CiteScore: 1.5     h-index: 24

Document Type : Original Article

Authors

1 Department of Medical Labs. Techniques, Al-Esraa University College, Baghdad, Iraq

2 College of Pharmacy, University of Babylon, Babylon, Iraq

Abstract

The majority of benzodiazepines is administered orally and has various beneficial effects, including psychotropic, anxiolytic, hypnotic, sedative, muscle relaxing, anticonvulsant, and amnesic ones. These include benefits for alcohol dependence, epileptic seizures, irritable disorders, scare, and insomnia. The goal of this study was to create bicycles from benzodiazepines through cyclization steps. All generated compounds were examined by using several analytical techniques, including: FT-IR, 1H-NMR, Mass spectroscopy analysis, and other chemical characterization, with formatted compounds being assessed as antifungals and inhibitors. These compounds were utilized to explain biological activity against "Aspergilla's and Candida" albicans at various concentrations (5, 10, 15, and 20 mg/ml-1). The findings demonstrated that all compounds were active against all varieties of fungi and that oxazepine, diazepine bicycles, and heteroatoms in the structure inhibited the corrosion of mild steel in 0.5M HCl.

Graphical Abstract

Synthesis, Examination of Various Seven Rings, and Effects on Corrosion and Fungus

Keywords

Main Subjects

Introduction

Any important family of organic chemical compounds that have a part or all of their atoms connected in rings with at least one atom of an element other than carbon are known as heterocyclic compounds, sometimes known as heterocyclic (C) [1]. Heterocyclic compounds are needful for our life, like alkaloids, antibiotics, hemoglobin, hormones, and enormous numbers of designed drugs and pigments [2]. The majority of hallucinogens and many naturally occurring colors, vitamins, and antibiotics are heterocyclic substances. Because they are frequently utilized in forensic and clinical contexts, the benzodiazepine (oxazepine) and diazepine medication classes are used as relaxants, mild tranquilizers, hypnotics, and muscle relaxants [3]. In the pharmaceutical and medical fields, Schiff bases are well- known due to the broad range of biological efficacy that have been demonstrated for them. Schiff bases are the condensation products of the primary amines and energetic carbonyl groups [4]. According to their chemical makeup, mode of operation, etc., corrosion inhibitors can be categorized. Because they are simple to make, inexpensive to produce, and have a high level of protection, organic corrosion inhibitors are one of the popular kinds [5]. Adsorption on the steel superficies and preventing the active corrosion positions are causes of the prevention strategy. The forming of a pre-emptive barrier between "the attacker solution and the metal surface" prevents the mind from dissolving and minimizes corrosion damage. In both theory and practice, it has been demonstrated that derivative inhibitors with hetero-atoms, like N, O, and S effectively prevent corrosion in a diverse species of acidic solutions. Therefore, seven heterocyclic compounds were created in this study and chosen to operate as corrosion inhibitors for steel in HCl solution and antifungal activity [6].

Materials and Methods

Chemical study [7]

Synthesis of 2,2'-((1,2-phenylenebis(methaneylylidene))bis(azaneylylidene))dibenzoic acid (I)

Phthalaldehyde (0.01 mole) was dissolved in 25 mL absolute ethanol and condensed with (0.02 mole) of anthranilic acid, followed by the addition of 1-2 drops of glacial acetic acid, all while continuously shaking for 20-25 min on a magnetic stirrer at 65-70 °C in four hours to prepare the combination for recrystallization from 100% ethanol, the mixture was evaporated and dried to give compound (I).

Synthesis of 2,2'-(1,2-phenylenebis(4,7-dioxo-4,7-dihydro-1,3-oxazepine-2,3(2H)-diyl)) dibenzoic acid (II)

As a solvent, (0.01 mole) of compound (I) was dissolved in 20 mL of dry benzene, and then (0.02 mole) maleic anhydride was added gradually to finish the reaction at 60-65 °C in 12 hours. To prepare the combination for recrystallization from absolute ethanol, the mixture was evaporated and dried to give compound (II).

Synthesis of 2,2'-(2,5,8,11-tetraoxo-2,5,8,11,12a,16b-hexahydrobis([1,3]diazepino)[2,1-a:1',2'-c]phthalazine-1,12-diyl)dibenzoic acid [III]

Hydrazine hydrate (80%) (0.02 mole) was condensed (0.01) mole from compound (II) in the presence of acetone as a solvent while refluxing in (10 hours). To prepare the combination for recrystallization from absolute ethanol, the mixture was evaporated and dried to give compound (III). TLC was applied to the final product, as displayed in Scheme 1. All the physical properties of compounds (I-III) are listed in Table 1.

 

Table 1: All chemical and physical parameters as well as additional characterization

Compound No.

Yield (%)

Color

mp (°C)

Rf.

Solvents

(TLC )

(I)

70

Deep Yellow

188

0.68

Ethanol:Hexane

(II)

76

Yellowish Orange

196

0.60

Ethanol:Hexane

(III)

82

Orange

223

0.64

Ethanol:Hexane

Scheme 1: Synthesis of compounds (I-III)

Corrosion study

Carbon steel used in the trial sample has the chemical elements (in %wt.): (0.1 C), (0.335 Mn), (0.033 Si), (0.0067 S), (0.0056 P), (0.057 Al), (0.0476 Cu), (0.0201 Cr), (0.001 Co), (0.0007 Ti), and the remaining amount is F. The steel electrode was prepared for each measurement by being scrabbled with emery papers with a grade of (800-1500), laundered ultrasonically with distilled H2O, and finally dehydrated under the dry air. Acetone was then made by mixing Angler Grade 37% HCl with alcohol. The corrosion inhibition of mild steel in 0.5 M HCl by synthesized compounds was studied by using weight loss measurements. To ensure a reasonable level of repeatability, each measurement was carried out three times at a temperature range of 20–50 °C [8].

Isolation of the studied fungi 1-3

Aspergilla's species are significant both medically and commercially. A few species can infect both people and other animals. Opportunistic pathogenic yeast Candida albicans is a frequent constituent of the flora of the human gut. It can even persist without a human body. "Candidaalbicans and Aspergilla" were two fungi studied in this paper. While the samples were immediately put on (PDA) Potato dextrose agar media, and then chloramphenicol was added to inhibit bacterial development, and they were incubated at 25 °C for 48 hours. Thereafter, by using a conventional taxonomic key, these fungi were identified based on their micro- and macro-morphological properties [9].

Results and Discussion

Spectral investigation

Typically, Schiff base (I) was investigated by melting points and FT-IR spectroscopy. The FT-IR spectrum revealed the disappearance of absorption peaks caused by NH2 and C=O groups with the emergence of a new stretching vibration at 1661 cm-1 in which is assigned to azomethine group (CH=N), peak at 1702 cm-1 due to the C=O group, and at 3341-2831 cm-1 because of the hydroxyl of the carboxyl group. The 1,3-oxazepine (II) was synthesized by addition reaction (2+5) of azomethine C=N with maleic anhydrides in dry benzene, due to the cyclic amid group (CO-N) in lactam new bands formed at 1641 cm-1. A band at 1755 cm-1 was caused by a lactone, band at 3330-2700 cm-1 owing to OH hydroxyl of carboxyl group, band at 3044 cm-1 due to alkene (CH=CH), and another band at 1711 cm-1 due to carbonyl of carboxyl group in carboxylic acid [10]. The most characteristic evidence of the FT-IR absorption bands of compound (III) showed that other bands at 1710 owing to carbonyl of carboxylic acid, band at 3290-2775 cm-1 due to hydroxyl of carboxyl group, band at 3031 due to alkene (-CH=CH), and new bands at 1648 and 1620 cm-1 due to two groups of cyclic amid group in lactam ring. The collective FT-IR spectral data obtained for target compounds are listed in Table 2.

1H-NMR spectral identification

Compound (II), 1H-NMR spectrum (DMSO-d6), revealed a singlet signal for one proton of carboxyl group at δ 12.17 ppm. Many signals indications at δ 7.83-7.77 ppm are the result of twelve aromatic protons. Finally, the 1H-NMR spectrum reveals two peaks at δ 6.06 and 6.04 and δ 7.05 ppm that could be identical to CH=CH ring of oxazepine ring and one proton of CH-N group [11, 12].

The 1H-NMR spectrum (DMSO-d6), of compounds (III) showed a sharp signal at δ 3.34 ppm for one proton of diazepine group (N-CH-N), doublet signal at δ 6.29 and 6.11 ppm for two protons of CH=CH and twelve aromatic protons appear at the range δ 7.83-7.54 ppm. Furthermore, a singlet signal of proton of carboxyl group absorbed at δ 12.22 ppm. All the 1H-NMR spectra data are given in Tables 3.

 

Table 2: Characteristic FT-IR absorption band spectra (cm-1) of compounds (I-III)

Compound No.

υ (O-H) carboxylic

υ (C-H) aromatic

υ (C=O)

carboxylic acid

υ (C=O)

Lactone

υ(C=O)

lactam

υ(C=N)

 

υ (C=C)

aromatic

(I)

3341-2831

3095

1702

-

-

1661

1575,1489

(II)

3330-2700

3044

1711

1755

1641

-

1588, 1528

(III)

3290-2775

3031

1710

-

1648, 1620

-

1574, 1470

 

Table 3: 1H-NMR spectral data for compounds (II and III)

Compound No.

Signals in 1H-NMR spectra in DMSO-d6

[II]

12.17 (s,1H, COOH), 7.83-7.77 (m, 12H, Ar-H), 7.05 (s, 1H, CH-N), 6.06-6.04 (d, 2H, CH=CH)

[III]

12.22 (s, 1H, COOH), 7.54-7.83 (m, 12H, Ar-H), 6.11-6.29 (d, 2H, CH=CH), 3.34 (s, 1H, N-CH-N),

 

Mass spectra of new compounds

Figure 1 displays the mass spectrum of compound (II): C30H20N2O10 (M.Wt.=568.11) showed the base peak at (m\z = 119), further it revealed several fragments at (m\z = 308,221, 187, 147, and 92) which was in agreement with the molecular weight of structure proposed for this compound (II). Figure 2 depicts the mass spectrum of compound (III): C30H20N4O8 (M.Wt. = 564.12) indicated the interesting base peak at (m\z = 119), and also it showed several fragments at (m\z = 321, 287, 256, 162, 147, and 92). The same structure was discovered by comparing the predicted structure of the synthesized compound to their spectral fragments. Several spectra are depicted in illustrations [13-15].

 

Figure 1: Mass–spectrum of compound (II)

Figure 2: Mass-spectrum of compound (III)

 

Corrosion investigation

According to Table 1, the concentration of derivatives causes a reduction in the rate of steel corrosion at a given testing temperature. As concentrations of 1, 2, and 3 compounds are increased, values of inhibitor efficiency are increased, reaching an ultimate value of the inhibition efficiency 95.8% at higher temperatures and inhibitor levels, Table 4, and Figure 3 displays the Langmuir adsorption isotherms of derivatives [16, 17].

 

Table 4: The rate of low carbon steel alloy corrosion and the effectiveness of synthetic (oxazepine, diazepine) corrosion inhibitors under various circumstances in 0.5 M HCl solution

Inhibitor efficiency

(%)

Corrosionrate (g/m,48 hours)

Temperature

(°C)

Inhibitor conce. (M)

Test No.

-

33.99

20

Zero

1

-

80.52

30

Zero

2

-

142.96

40

Zero

3

-

419.21

50

Zero

4

71.8

9.57

20

0.001

5

75.4

8.36

-

0.002

6

81.7

6.21

-

0.003

7

85.1

5.06

-

0.004

8

81.2

15.17

30

0.001

9

81.3

15.05

-

0.002

10

86.1

11.23

-

0.003

11

86.6

10.75

-

0.004

12

85.1

21.27

40

0.001

13

87.1

18.47

-

0.002

14

87.7

17.66

-

0.003

15

88.3

16.83

-

0.004

16

94.6

22.57

50

0.001

17

95.1

20.52

-

0.002

18

95.5

18.91

-

0.003

19

95.8

17.66

-

0.004

20

 

 

Figure 3: The Langmuir adsorption isotherms of derivatives in (0.5 M HCl) solution on the surface of steel at diverse temperatures

 

Biological investigation

The seven generated rings derivatives were examined by using a live fungal study on various types of fungi to gauge how well the synthesized derivatives affected the growth of the study's chosen fungi. Evaluation of derivatives was done against two different fungi, aspergillus and candida albicans, at four different concentrations (5, 10, 15, and 20 g) for all derivatives [18-21]. The antifungal activity of the synthesized compounds was assessed by comparing the widely used antifungal Fluconazole as a common antifungal drug are listed in Table 5.

 

Table 5: Antifungal Assay of derivatives in different Concentration

Compounds

Aspergillus

Candida albicans

(I)

++

+

(II)

++

++

(III)

+++

+++

Fluconazole

+++

+++

+ Inhibition (4-8) mm

++ Inhibition (9-12) mm

+++ Inhibition (13-16) mm

 

Conclusion

Through the analysis of spectrum data by using FT-IR, 1H-NMR, and mass spectroscopy, these derivatives were confirmed. A lot of the chemicals have similar effects to those of popular drugs. It was also determined how well the drugs reduced inflammation in vitro, because the structure of these compounds contains lactone and lactam groups. Given their (oxazepine and diazepine) group and other cycle-based structures, the produced compounds demonstrated a good antifungal activity. These compounds as corrosion inhibitors for steel in acidic solution have undergone the successful testing.

Acknowledgments

We are thankful to the Department of Medical Laboratory Techniques, Al-Esraa University College, Iraq for making available the facilities used to carry out the antifungal activity of synthesized compounds. We also express our profound gratitude to the College of Pharmacy, University of Babylon, Iraq for giving very important advices to perfectly perform the relevant chemical synthesis along with helping the other members of the research team with his unlimited support corrosion, investigating experience for the synthesized compounds.

 

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:

Aziz Latif Jarallah

https://orcid.org/0000-0003-2572-3793

Aseel Fadhil Kareem

https://orcid.org/0000-0003-2700-4151

HOW TO CITE THIS ARTICLE

Aziz Latif Jarallah, Aseel Fadhil Kareem. Synthesis, Examination of Various Seven Rings, and Effects on Corrosion and Fungus. J. Med. Chem. Sci., 2023, 6(3) 532-539

http://dx.doi.org/10.26655/JMCHEMSCI.2023.3.10

URL: http://www.jmchemsci.com/article_157778.html

[1]. Vitaku E., Smith D.T., Njardarson J.T., Analysis of the structural diversity, substitution patterns, and frequency of nitrogen heterocycles among US FDA approved pharmaceuticals: miniperspective, Journal of medicinal chemistry, 2014, 57:10257 [Crossref], [Google Scholar], [Publisher]
[2]. Alfatlawi I.O., Nuha S.S., Zainab M.J., Aljamali N.M., Intisar O.A., Synthesis of New Organic Compounds Via Three Components Reaction with Studying of (Identification, Thermal Behavior, Bioactivity on Bacteria of Teeth), Journal of Global Pharm Techno, 2017, 11:157 [Google Scholar], [Publisher]
[3]. Neshan F.A., Al-Rawi M.S., Tomma J.H., ''Synthesis, Characterization and Study Biological Activity of Five and Seven Heterocyclic Compounds'', International Journal of Drug Delivery Technology, 2019, 9:587 [Publisher]
[4]. Mukhlus A.A., Al-Rawi M.S., Tomma J.H., Al-Dujaili A.H., Synthesis And Characterization Of New Oxazepines Derived From D-Erythroascorbic Acid, Synthesis, 2017, 25 [Google Scholar], [Publisher].
[5]. Adnan S., Ghafil A., "Synthesis and Identification of New (azo-heterocyclic) Derivatives and Study of their Biological Activity as Anti-bacteria and Fungi", IJDDT, 2021, 11:59 [Publisher]
[6]. Ahmed K., Ali M., Kaduim A, Abu Bakar M& Takriff M., "Adsorption kinetics of 4-Amino- 5 -Phenyl-4H-1, 2, 4-Triazole-3-thiol on mild steel surface inhibitor", Port Electrochim Acta, 2010, 28:221 [Crossref], [Google Scholar], [Publisher]
[7]. Kareem A.F., Ghanim H.T., Antimicrobial Study against Seven Cycles Compounds Derivatives from Pyrimidine, Journal of. Forensic, Medicine &, Toxicology, 2020, 14:794 [Crossref], [Google Scholar], [Publisher]
[8]. Ahmed S.K., Ali W.B., Khadom A.A., Synthesis and investigations of heterocyclic compounds as corrosion inhibitors for mild steel in hydrochloric acid, International Journal of Industrial Chemistry, 2019, 10:159 [Crossref], [Google Scholar], [Publisher]
[9]. Kadhum S.A., Kareem A.F., Antimicrobial Study of Azo-imidazole (five cycles) Compounds, Muthanna Medical Journal, 2017, 4:97 [Google Scholar], [Publisher]
[10]. Sivaev I.B., Bragin V.I., Bregadze V.I., Votinova N.A., Sjoberg S., Synthesis of Schiff bases and benzylamino derivatives containing [1-B10H9NH3]− anion, Russian chemical bulletin, 2014, 53:2092 [Crossref], [Google Scholar], [Publisher]
[11]. Al-Rawi M.S., Hussei D.F., Al-Taie A.F., Al-Halbosiy M.M., Hameed B.A., Cytotoxic effects of new synthesis heterocyclic derivatives of Amoxicillin on some cancer cell lines, In Journal of Physics: Conference Series, 2018, 1003:012012 [Crossref], [Google Scholar], [Publisher]
[12]. Alsahib S.A., Baqer S.R., Synthesis, identification of some new derivatives of 4-amino antipyrine bearing six and seven membered rings, In Journal of Physics: Conference Series, 2021, 1853:012010 [Crossref], [Google Scholar], [Publisher]
[13]. Muhiebes R.M., O Al-Tamimi E., Modification of Creatinine to Form New Oxazepane Ring and Study Their Antioxidant Activity, Chemical Methodologies, 2021, 5:416 [Crossref], [Google Scholar], [Publisher]
[14]. Hamad B.K., Ahamed M.R., "Synthesis of new compounds with seven rings (oxazepine) through the ring closure of Schiff bases with study of biological activity", Eurasian Chemical Communications, 2022, 4:1306 [Crossref], [Google Scholar], [Publisher]
[15]. Nashaan F.A., Al-Rawi M.S., Alhammer A.H., Rabie A.M., Tomma J.H., ''Synthesis, characterization, and cytotoxic activity of some imides from galloylhydrazide'', Eurasian Chemical Communications, 2022, 4:966 [Crossref], [Google Scholar], [Publisher]
[16]. Raphael V.P., Kakkassery J.T., Shanmughan S.K., Paul A., Study of synergistic effect of iodide on the corrosion antagonistic behaviour of a heterocyclic phenylhydrazone in sulphuric acid medium on carbon steel. International Scholarly Research Notices, 2013, 2013:390823 [Crossref], [Google Scholar], [Publisher].
[17]. Ghanavati B., Bozorgian A., Esfeh H.K., Thermodynamic and Kinetic Study of Adsorption of Cobalt II using adsorbent of Magnesium Oxide Nanoparticles Deposited on Chitosan, Progress in Chemical and Biochemical Research, 2022, 5:165 [Crossref], [Google Scholar], [Publisher]
[18]. Illueca F., Vila-Donat P., Calpe J., Luz C., Meca G., Quiles J.M., Antifungal activity of biocontrol agents in vitro and potential application to reduce mycotoxins (aflatoxin B1 and ochratoxin A), Toxins, 2021, 13:752 [Crossref], [Google Scholar], [Publisher].
[19]. Abdulghani S.M., Al-Rawi M.S., Tomma J.H., Synthesis of New 1, 2, 4-triazole Derivatives with Expected Biological Activities, Chemical Methodologies, 2022, 6:59 [Crossref], [Google Scholar], [Publisher]
[20]. Uttu A.J., Sallau M.S., Iyun O.R.A., Ibrahim H., ''Isolation, Characterization and In Silico Molecular Docking Studies of Two Terpenoids from Strychnos innocua (Delile) Root Bark for Antibacterial Properties'', Advanced Journal of Chemistry-Section A, 2022, 5:241 [Crossref], [Google Scholar], [Publisher]
[21]. Muhiebes R.M., Al-Tamimi E.O., Synthesis of new heterocyclic containing azo group from 2-N-chloro acetamido creatinine and studying their biological activity, Eurasian Chemical Communications, 2021, 3:401 [Crossref], [Google Scholar], [Publisher]