Antimicrobial Study of Novel Triazoles Synthesized from Chalcones

Introduction

 Chalcone is the one of the well-known heterocyclic motif in the field of heterocyclic chemistry. Chalcone word originally came from the Greek latter “chalcones” which is called “bronze” is the term for the chalcone origination. Chalcones containing wide variety of compounds shows various medicinal application ¹.  Chalcones is the example of the molecule with two types of double bond called α, β-unsaturated compounds with carbon oxygen and carbon carbon double bond are present. Here in the chalcones two double bond are in conjugation with respect to each other and in the reaction carbon carbon double bond gets easily break and provide reactivity at this site in the chalcones so number of heterocyclic compounds will be synthesized by this rout.

Chalcones are frequently found in many plants as the naturally occurring compounds and its provide separate class of the compounds. Various precursor for the synthesis of flavanones and Isoflavones are the chalcones which are very useful in the biosynthesis.

Two aromatic rings with carbonyl group containing compound 1,3-diphenyl-2propen-1-ones are crucial precursor in the flavonoid and isoflavanoid synthesis. Claisen Schmidt reaction of alpha methyl ketone and aldehyde under basic condition produces chalcones. Other methods are also available for the synthesis of chalcones.  Chloroquine resistance and chloroquine sensitive compounds are exhibited antimalarial activity in the in vitro against various plasmodium².  Synthesis of chalcones using acetic acid and perchloric acid as the acidic condition has been reported by M. A. Shalaby et. al.³.  Various chalcones were identified as the tyrosinases and new depigmenting agent which shows antioxidant and ant inhibitor activity ⁴.

Quinazoline and quinazolinone chemicals are also included in many pharmacological molecules and are utilized to prepare a variety of functional materials for synthetic chemistry. Quinazoline and quinazolinones shows divers antimicrobial activity provide study in the field as a good promising ⁵. Based on the ring system’s substitution patterns, quinozolinones will be categorized into five groups⁶. 2,3,2,4- disubstituted 4 (3H) quinazolinones, It consists of 2,4-disubstituted-4(3H)-quinazolinones, 4-substituted quiinazolines, 2,3-disubstituted-4(3H)-quinazolinones and 5-disubstituted-4(3H)-quinazolinones. These compounds can be categorized into three different groups⁷ based on where the keto or oxo group is located. Out of the three quinazolinone structures 2-(1H)-quinazolinones, 4-(3H)-quinazolinones and 2,4 (1H, 3H)-diquinazolinones are very common as the intermediates in number of biosynthesis or as in the several natural products. Due to its numerous pharmacological actions, the quinazolinone nucleus has drawn considerable attention⁸. Many of them have therapeutic properties, including anticancer ^9-11, anti-inflammatory ^12-13, antimicrobial ¹⁴, antihypertensive ¹⁵, and antifungal effects. According to reports, different substituents at the quinazolinone nucleus’ 2/3 position have a significant impact on pharmacological action ¹⁶.

In the presence research paper, we have synthesized novel Triazole based Quinazolinones C1–C12 from chalcones and 2-aminotriazole.  Chalcones were synthesized from alpha methyl ketone and a variety of aromatic aldehydes. Characterization of all synthesized compounds were done using various spectroscopic techniques and all synthesized compounds were screened for their biological activity.

Materials and Methods

Chemicals (Reagents)

Aldehydes, cyanuric chloride, 2-aminotriazole, sodium hydroxide and ethanol were purchased from the Merck, Mumbai, India and all are of reagent grade and used as obtained without doing further purification.

Experimental

¹HNMR spectra were recorded using instrument BRUKER AVANCE with 400MHz frequency and 100MHz frequency were used for ¹³CNMR spectra. Parts per million (ppm) unit is used for the chemical shift value. FTIR-3000 Spectrophotometer of ABB Bomem Inc. was used for IR spectra. Shimadzu LCMS-2010 instrument is used for MASS spectrum analysis.

Synthesis of Quinazolinones

Synthesis of Compounds 3a-l

 Take 5.79g (0.01mol) of compound 1a having alpha methyl group in 500 ml round bottom flask, add 40ml ethyl alcohol to it and stir it. Add 0.01mol aromatic aldehyde to it followed by addition of 0.01mol amount of 2% sodium hydroxide solution and reflux the entire mixture for 10-12 hr. After completion of reaction, cool the mixture and pour it in to ice water. Filter the product obtained and recrystallized it using ethanol (Scheme-1).

Scheme 1: Synthesis of cholcones from Aromativ aldehydes. Click here to View Figure

Substituted triazole based Quinazolinones C1-C12 Synthesis

Take this prepared chalcone (6.67 gm 0.02 mol) and 2-aminotriazole (1.0gm 0.02 mol) inethanolic sodium hydroxide solution (25ml), stirred the mixture. Reflux the entire mixture for 8-10 hr. The reaction mixture was refluxed for 8-10 hrs. After completion of reaction, cool the mixture and pour it in to ice water. Filter the product obtained and recrystallized it using ethanol. The product obtained is substituted Triazole based quinazoline 4-one derivative. Further modification of this prepared compound is possible by react it with 0.01 mol of cyanuric chloride using 40 ml of 40% sodium hydroxide in 40 ml of ethanol for 30- to 40-minutes. TLC is used to confirm the reaction’s completion. After the reaction was completed, the solution was cooled and put into crushed ice (Scheme- 2).

Table 1: Data of synthesis of triazole based quinazolinones C1-C12

Sr No.	Code	R	% Yielda	Melting Point (°C)
1	C1	-H	82	212
2	C2	2-OH	77	242
3	C3	3-OH	78	255
4	C4	4- OH	79	232
5	C5	2-CL	76	228
6	C6	3-Cl	82	225
7	C7	4-Cl	84	240
8	C8	2-NO2	84	221
9	C9	3-NO2	84	247
10	C10	4-NO2	83	214
11	C11	2-OCH3	75	205
12	C12	4-OCH3	74	226

 ^a Isolated yield

Result and Discussion

Optimization of Reaction

A reaction between alpha methyl ketone 1a and benzaldehyde 2a in 40ml ethanol using different concentration of sodium hydroxide to produced compound 3a was taken as the model reaction.  Data obtained are shown in the Table 2.

Table 2: Effect of different amount of NaOH on synthesis of chalcones

Entry	% of NaOH Sol	Moles of NaOH ml	Timea (Hours)	Yieldsb (%)
1	1	0.01	10	65
2	2	0.01	10	82
3	3	0.01	10	75
4	4	0.01	11	78
5	5	0.01	11	79

^a Reaction was monitored by TLC, ^b Isolated yields.

It was found that best result was obtained by taking 2% 0.01 mol NaOH solutionamount with 82% yield of product in 10 hours. So, this amount was taken as optimum amount and a library of triazole based Quinazolinones C1-C12 were synthesized according Scheme-2.

Scheme 2: Synthesis of substituted Triazole based Quinazolinones C1-C12. Click here to View Scheme

Biological Activity

Preparation of Media

Nutrient agar is used for measure of bacterial activity. These steps are used to create nutrient agar:

15gm Agar-Agar, 5gm Peptone, 3gm Metal Extract, 5gm NaCl To dissolve all the components, one liter of distilled water was mixed with peptone before being boiled. The medium was stabilized in an autoclave for 20 minutes at 125°C and 15 pound pressure. A sterilized Petri plate was filled with 20 cc of the medium after it had been cooled to 45°C. The medium’s pH was changed to be in the range of 7.0 and 7.5. The aforesaid organism’s culture was created in nutrient broth that had been dissolved in purified water. Nutritional broth contains the following.

1) 10gm Beef extract, 2) 10gm Peptone and 3) 5gm Sodium chloride

Experimental results of biological activity

Table 3: Data of biological activity of synthesized compounds C1-C12.

Compound code	S. aureus  gram +ve	B. megaterium gram +ve	E. Coli gram -ve	P. vulgaris gram -ve
C1	8	12	7	8
C2	6	8	9	6
C3	8	8	6	9
C4	10	7	10	5
C5	9	8	8	7
C6	6	4	7	6
C7	5	6	5	9
C8	8	10	9	11
C9	7	9	10	12
C10	9	5	8	9
C11	5	8	11	10
C12	11	9	6	10
Ampicillin	15	14	17	16
Gentamycin	16	15	14	16

 

Figure 1: Biological activity of synthesized compounds C1-C12. Click here to View Figure

Characterization

All the synthesized compounds were confirm using spectroscopic techniques such as ¹HNMR, ¹³CNMR, IR and MASS. Here we have given the data of the two selected model compounds called C2 and C11 as below as the representative compounds of the series.

Figure 2: Compound-C2 Click here to View Figure

Figure 3: Compound-C11 Click here to View Figure

Conclusion

In conclusion the highly functionalized substituted triazole based quinazoline 4-one derivative C1-C12 were synthesized from substituted chalcone and 2-Aminotriazole followed by further reaction with Cyanuric Chloride using ethanol as the solvent. All synthesized compounds were screened for their biological activities against gram positive and gram-negative bacterial strands. Most of compounds shows the satisfactory results in the biological activity.

Acknowledgement

I thankful to my research Guide Dr. Gaman G. Barat Sir for provided valuable guidance to do research work. I acknowledge gratitude to Principal of Arts, Science and Commerce College, Pilvai for provided necessary research facilities. I also thankful to Head, Department of Chemistry, HNGU, Patan for provided time-based information and all kind of support.

Conflict of Interest

The authors declare no conflict of interest.

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