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Document Type : Original Article

Authors

Department of Chemistry, College of Education for Pure Science Ibn AL Haitham, Baghdad University, Iraq

Abstract

The novel compounds were prepared to start from cephalexin in this work. It was converted into five-membered rings (1,3-oxazole and 1,3-thiazole). The cephalexin was reacted with ethanol absolute and hydrochloride at first to obtain compound (2), and in the second step, compound (2) reacted with thiourea to obtain a compound (3), then compound (2) reacted with urea to obtain a compound (4); when compound (4) was reacted with 4-phenyl phenacyl bromide, we got 1,3-oxazole derivative from this reaction, also when compound (3) reacted with 4-phenyl phenacyl bromide in the presence of absolute ethanol, we got 1,3-thiazole derivative. The melting points of the synthesized compounds were recorded, the purity was checked by TLC, and the structures of the prepared compounds were identified by FT-IR and 1H-NMR spectra. The biological activity of these compounds was tested.

Graphical Abstract

Synthesis of New 1,3-Oxazole and 1,3-Thiazole Derivatives with Expected Biological Activity

Keywords

Main Subjects

Introduction

1,3-Oxazole is distinctive five-membered nitrogen and oxygen-containing heterocyclic compound. The versatility of this heterocyclic ring system makes it an important class of heterocyclic compounds [1].

Oxazole, the utility of oxazole as intermediates for the synthesis of synthesizing new chemical entities in medicinal chemistry, have been has increased in the past few years. Oxazole is an essential heterocyclic nucleus having with a wide spectrum of biological activities which. It drew the attention of researchers around the globe to synthesize various oxazole derivatives and screen them for their various biological activities. The present review article aims to review the work reported on the therapeutic potentials of oxazole scaffolds which are valuable for medical applications during the new millennium. It was first made in 1947. Substitution patterns in oxazole derivatives are essential for determining biological activity, for example, antibacterial, anti-cancer, antitubercular, anti-inflammatory, antidiabetic, antiobesity, and antioxidant, among others [2].

Thiazole is a five-membered aromatic heterocyclic chemical molecule with the molecular ring formula C3H3NS. Hantzch and Weber were the first to describe thiazole in 1887. In 1889, Prop verified its structure. The sulfur atom is the starting point for thiazole numbering. Numerous publications have been published highlighting their chemistry and pharmacological applications. In thiazoles, the Pi-electron delocalization is more significant than in equivalent oxazole’s [3]. Free thiazole is a light-yellow liquid with a pyridine-like smell. Thiazole derivatives are one of the most active groups of chemicals with a wide range of applications, such as antibacterial activity [4], antifungal properties [5], antimalarial properties [6], antitubercular action [7], antiviral action [8], anti-inflammatory activity [9], antidiabetic activity [10]. Anthelmintic action [11-17], anticonvulsant action (12,18), antioxidant activity [13-19] and as well as anti-cancer properties [14-20]. Many thiazole scaffolds, such as commercialized anti-cancer medicines, have been discovered to have solid antitumor efficacy [15].

Materials and Methods

The melting points (°C) of all the materials are unadjusted. A Perkin-Elmer spectrophotometer was used to measure the FT-IR spectra. On a 400 MHz device, the 1H-NMR spectra were acquired. TMS was used as the internal reference while DMSO was used as the solvent. Melting points (°C) were determined using Gallen Kamp melting point equipment with a heated stage, and no adjustments were made. Infrared spectra were captured using a Fourier Transform infrared SHIMADZU (8300) (F.T.IR) infrared spectrophotometer, and KBr discs were examined using a SHIMADZU (8400) (F.T.IR) infrared spectrophotometer (Ibn -Sina company, Baghdad-Iraq). Fertigfollen precoated sheets type polygram Silk was used for thin-layer chromatography (TLC), and the plates were produced using iodine vapor. Thiourea, urea, and 4-phenyl phenacyl bromide were utilized in the experiment.

General synthetic procedures

(A) Synthesis of ethyl 7-(2-amino-2-phenylacetamido)-3-methyl-8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylate (2)

By dissolved 7 g from 7-(2-amino-2-phenyl acetamido)-3-methyl-8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylic acid (1) in 25 mL pure ethanol with hydro chloride added. The mixture was then refluxed for 5 hours while being monitored using TLC. The compound (2) was then cooled, the surplus solvent was evaporated, and the product produced was collected. Darkorange, yield: 79%, mp 96-98 °C.

 (B) Synthesis of 7-(2-amino-2-phenyl acetamido)-N-carbamothioyl-3-methyl-8-oxo-5-thia-1-azabicycle [4.2.0] oct-2-ene-2-carboxamide (3)

Combining thiourea (0.2 g) with 1 g ester (2) in pure ethanol (25 mL), after confirming through TLC, the mixture was refluxed for 7 hours to obtain the solid compound (3) as a result of solvent evaporation (Scheme 1). Light brown, yield: 78%, mp 72-74 °C.

(C) Synthesis of 7-(2-amino-2-phenylacetamido)-N-carbamoyl-3-methyl-8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-carboxamide (4)

Through combining urea (0.168 g) with 1 g ester (2) in pure ethanol (25 mL). After confirming through TLC, the mixture was refluxed for 7 hours. To obtain the solid (4) as a result of solvent evaporation (Scheme 2). Brown, yield: 85%, mp 52-54 °C.

(D) Synthesis of N-(4-([1,1'-biphenyl]-4-yl) oxazol-2-yl)-7-(2-amino-2-phenylacetamido)-3-methyl-8-oxo-5-thia-1-azabicycle [4.2.0] oct-2-ene-2-carboxamide (8)

The chemical compound (8) was synthesized by dissolving compound 4 (0.5 g) in pure ethanol (25 mL) and then adding 4-phenyl phenacyl bromide (0.370 g). After that, the mixture was allowed to reflux for 8 hours [with TLC monitoring; ethanol]; The precipitate was then filtered before being recrystallized with ethanol absolute recrystallizing with absolute ethanol (Scheme 3). Light brown, yield: 81%, mp 58-60 °C.

Scheme 1: Synthesis of compound 3

Scheme 2: Synthesis of compound 4

Scheme 3: Synthesis of compound 8

(E) Synthesis of N-(4-([1,1'-biphenyl]-4-yl) thiazol-2-yl)-7-(2-amino-2-phenylacetamido)-3-methyl-8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-carboxamide (9)

The chemical compound (9) was synthesized by dissolving compound 3 (0.5 g) in pure ethanol (25 mL) and then adding 4-phenyl phenacyl bromide (0.370 g). After that, the mixture was left to reflux for 8 hours [monitored by TLC; ethanol], The precipitate was then filtered before being recrystallized with absolute ethanol (Scheme 4). Pale golden, yield: 96%, mp 116-118 °C.

Scheme 4: Synthesis of compound 9

Results and Discussion

The melting temperatures of the synthesized compounds were recorded, and the purity was confirmed using FT-IR and 1H-NMR spectra. The FT-IR spectrum reveals that the hydroxyl group (O-H) has disappeared at 3300 cm-1 and the band appeared at 1762 cm-1 due to the carbonyl ester group in the compound (2)  and we can the results of infrared spectroscopy showed bands other  as in Table 1, 1H-NMR spectrum for compound 2 shows the following distinctive chemical shifts: At 7.54-7.31 ppm the aromatic ring protons emerged as numerous signals, a signal at 4.97 ppm as a result of the O-CH2- group, at δ 1.96 ppm due to the -CH3 group, the signal at δ 2.49 ppm for Me, δ 9.57 ppm NH2, at δ 9.55 ppm for NH, at δ 4.98 ppm for Ar-CH-NH2 at δ 5.05 ppm =N_CH- and at δ 4.98 ppm for _CH_S_. 1H-NMR of compounds (3), (4), (8), and (9) are listed in Table 2. Compound (3) is prepared by reacting an ester compound (2) with thiourea in the presence of ethanol in its pure for; for 7 hours, the mixture was refluxed. The FT-IR spectrum of compound (3) in this reaction appears in a new band at 1091 cm-1 for the C=S group in thiourea added with a disappearing band at 1226 for C-O from compound 2, and other bands found as in Table 1.

A plausible mechanism for the new synthesis of oxazole and thiazole derivatives are is shown in Schemes 5, 6 and 7.

Table 1: FT-IR of compounds

Table 2: 1H-NMR of compounds

Scheme 5: Synthesis of new oxazole and thiazole derivatives

Scheme 6:  The mechanism of the reaction  for compound 8

Scheme 7: The mechanism of the reaction for compound 9

Biological activity

Antibacterial activity of several of the generated compounds was examined in vitro against four pathogenic strains: Bactria S.aureus (G+), Bacillus (G+), E.coli, and K.pneumoniae using the appropriate diffusion method (G-). The obtained data revealed that several of these substances had quantifiable activity, as shown in Table 3, and the imaging of the biological activity of bacteria (G + and G-) and activity of fungi are shown in Figure 1.

 

Table 3: Bacteria s.aureus (G+), Bacillus(G+), E.coli, and Klebsiella pneumonia (G-)

Figure 1: imaging the biological activity of bacteria (G + and G-) and activity of fungi

Conclusion

The synthesized compounds were confirmed using spectroscopic techniques (FT-IR and 1H-NMR). Some of the prepared compounds gave excellent efficiency. The biochemical studies revealed that the newly synthesized compounds caused activators effects on four types of bacteria (Bactria S.aureus, Bacillus, E.coli, and K.pneumoniae) and one type of fungal (Cndidaalbicas).

Acknowledgments

I extend my thanks and appreciation to the supervising professor, Dr. Ibtisam Khalifa Jassim and all the doctors of the Department of Chemistry, College of Education for Pure Sciences, Ibn Al-Haytham, University of Baghdad, and I extend my thanks and gratitude to everyone who helped me complete the scientific research project.

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.

Conflict of Interest

There are no conflicts of interest in this study.

ORCID

Ahmed Jasim Mohammed

https://orcid.org/0000-0002-4578-0069

HOW TO CITE THIS ARTICLE

Ahmed Ja. Mohammed , IbtisamKh.Jassim. Synthesis of New 1,3- Oxazole and 1,3-Thiazole Derivatives with Expected Biological Activity. Chem. Methodol., 2022, 6(12) 953-961

https://doi.org/10.22034/10.22034/chemm.2022.353601.1585

URL: http://www.chemmethod.com/article_156306.html

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