Document Type : Original Article

Author

Department of Science College of Basic Education, University of Sumer Rifai, Iraq

Abstract

In this study, a derivative of azetidine was obtained by refluxing Schiff-base with an aromatic aldehyde. Schiff-base was prepared by reaction of hydrazine hydrate with chloroacetylchloride without heating. FT-IR and 1H-NMR proved all prepared compounds and chemical structures. The final compound (d), the target of this work, was screened for antioxidant activity and exhibited good results.

Graphical Abstract

Synthesis, Characterization of Azetidine Derivative and Studying the Antioxidant Activity

Keywords

Main Subjects

Introduction

The azetidin-2-one is well known as the [β-lactams] ring of a four-membered cyclic amide it is named due to the N atom, which is linked to β-carbon lined with carbonyl [1]. The history of the azetidine compounds back to 1907, the Schiff base reaction [2] from aniline and aldehyde Cycloaddition reaction. Chemistry of this has a wide spectrum and essential part in organo-synthetic chemistry [3] since the revelation of Alexander Fleming for prepared Penicillin and the need of more active compounds against the activity of bacteria and fungi due to the resistance of the micro-species [4, 5]. The molecular action of the β-lactams derivative antibiotic is power selective and irreversible inhabitation when it is use for processing enzymes of developing peptidoglycan layer [6]. The azetidine-2-one is a very important type of synthetic chemical structure possessing very wide bands of biological activities such as anti-bacterial [7], anti-inflammatory [8], CNS activity, and anti-cancer activity [9] so, which made this type of four-membered structure very strong and widely used for a different type of micro-activity by bacteria or virus which affected the vital cell of human [10].

Materials and Methods

All chemical ingredients were obtained from SD fine chemical Co. All synthesized compounds were purified by recrystallization, and Gallen Kamp capillary melting point was used to calculate melting points. (Bruker) tensor M27 spectrometer was used to predict FT-IR measurements. 1H-NMR spectra appeared in a Bruker spectrophotometer ultra-shield at (400) MHz using DMSO as an internal standard.

Preparation of 2-chloroacetohydrazide (a) [11, 12]

In a round bottom flask, 50 mL supplied with a magnetic stirring bar, hydrazine hydrate 7.5 mL. The round bottom flask was cooled to 5 °C with stirring and added dropwise chloroacetylchloride (1.1 mL). The mixture was stirred 2 hrs under room temperature. Compound (a): Pale yellow, bp 220-225 °C, yield 85%, FT-IR (KBr) (νmax/ cm-1): 3410, 3400, 3288, 2982, 2870, 1625, and 724.  1H-NMR (400 MHz, DMSO): δ 12 (s, 2H, NH2), 11.4 (s, 1H, NH), 7.3-8.1 (m, 4H, ArH).

Preparation of 2-(1H-pyrrol-1-yl) Aceto hydrazide (b) [13, 14]

Pyrrole 10 mL with a few drops of KOH, 2-chloroacetohydrazide (a) 6 mL was added in three portions for one hour with continuous stirring. The mixture refluxed for 4h at 75-85 °C, the mixture was cooled off and concentrated under reduced pressure. The solid obtained was washed with cold water and recrystallized from absolute ethanol. Compound (b): Dark yellow, bp 190-195 °C, yield 75%, FT-IR (KBr) (νmax/ cm-1): 3410, 3401, 3295, 3285, 3051, 2920, 2901, 2870, 1630, and 1100.

Preparation of N'-benzylidene-2-(1H-pyrrol-1-yl) Acetohydrazide(Schiff base) (c) [15, 16]

5.5 g of 2-(1H-pyrrol-1-yl) acetohydrazide (b and benzaldehyde (7 mL, 0.01 mol) in the presence of methanol 30 mL; the contents were refluxed for 3hrs at 70-75 °C. Ice water to the reaction mixture was added. The solid which is formed was dried and recrystallized from ethanol. Compound (c): Brown, mp 194-197 °C, yield 70%, FT-IR (KBr) (νmax/ cm-1): 3240, 3056, 2970, 2825, 1674, 1625, 1430, and 1050. 1H-NMR (400 MHz, DMSO): δ 12 (s, 2H, NH2), 11.4 (s, 1H, NH), 7.3-8.1 (m, 4H, Ar-H), 11.3 (s, 1H, NH), 7.41-8.2 (m, 5H, Ar-H), 6.2 (d, 1H, CH-Ph).

Preparation of N-(3-chloro-2-oxo-4-phenylazetidin-1-yl)-2-(1H-pyrrol-1-yl) Acetamide (d) [17]

To a solution of N'-benzylidene-2-(1H-pyrrol-1-yl) Acetohydrazide (c) (4.6 g) in ethanol 20 mL, triethylamine 1 mL was added to this a solution of chloroacetylchloride (1.13 mL) added drop by drop with vigorous stirring. The mixture was refluxed for up to 3h at 90-100 °C. The solid obtained was filtered several times, and concentrated under reduced pressure, recrystallized from absolute ethanol. Compound (d): Off white, mp 187-190 °C, yield 81%, FT-IR (KBr) (νmax/ cm-1): 3050, 3331, 3290, 2860, 2847, 1670, 1661, and 1350. 1H-NMR (400 MHz, DMSO): δ 11.5 (s, 1H, NH), 7.5-8.07 (m, 5H, Ar-H), 6.4 (d, 1H, CH-Ph), 5.5 (d, 1H, CH-Cl), 4.3 (s, 2H, CH2).

Antioxidant activity [18-21]

Methanol solutions were prepared at 1000 ppm from the prepared compound (d). Different volumes were prepared at 5, 10, 15, 20, 25 of each methanol, a solution of compound (d) in the separate tubes containing 5 mL of 0.005 % methanol solution of DPPH-free radical. For each test, the solution was prepared in triplicate. The solution was disturbed and stored in the dark for two hours till constant values were obtained. The absorption of the samples was calculated at wavelength 517 nm and recorded. DPPH, root scan activity for each sample, and benchmark were measured by exploiting the chemical, mathematical relation below:

 [At] represents the consumption of samples, and [A0] indicates the consumption of the controls. The mean values of three separated samples have been measured for all compounds, and an (Ascorbic acid) has been applied as the standard test. The results showed in the Table 1.

Result and discussion

The substituted acid-hydrazide derivatives were exerted to make the new azetidine-2-one derivative the final compound (d), which included four steps Scheme 1. Stretching band to NH group at 3290-3331 cm-1. Carbonyl at 1670 cm-1. C-H aliphatic at 2847 cm-1. C-H aromatic at 3050 cm-1, were observed in the FT-IR spectra, other stretching-bands were shown. The DPPH-free radical test is established on the capacity of the scavenging ability of antioxidants to the “DPPH-free radical”. These free radicals are reacted with appropriate reducing agents and the electron becomes paired off, and the solution loses its color according to the number of electrons taken up. Results in Table 1 and Figure 1 indicated definite “scavenging activity” of the (d) compound to the DPPH-free radical in contrast with the “Ascorbic acid.” The maximum percentage scavenging effects of (d) compound on (DPPH) at the concentration of 25 μg was 85%.

 

Table 1: Scavenging % for prepared compound d

Compound

1000 ppm

5 μL

10 μL

15 μL

20 μL

25 μL

 

Aa

Ao

(I%)

Aa

Ao

(I%)

Aa

Ao

(I%)

Aa

Ao

(I%)

Aa

Ao

(I%)

d

0.306

0.655

53

0.252

0.655

62

0.191

0.655

71

0.144

0.655

78

0.101

0.655

85

Vit. C

0.245

0.655

63

0.19

0.655

71

0.121

0.655

82

0.085

0.655

87

0.044

0.655

93

Figure 1: The DPPH-free radical scavenging action of compound d

Scheme 1: All synthesized compounds

 

Conclusion

In this study, the azetidine-2-one derivative showed antioxidant ability, which is an addition for other activity of this wide spectrum compound like anti-bacterial, anti-fungal and anti-cancer.

Acknowledgments

I would like to extend my sincere appreciation to my colleague Dr. Maithim A. Redha, and thanks to everyone who helped me to complete this research.

Disclosure Statement

No potential conflict of interest was reported by the authors.

Funding

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

Authors' contributions

All authors contributed to data analysis, drafting, and revising of the paper and agreed to be responsible for all the aspects of this work.

ORCID:

Osama S. Hashim

https://orcid.org/0000-0003-4716-9797

HOW TO CITE THIS ARTICLE

Osama S. Hashim. Synthesis, Characterization of Azetidine Derivative and studying the Antioxidant activity. J. Med. Chem. Sci., 2023, 6(3) 553-558

http://dx.doi.org/10.26655/JMCHEMSCI.2023.3.12

URL: http://www.jmchemsci.com/article_157980.html

[1]. Lowe J.T., Lee IV M.D., Akella L.B., Davoine E., Donckele E.J., Durak L., ... & Marcaurelle L.A., Synthesis and profiling of a diverse collection of azetidine-based scaffolds for the development of CNS-focused lead-like libraries, The Journal of Organic Chemistry, 2012, 77:7187 [Crossref], [Google Scholar], [Publisher]
[2]. Han M., Song C., Jeong N., Hahn H.G., Exploration of 3-aminoazetidines as triple reuptake inhibitors by bioisosteric modification of 3-α-oxyazetidine, ACS Medicinal Chemistry Letters, 2014. 5:999 [Crossref], [Google Scholar], [Publisher]
[3]. Parmar D.R., Soni J.Y., Guduru R., Rayani R.H., Kusurkar R.V., Vala A.G., Azetidines of pharmacological interest, Archiv der Pharmazie, 2021, 354:2100062 [Crossref], [Google Scholar], [Publisher]
[4]. Haredi Abdelmonsef A., Eldeeb Mohame M., El-Naggar M., Temairk H., Mohamed Mosallam A., Novel quinazolin-2, 4-dione hybrid molecules as possible inhibitors against malaria: synthesis and in silico molecular docking studies, Frontiers in Molecular Biosciences, 2020, 7:105 [Crossref], [Google Scholar], [Publisher]
[5]. Ding D., Nickell J.R., Deaciuc A.G., Penthala N.R., Dwoskin L.P., Crooks P.A., Synthesis and evaluation of novel azetidine analogs as potent inhibitors of vesicular [3H] dopamine uptake, Bioorganic & Medicinal Chemistry, 2013, 21:6771 [Crossref], [Google Scholar], [Publisher]
[6]. Fawcett A., Murtaza A., Gregson C.H., Aggarwal V.K., Strain-release-driven homologation of boronic esters: application to the modular synthesis of azetidines, Journal of the American Chemical Society, 2019, 141:4573 [Crossref], [Google Scholar], [Publisher]
[7]. Schmid S.C., Guzei I.A., Schomaker J.M., A stereoselective [3+ 1] ring expansion for the synthesis of highly substituted methylene azetidines, Angewandte Chemie International Edition, 2017, 56:12229 [Crossref], [Google Scholar], [Publisher]
[8]. Kim E.A., Cho C.H., Kim J., Hahn H.G., Choi S.Y., Yang S.J., Cho S.W., The azetidine derivative, KHG26792 protects against ATP-induced activation of NFAT and MAPK pathways through P2X7 receptor in microglia, Neurotoxicology, 2015, 51:198 [Crossref], [Google Scholar], [Publisher]
[9]. Couty F., Drouillat B., Evano G., David O., 2‐Cyanoazetidines and Azetidinium Ions: Scaffolds for Molecular Diversity, European Journal of Organic Chemistry, 2013, 2013:2045 [Crossref], [Google Scholar], [Publisher]
[10]. Andresini M., De Angelis S., Uricchio A., Visaggio A., Romanazzi G., Ciriaco F., Corriero N., Degennaro L., Luisi R., Azetidine–borane complexes: synthesis, reactivity, and stereoselective functionalization, The Journal of Organic Chemistry, 2018, 83:10221 [Crossref], [Google Scholar], [Publisher]
[11]. Wang B.J., Duncton M.A., A Single-Step Synthesis of Azetidine-3-amines, The Journal of Organic Chemistry, 2020, 85:13317 [Crossref], [Google Scholar], [Publisher]
[12]. Salehi Sardoei, A. (2022). Review on Iranian Medicinal Plants with anticancer Properties, International Journal of Advanced Biological and Biomedical Research, 2022, 10:44 [Crossref], [Google Scholar], [Publisher]
[13]. Dubois M.A., Smith M.A., White A.J., Lee Wei Jie A., Mousseau J.J., Choi C., Bull J.A., Short synthesis of oxetane and azetidine 3-aryl-3-carboxylic acid derivatives by selective furan oxidative cleavage, Organic Letters, 2020, 22:5279 [Crossref], [Google Scholar], [Publisher]
[14]. Reiners F., Joseph E., Nißl B., Didier D., Stereoselective Access to Azetidine-Based α-Amino Acids and Applications to Small Peptide Synthesis, Organic Letters, 2020, 22:8533 [Crossref], [Google Scholar], [Publisher]
[15]. Tayama E., Nakanome N., Synthesis of optically active 2-substituted azetidine-2-carbonitriles from chiral 1-arylethylamine via α-alkylation of N-borane complexes, RSC Advances, 2021, 11:23825 [Crossref], [Google Scholar], [Publisher]
[16]. Mughal H., Szostak M., Recent advances in the synthesis and reactivity of azetidines: strain-driven character of the four-membered heterocycle, Organic & Biomolecular Chemistry, 2021, 19:3274 [Crossref], [Google Scholar], [Publisher]
[17]. Isoda T., Yamamura I., Tamai S., Kumagai T., Nagao Y., A practical and facile synthesis of azetidine derivatives for oral carbapenem, L-084, Chemical and Pharmaceutical Bulletin, 2006, 54:1408 [Crossref], [Google Scholar], [Publisher]
[18]. Modi B., Kumari Shah K., Shrestha J., Shrestha P., Basnet A., Tiwari I., Prasad Aryal S., Morphology, Biological Activity, Chemical Composition, and Medicinal Value of Tinospora Cordifolia (willd.) Miers, Advanced Journal of Chemistry-Section B, 2021, 3:36 [Crossref], [Google Scholar], [Publisher]
[19]. Layim M.D., Magtoof M.S., Material design and biologically activity of some new azetidines and azetidine-2-ones as antioxidant, Materials Today Proceeding, 2022, 61:878 [Crossref], [Google Scholar], [Publisher]
[20]. Hameed S.F., Turkie N.S., Determination of catechol by continuous flow injection analysis via turbidmetric utilizing NAG-4SX3-3D analyzer, Eurasian Chemical Communication, 2022, 4:790 [Crossref], [Google Scholar], [Publisher]
[21]. Ukwubile C., Idriss U., Isah A., Phytochemical evaluation, in vitro-in vivo antioxidant and cytotoxicity activities of various layers of watermelon fruit Citrullus lanatus (Cucurbitaceae) Matsum. & Nakai, Progress in Chemical and Biochemical Research, 2022, 5:97 [Crossref], [Google Scholar], [Publisher]