Web of Science (Emerging Sources Citation Index), Scopus, ISC

Document Type : Original Research Article

Authors

Department of Chemistry, College of Science, University of Baghdad, Baghdad, Iraq

Abstract

In this study, Schiff base derivatives were reacted with different cyclic anhydrides to prepare some oxazepine ring derivatives. The Schiff base derivatives containing the 2-mercabto benzothiazole moiety were obtained via the reaction of different aromatic aldehyde with 2-(benzothiazol-2-ylthio) acetohydrazide. Furthermore, 2-(benzothiazol-2-ylthio) acetohydrazide was obtained via the reaction of 2-mercabto benzothiazole with ethyl chloroacetate, and then with hydrazine hydrate. The new synthesized compounds were characterized via spectral data (IR and NMR). The antibacterial activity was studied against the examples of Gram-positive (E. coli) and Gram-negative (Staphylococcus aureus) bacteria, and antifungal against Candida fungal.

Graphical Abstract

Synthesis of new compounds with seven rings (oxazepine) through the ring closure of Schiff bases with study of biological activity

Keywords

Main Subjects

Introduction

Chemists have long faced with the unique challenges in the field of heterocyclic chemistry ‎[1]‎ due to its vast amount of knowledge and variety. Despite this, heterocyclic chemistry and synthesis techniques are at the heart of the current medical chemical and pharmaceutical research ‎[2].‎ It is critical for medicinal chemists to have a thorough understanding of heterocyclic chemistry ‎[3].‎

The ubiquitous usage of nitrogen-containing heterocycles in medicine, industry, and agriculture has attracted attention related to them ‎[4].‎ 2-mercapto-1,3-benzoxazole MBO as well as its derivatives are employed to shield the metals from the environmental corrosion ‎[5-9]‎ as chelating agents in analytical chemistry for the discovery of metal ions and complexes for the selective flotation of sulfide minerals in metallurgy. The rubber vulcanization accelerators like 2-Mercapto- 1,3-benzothiazole (MBT) and its derivatives are quite common ‎[10-13].‎

Any seven-membered ring with oxygen in the first position and nitrogen in the third position, plus five carbon atoms, is called oxazepine‎[14]‎. Many kinds of heterocyclic oxazepine include 1,3-oxazepine [3, 15-19], as depicted in Figure 1, Structure (1-1) ‎[20]‎.

The basic structure consists of seven-membered rings of 1, 3-oxazepine-4, 7-diones as well as two carbonyl groups ‎[15,21]. ‎The synthesis of oxazepine has been studied and reported through the periods of time ‎[22]‎. It is synthesized by pre-cyclic cyclo-addition of Schiff base or hydrazone with maleic, phthalic, and succinic anhydrides ‎[23,24] as well as by using green chemistry [18,25,26]. ‎Various oxazepine derivatives have been found to have a wide range of biological actions, including antibacterial, antifungal, hypnotic muscle relaxant, antagonistic, inflammatory, antiepileptic, and antimicrobial properties ‎[18,23,25,27].‎

Experimental

Materials and methods

The melting points were recorded using a melting point apparatus (Gallenkamp) with the sample in an open capillary glass tube in an electrically heated metal block apparatus. FT-IR spectra were recorded on an 8400 S FT-IR spectrophotometer (SHIMADZU) and the solid samples were analyzed as smears. 1H-NMR spectra were recorded on Ultra Shield 400 MH, with tetramethyl silane as the internal standard and DMSO as solvent.

General procedures

Synthesis of ethyl 2-(benzo[d]thiazol-2-ylthio)acetate (1) [28]

A mixture of (5.25 mL) of 2-mercapto benzothiazole with 45 mL DMF and (6 mL) of trimethylamine were mixed for (20 min). Thereafter, 4.5 mL of ethyl chloroacetate was gradually added with mixing for half an hour at (r.t.). The reaction was elevated for a period of 14 hours at a temperature from (60 to 65 °C). The reaction mixture was poured over the ice and sodium bicarbonate was added and separated by the separating funnel. Brown Oil, 87%.

Synthesis of 2-(benzo[d]thiazol-2-ylthio) acetohydrazide (2) [29]

A mixture of 2-(benzo[d]thiazol-2-ylthio) ethyl acetate was stirred in (25 mL) of methanol and 10 mL of 99% hydrazine hydride for (24 hours) at room temperature. The mixture was poured into a porcelain lid to evaporate the excess methanol and hydrazine. Pale Yellow Oil, 82%.

Synthesis of new Schiff bases from 2-(benzo[d]thiazol-2-ylthio) acetohydrazide (3-7) [29]

A mixture of compound (2) (0.01 mol) was added to the aromatic aldehydes (0.01 mol) in absolute ethanol (25 mL) and (3-5 drops) of glacial acetic acid (G.A.A.) which was stirred for approximately (4-8 hours). Under the reduced pressure, the excess solvent was evaporated. The raw material was dried, and then it was recrystallized from chloroform. All the physical and performance properties of the vehicles are presented in Table 1.

Synthesis of oxazepine derivatives (8-22) [27]

A mixture of Schiff bases (4-7) (0.01 mol) and (0.02 mol) of (succinic anhydride, phthalic anhydride, and maleic anhydride) were re-condensed in THF (30 mL) as a solvent for (14- 16 hours). The solvent is evaporated under the reduced pressure. The appropriate product has been recrystallized from chloroform. Some of the physical properties and performance of the compounds (8-12) are listed in Table 1.

Result and discussion

Ethyl 2-(benzo[d]thiazol-2-ylthio) acetate (1) was prepared by the reaction of 2-mercaptobenzothiazole with ethyl chloroacetate in the presence of triethylamine as a catalyst, by the nucleophilic attack of the thiol group in 2-mercaptobenzothiazole on carbon in ethyl chloroacetate because the halo group is a good leaving group and the sulfur compound is a good nucleophile, the reaction is a nucleophilic substitution reaction (SN2) which removes proton from the thiol group followed by the removal of the HCl molecule. The halo assembly can be easily replaced to obtain a compound which produces a desired harvest [1], as indicated in scheme 1. Compound 1 was characterized by FTIR spectroscopic data demonstrating a strong band at 1737 cm-1 due to the ester carbonyl group and bands at 1737 cm-1 and 2927.74 cm-1 for the aliphatic (CH). Group. S-H absorption bands at 2567 cm-1 disappeared from compound 1 were introduced in the nucleophilic substitution reaction with hydrazine hydrate, and an ethoxy group was replaced by a hydrazine group (NH-NH2) to produce the corresponding acetohydrazide. FTIR spectral data of compound 2 illustrated the disappearance of C=O ester band and the appearance of clear absorption bands at 3109 cm-1 for N-H as well as (3286- 3199) cm-1 due to the asymmetrical and symmetrical stretching vibrations of (NH2) indicating the formation of acetohydrazide. The compound acetohydrazide (2) was converted into a Schaff base derivative (3-7) by reacting with various aromatic aldehydes in absolute EtOH as a solvent and GAA as a catalyst. FTIR spectral data of compounds (3-7) depicted the disappearance of the (NH2) absorption band at (3286-3199) cm-1, and the appearance of clear absorption bands at (1591-1623) cm-1 for (C=N) imine. Full details of FTIR spectroscopy data of compound (3-7) are indicated in Table 2. The synthesis of diazetidine derivatives was carried out by treatment of compound (3-7) with cyclic anhydride (succinic, malic, and phthalic) via nucleophilic substitution, and then cyclization reaction was done, as well. These compounds were identified from FTIR spectra demonstrating the new and clear absorption bands of (C=O) for oxazepine ring at (1693-1780) cm-1 with the disappearance of the absorption bands for (C=N) group at (1591-1623). Full details of FTIR spectroscopy data of compounds (8-22) were listed in Table 2.

1H-NMR spectra for compound 9 illustrates the singlet signal at 4.27 ppm for two protons for S-CH2-CO, the triplet signal at 2.44 and 2.5 ppm for four protons for CH2-CH2 in oxazepine ring, the singlet signal at 7.85 for N-CH-O for oxazepine ring, and the singlet signal at 11.50 ppm for one proton amidic NH-CO as well as multiple signals at 7.1- 8.31 ppm for eight aromatic protons.

1H-NMR spectra for compound 11 demonstrates the singlet signal at 3.92 ppm for two protons S-CH2-CO, the triplet signal at 7.61, and 7.96 ppm for two protons for CH=CH in oxazepine ring, the singlet signal at 7.86 for N-CH-O for oxazepine ring, the singlet signal at 11.33 ppm for one proton amidic NH-CO, and multiple signals at 7.65- 8.31 ppm for eight aromatic protons.  

Biological activities

The agar diffusion method was used for evaluating the biological activity of new synthesized compounds, the compounds were tested against two types of bacteria +ve Gram stain (Staphylococcus aureus), -ve Gram stain (E. coli), and (Candida) fungi.

The research species were first cultivated in the nutrient bread and incubated for 24 hours at 37 °C. Then, the fresh prepared bacterial cells were scattered into the “Nutrient Agar”.

Some of new synthesized compounds depicted the antimicrobial activity against Staphylococcus aureus, E. coli bacteria and Candida. Some of compounds (10, 11,15, 16, and 17) and campier these compounds with starting marital and some drugs exhibited a broad spectrum of bioactivity against both Staphylococcus aureus and E. coli bacteria as well as Candida.  

Anti-bacterial screening for some selected compounds

Some of the selected compounds showed an acceptable efficacy against the bacteria as follows:

  • Compound 10 is highly effective against both types of bacteria and is close to the strength of the two drugs used for comparison.
  • Compounds 13 and 14 indicated the high activity against E. coli as being stronger than both drugs.
  • As for compound 20, it gave a high activity against Candida fungi which was stronger than the drug used for comparison.
  • As for the rest of the prepared compounds, they gave varying activities from weak ones to the medium activities and close to the activity of amoxicillin. The Gram-positive bacteria are dense and have no external lipid membrane, whereas Gram negative bacteria are fine and have the external lipid membrane besides a small peptidoglycan layer, as depicted in Figures (2-5).

In case, the compounds have the ability to affect both the peptidoglycan of the wall and the outer lipid membrane of the bacteria.

The cell membrane of fungal consists of mucoid, lipoglyceride, and sterol as the main compositions of the cell membrane of this fungus. Therefore, we can suggest that inhibition of the fungus is based on the ability of the tested compounds to hydrolyze mucoid, lipo-glyceride, and sterol of the fungus.

   

Conclosion

The compounds (1-22) were prepared, the reactions were controlled by using the TLC test, and all prepered compounds were identified using FT-IR, some of which were identified using 1HNMR and the anti-bacteria and anti-fungi activities were among the biological activities tested on them. When compared to the standard medications, several synthesized compounds were demonstrated to have the substantial antifungal efficacy, while others demonstrated the anti-bacterial efficacy.

Acknowledgments

I would like to thank my supervisors first, and I would also like to extend my thanks and gratitude to the Department of Chemistry in the College of Science, University of Baghdad, and in particular, to the workers in the service laboratory in the department (Ms. Hajja Munira) for what she has given us, and I extend my thanks to Dr. Taghreed S. Hussein, and Mr. Aqeel Sami Maged for their advice in my work.

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How to cite this article: Bushra Karim Hamad*, Mohmmad R. Ahamed. Synthesis of new compounds with seven rings (oxazepine) through the ring closure of Schiff bases with study of biological activity. Eurasian Chemical Communications, 2022, 4(12), 1306-1317. Link: http://www.echemcom.com/article_154195.html

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Copyright © 2022 by SPC (Sami Publishing Company) + is an open access article distributed under the Creative Commons Attribution License(CC BY)  license  (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

 

 

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