was done to evaluate the antibacterial activity of eight synthesized derivative compounds against two multi-drug resistant pathogenic bacteria isolated from patients infected with burn infection; Staphylococcus aureus and Pseudomonas aeruginosa. Three concentrations were selected 50, 100 and 150 mg/mL from each of the synthesized derivative compounds. The derivative compound D1 with the concentrations of 100 and 150 mg/mL exhibited excellent effect against P. aeruginoa with inhibition zone diameters of 28.10 ± 0.5 and 28 ± 0.05 mm, respectively.

 

Keywords: Chalcone; Azide; 1,2,3-Triazole; Biological activity; Anti-inflammatory

 

Introduction

Triazole is one of the most important heterocyclic compounds due to its wide range of pharmaceutical applications and synthetic media [1]. Wolff and co-workers discovered that 1,2,3-tetrazoline could be prepared by a 1,3-dipoler addition reaction, where the reactivity of alkenes in this type of cycloaddition was significantly influenced by the electronic properties of the double bond, and the reaction with electron deficient alkenes required long reaction time of weeks or even months [2]. Chalcone derivatives containing α,β-unsaturated carbonyl have a wide range of biological activities in medical and pharmaceutical drugs such as oxidation resistors, anti-inflammatory, antimicrobial, anti-tubercular and anticancer [3-7]. Synthesis and biological evaluation of 1,2,3-triazole tethered pyrazoline and chalcone derivatives were reported by Hussaini et al. It was indicated that some of the prepared compounds had significant activities against the prostate cancer cell line DU145 and caused accumulation of cells in G2/M phase and inhibited tubulin polymerization. Furthermore, these compounds reduced the mitochondrial membrane potential, and thereby indicating their ability to trigger apoptosis [8]. In the present study, novel 1,2,3-triazol-chalcone derivatives from N-acetyl-5H-dibenzo azepine-5-carboxamide were synthesized and characterized. Biological screening of the prepared compounds were also investigated.

 

Experimental

General synthesis procedure for chalcone derivatives (A)-(D) [9]

A solution of N-acetyl-5H-dibenzo [b,f] azepine-5-carboxamide (0.01 mol) in absolute ethanol (50 mL) was refluxed with various aromatic aldehydes in the presence of 10% NaOH (5 Ml) for 3 h; the concentration was cooled and poured onto ice. The solids thus obtained recrystallization ethanol solvent. The reaction showed by thin layer chromatography (TLC) that was completed by using benzene : methanol = 4 : 1 as a solvent. 1-(E)-N-(2(2-hydroxynaphthalen-1-yl)vinyl-5H-dibenzo [b,f] azepine-5-carboxamide (A). 2-(E)-N-(4-hydroxy-3-methoxystyryl)-5H-dibenzo [b,f] azepine-5-carboxamide (B). 3-(E)-N-(4-methoxystyryl)-5H-dibenzo [b,f] azepine-5-carboxamide (C). 4-(E)-N-(4-hydroxystyryl)-5H-dibenzo [b,f] azepine-5-carboxamide (D).

 

Table 1 Physical properties of A –D compounds

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

General synthesis procedure of 4, 4’sulfonylbis azidobenzene (G) [10]

Dapsone (0.001 mol) was dissolved in 10 mL of dilute HCl in a round bottomed flask. Reaction was cooled to 0 - 5 ℃. Sodium nitrite (0.002 mol) was added in small portion (4 portions) to the reaction mass by maintaining the temperature at 0 - 5 ℃, and the reaction was maintained for 15 min. A solution of sodium azide (0.002 mol) was added in a dropwise manner to the reaction mixture at 0 ℃. The reaction mixture was stirred for 20 min at 0 ℃. The product was extracted by using chloroform followed by washing with water up to neutral pH. Organic layer was dried with anhydrous sodium sulfate and then the solvent was removed to yield aryl azide derivatives with melting point (m.p.) = 188 - 190 ℃.

 

General synthesis procedure of 1, 2, 3-triazole derivatives (A1)-(D1) [10] 

A solution of unsaturated compounds (2 eq) dimethyl sulfoxide DMSO (5 mL) was added to the suspension of sodium ascorbate (1.2 eq) and CuSO4.5H2O (1.2 eq) in DMSO (4mL). The mixture was stirred for 10 min and the aryl azide was add to the mixture derivatives (2.2 eq). The mixture was heated to 50 ℃ with 28-h stirring. The reaction mixture was diluted with distilled water (30 mL), extracted with EtOAc (3 × 30 mL), dried over Na2SO4, and evaporated. Ethanol solvent was used in recrystallization, and TLC was used to prove that the reaction was completed by using benzene : methanol = 4 : 1 as a solvent. 1-N,N'-(1,1'-(sulfonylbis(4,1-phenylene))bis(4-(2-hydroxynaphthalen-1-yl)-4,5-dihydro-1H-1,2,3-triazole-5,1-diyl))bis(5H-dibenzo [b,f] azepine-5-carboxamide) (A1). 2-N,N'-(1,1'-(sulfonylbis(4,1-phenylene))bis(4-(4-hydroxy-3-methoxy phenyl)-4,5-dihydro-1H-1,2,3-triazole-5,1-diyl))bis(5H-dibenzo [b,f] azepine-5-carboxamide) (B1). 3-N,N'-(1,1'-(sulfonylbis(4,1-phenylene))bis(4-(4-methoxyphenyl)-4,5 dihydro-1H-1,2,3-triazole-5,1-diyl))bis(5H-dibenzo [b,f] azepine-5-carboxamide) (C1). 4-N,N'-(1,1'-(sulfonylbis(4,1-phenylene))bis(4-(4-hydroxyphenyl)-4,5-dihydro-1H-1,2,3-triazole-5,1-diyl))bis(5H-dibenzo [b,f] azepine-5-carboxamide) (D1).

 

Table 2 physical properties of A1- D1 compounds

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Biological activity test

Biological activity testing was done to evaluate the antibacterial activity of eight synthesized derivative compounds against two multi-drug resistant pathogenic bacteria isolated from patients infected with burn infection: Staphylococcus aureus (S. aureus) as gram-positive bacterium and Pseudomonas aeruginosa (P. aeruginosa) as gram-negative bacterium. These pathogenic bacteria were provided from medical laboratory of Faculty of Science, University of Kufa, Iraq. Antibacterial activity test was performed by using agar well diffusion method [12, 14]. Briefly, three concentrations were selected (50, 100 and 150 mg/mL) from each crud synthesized derivative compound. By crock-poorer (Oxoid, UK), four wells were made in Muller-Hinton agar surface (Oxoid, UK) swabbed with two pathogenic bacteria according to 0.5 McFarland turbidity. Forty µL of each dilution was transferred to each well and left at 20 oC for 2 h and incubated at 37 oC overnight. Triplicates were done for each test. The inhibition zone around each well was measured in millimeters.

 

Statistical analysis

SPSS V.8 windows software was used in statistical analysis to make comparisons between diameters of inhibition zones (mm) according to T-test. P-value < 0.05 was considered indicative of statistical significance [12].

 

Results and Discussion

Synthesis of chalcone derivatives (A)-(D)

The compounds (A)-(D) were synthesized by treatment of N-acetyl-5H-dibenzo [b,f] azepine-5-carboxamide with different benzaldehyde derivatives in the presence of ethanol and 10% NaOH. The prepared compounds (A)-(D) were characterized by Fourier-transform infrared spectroscopy (FTIR), and the band located at 1602 - 1683 cm-1 was due to the stretching vibration (C=C) of vinyl group of all compounds [15-17]. Other information of functional groups is also shown in Table 3.

 

Scheme 1 Equation of synthesis of chalcone derivatives (A)-(D).

 

Table 3 FTIR data of chalcone compounds (A)-(D)

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Synthesis of 4, 4’-sulfonylbis (azidobenzene) (G)

The compound (G) was synthesized by treatment of a Dapsone with HCl and NaNO2 to form diazonium salts at 0 - 5 oC, followed by reaction of diazonium salts with NaN3 at the same temperature. The FTIR spectra showed the typical azide (N3) group absorption at 2105 cm-1, and disappearance bands at 3328 and 3449 cm-1 due to amine group [18, 19].

 

Scheme 2 Equation of synthesis of 4, 4’-sulfonylbis (azidobenzene).

 

Synthesis of 1, 2, 3-triazoline derivatives (A1)-(D1)

The compounds (A1)-(D1) were synthesized by 1, 3-dipoler cycloaddition reaction catalyzed with CuSO4.5H2O of unsaturated compounds. The prepared compounds (A1)-(D1) were characterized by FTIR, which showed the disappearance of azide and two asymmetric absorption bands located at 1315 - 1334 cm-1 ascribing to the (SO2) [20-22] in azide. Other information of functional groups is listed as follows: Proton nuclear magnetic resonance (1H-NMR) spectrum (300 MHz, DMSO-d6 of compound (A) showed the following characteristic chemical shifts, 8.04 - 7.20 (m, 8H, Ar-H) (Fig. 5). 1H-NMR (301 MHz, DMSO-d6) of compound (D) showed δ 9.36 (s, 1H, NH-amide), 8.64 (s, 1H, CH=CH), 8.10 - 7.31 (m, 16H, Ar-H), 7.28 (d, 1H, OH), 6.62 (d, 1H, NH) (Fig. 6). 1H-NMR (301 MHz, DMSO-d6) of compound (B1) showed 7.86 - 7.02 (m, 34H, Ar-H), δ 9.34 (s, 2H, NH-amide), 8.53 (s, 2H, CH=N in triazole ring), 6.62 (d, 2H, OH), 5.59 (d, 2H, NH-ring), 3.70 (s, 6H, O-CH3) ( Fig, 7). 1H-NMR (301 MHz, DMSO-d6) of compound (D1) showed δ 8.53 (s, 2H, NH-amide), 7.99 - 7.32 (m, 34H, Ar-H), 7.04 (d, 2H, OH), 5.40 (d, 2H, NH-ring) (Fig. 8). Antibacterial activity test of derivative compounds (50 mg/mL) against S. aureus onto Muller-Hinton agar surface was conducted (Fig 9). Antibacterial activity test of derivative compounds (150 mg/mL) against P. aeruginosa onto Muller-Hinton agar surface was conducted (Fig. 10).

 

Scheme 3 Equation of synthesis of 1, 2, 3-triazoline derivatives (A1)-(D1).

 

Fig. 1 FTIR spectrum of amide compound.

 

Fig. 2 FTIR spectrum of compound (A).

 

Fig. 3 FTIR spectrum of compound (B1).

 

Fig. 4 FTIR spectrum of compound (D1).

 

Fig. 5 1H-NMR spectrum (300 MHz, DMSO-d6) of compound (A).

 

Fig. 6 1H-NMR (301 MHz, DMSO-d6) of compound (D).

 

Fig. 7 1H-NMR (301 MHz, DMSO-d6) of compound (B1).

 

Fig. 8 1H-NMR (301 MHz, DMSO-d6) of compound (D1).

 

Biological activity

According to inhibition zones’ diameters, derivative compounds (C1), (D) and (D1) had good antibacterial activity against pathogenic bacteria with high inhibition zones in all concentrations (50, 100 and 150 mg/mL) (Fig. 1 and 2). The derivative compound (D1) with concentrations of 100 and 150 mg/mL had excellent effect against P. aeruginoa with inhibition zone diameters of 28.10 ± 0.5 and 28 ± 0.05 mm, respectively. All inhibition zones diameters in mm against two pathogenic bacteria are shown in Table 4.

 

Table 4 Diameters of inhibitions zones of eight derivatives compounds against S. aureus and P. aeruginosa.

Derivative compound	Multi-drug resistant bacteria
	S. aureus		P. aeruginosa
	Conc. (mg/mL)	M ± SE (mm) R = 3	Conc. (mg/mL)	M ± SE (mm) R=3
A	50	1.03 ± 0.08	50	1.16 ± 0.2
	100	0.73 ± 0.1	100	0.70 ± 0.05
	150	3.36 ± 2.3	150	1.26 ± 0.2
A1	50	1.13 ± 0.1	50	1.60 ± 0.1
	100	2.26 ± 0.1	100	2.20 ± 0.4
	150	2.13 ± 0.1	150	2.40 ± 0.5
B	50	2.66 ± 0.6	50	1.63 ± 0.9
	100	1.80 ± 0.60	100	1.26 ± 0.34
	150	2.43 ± 0.8	150	2.33 ± 0.7
B1	50	2.30 ± 0.1	50	2.40 ± 0.2
	100	9.33 ± 0.4	100	11.06 ± 0.7
	150	9.83 ± 0.7	150	11.53 ± 1
C	50	17 ± 1	50	18.8 ± 0.4
	100	18.70 ± 1.85	100	18.70 ± 2.3
	150	20.53 ± 0.9	150	21.10 ± 1.2
C1	50	20.93 ± 0.6	50	21.93 ± 0.6
	100	23.33 ± 1.3	100	25.100 ± 1.6
	150	24.400 ± 0.9	150	25.60 ± 0.8
D	50	22.93 ± 1.2	50	24.63 ± 2.2
	100	24.66 ± 0.6	100	25.50 ± 1.2
	150	26.23 ± 0.2	150	27.20 ± 0.2
D1	50	25.46 ± 0.3	50	27.06 ± 0.1
	100	27.66 ± 0.6	100	28.10 ± 0.5
	150	27.56 ± 0.7	150	28 ± 0.05

Note: Conc. = Concentration of derivative compounds; R = Numbers of replicates; M = Mean of diameter of inhibition zone (mm); SE = Standard error of mean.

 

Fig. 9 Antibacterial activity test of derivative compounds (50 mg/mL) against S. aureus onto Muller-Hinton agar surface.

 

Fig. 10 Antibacterial activity test of derivative compounds (150 mg/mL) against P. aeruginosa onto Muller-Hinton agar surface.

 

Conclusions

In this study, 1,2,3-triazole derivatives prepared were stable by resonance with high melting points relatively. And there were good antibacterial activities against Pseudomonas aeruginosa and Staphylococcus aureus.

 

Conflict of Interests

The authors declare that no competing interest exists.

 

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Copyright© Ruaa Wassim Adam, Hutham Mahmood Yousif Al-Labban, Ahmed Abduljabbar Jaloob Aljanaby, and Nadheema Abed Abbas. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.