Synthesis of 1,3-Benzoxazepine-1,5-diones containing Oxadiazole unit with Assessment of their verves Athwart Bacteria

Zeid Hassan Abood^*, Husham Attallah Suhail, Zahraa Kadum Chafcheer

Chemistry Department, College of Science, University of Kerbala, Kerbala-Iraq.

*Corresponding Author E-mail: husham.a@uokerbala.edu.iq

ABSTRACT:

Treatment of 4-aminobenzoyl hydrazide (1) with (CS₂) and potassium hydroxide in absolute (EtOH) resulted in formation of 5-(4-aminophenyl)-2-thiol-1,3,4-oxadiazole (2). Compound (2) has been converted to the diazonium salt which reacted with 2-hydroxybenzaldehyde for producing the aldehyde derivative (3). Reaction of compound (3) with (4-nitroaniline, 3-nitroaniline, 2-nitroaniline, 4-chloroaniline, 2-chloroaniline, 2,4-dichloroaniline and 4-bromoaniline) by (MW) method in (EtOH) afforded seven Schiff bases (4a–g). Cycloaddition of imines (4a–g) with phthalic anhydride in microwave oven gave seven 1,3-benzoxazepine-1,5-diones (5a–g) bearing oxadiazole moiety. Screening verves of final benzoxazepines was done on Staphylococcus aurous and Escherichia coli. The implications explained that compounds (5b, 5c, 5d, 5e, 5f and 5g) possess higher effect than gentamycin against Staphylococcus aurous. Moreover, the 1,3-oxazepine-1,5-diones (compounds 5a, 5b, 5c, 5d, and 5g) appeared better action against Escherichia coli comparably with the standard antibiotic.

KEYWORDS: 1,3-Benzoxazepine-1,5-diones, Cyclic Anhydrides, Imines, 1,3,4-Oxadiazoles, Antibacterial Activity.

1. INTRODUCTION:

Many of synthesized or natural product compounds that held seven-membered heterocyclic ring showed various biological verves¹. Benzoxazepine was introduced in 1965 for use in relief of the psychoneuroses characterized by anxiety and tension². Compounds containing oxazepine fused with benzene or other heterocyclic rings indicated several interesting and promising biological actions^3-6, like antihistaminic⁷, anti-HIV30^8,9, antidepressant¹⁰ , and antitumor activities¹¹. Anti-inflammatory¹². Asendin (Amoxapine) drug is used as antidepressant¹³ and active drug for schizophrenia¹⁴, hypnotic muscle relaxant², antiepileptic³, oxazepine compounds possess biological and medicinal prominence^15-18, in addition to pharmaceutical applications^19,20. Some oxazepine derivatives showed inhibitory effects on several enzymes²¹ and protein 90 (HSP90)²².

1,3,4-Oxadiazoles represent an interesting kind of heterocyclic compounds²³, also possess an importance in medicinal chemistry^24,25, pesticide chemistry²⁶ and field of polymers²⁷. Oxadiazoles also possess antitubercular^28,29, antimalarial³⁰, antileishmanial³¹, anticancer^32,33, antimicrobial^34,35, anti-inflammatory^36-38, analgesic^39,40, anti-HIV⁴¹, as a potential inhibitors of acetylcholinesterase⁴² and β-glucuronidase⁴³. Various methods for synthesizing oxadiazoles were published^44,45, and discussed with their pharmacological activities^46,47,. So, the synthesis and antibacterial actions of novel 1,3-benzoxazepine-1,5-diones bearing the biologically active 1,3,4-oxadiazole was reported in this article.

2. MATERIAL AND METHODS:

2.1. Chemicals and reagents:

4-Aminobenzoyl hydrazide was procured from Sigma Aldrich. Potassium hydroxide, Sodium nitrite, Sodium hydroxide, 4-chloroaniline, 2-chloroaniline, 2,4-dichloroaniline, 4-bromoaniline, Ethyl acetate and dimethyl sulfoxide were supplied from (BDH). Carbon disulfide, benzene and iodine by (GCC, Germany). 4-Nitrooaniline, 3-nitroroaniline, 2-nitroaniline and phthalic anhydride were purchased from Fluka. Ethanol (absolute) from J.T. Baker, Netherlands. Diethyl ether and n-Hexane from Scharlau, Spain. 2-Hydroxy benzaldehyde by S.D. Fine, India. Hydrochloric acid (Conc.) from Merck, Germany.

2.2. Synthesis of 5-(4-aminophenyl)-2-thiol-1,3,4-oxadiazole (2)⁴⁸

(1.51g, 10mmol) of 4-aminobenzoyl hydrazide (1) was dissolved in absolute ethanol (25mL) and put on ice bath. Carbon disulfide (1mL) was added drop-wise to this mixture with stirring, then potassium hydroxide (0.56g, 10mmol) was added. The reaction mixture was stirred for 15 min, then heated under reflux for 24 h in 70ºC. TLC (n-hexane: Ethyl acetate, 1:1, Rf = 0.64) showed that the reaction was completed. The mixture was then cooled to 25ºC. Evaporation of ethanol was done under vacuum, then (100mL) of water was added to the producing solid and acidification by (HCl). The crude solid was purified by recrystallization by ethyl alcohol to obtained pale yellow crystals, yield (1.4475g, 75 %), m.p. 234-236ºC.

2.3. Synthesis (E)-2-hydroxy-5-((4-(5-mercapto-1,3,4-oxadiazol-2-yl)phenyl)diazenyl)benzaldehyde (3)⁴⁹:

Compound (2) (1.93 g, 10mmol) was dissolved in (HCl: 3.2 mL) and (H₂O: 10mL) and cooled near (0°C), then (NaNO₂: 0.69g, 10mmol) in (H₂O: 5mL) was added. After that, (15mL) of (NaOH: 10%w/v)) was added to (1.22g, 10mmol) of salicylaldehyde with cooling near (5°C), addition of diazonium salt to phenoxide solution done drop by drop, then neutralized. The red solid was purified via recrystallization by ethyl alcohol, yield (1.956 g, 60 %), m.p. 166-168ºC.

2.4. General procedure for preparing imines (4a–g):

A mixture of aldehyde (3) (0.326g, 1mmol), anilines (1mmol) in ethanol (1mL) has been irradiated at (330W) for (30-40) min. End of reactions done by TLC (n-hexane: Ethyl acetate, 1:3). The crude yields have been recrystallized using ethanol.

2.5. General procedure for the preparation of 1,3-benzoxazepine-1,5-diones (5a–g):

Imines (4a–g) (1mmol), phthalic anhydride (0.148g, 1 mmol) and benzene (1 mL) were irradiated at (330W) for (30-40) min. TLC (n- hexane: EtOAc, 1:1) End of reactions done by TLC (n-hexane: Ethyl acetate, 1:1). The crude yields have been recrystallized using ethanol, (Figure 1).

2.6. Analytical Characterization:

The reactions were monitored by (TLC) through plates of silica (0.2mm, 60 F₂₅₄) and detection carried out with iodine vapor. Implementing melting points done by Stuart SMP Electro thermal 30 capillary (MP) apparatus. Deducing infrared done by Infrared Spectrophotometer SHIMADZU FTIR–8400S through (KBr) disc. Collection of proton magnetic resonance spectra were carried out using INOVA 500 MHz varian, USA NMR spectrometer using deutrated dimethylsulfoxid solvent, at University of Tehran, Iran. (CHNS) Analyses have been measured via Perkin Elmer 300A at University of Tehran, Iran.

Table 1: Some characteristics of compounds (4a-g) and (5a-g)

Entry	Physical state	Rf (developer)	Mp (^oC)	Yield (%)	Time (min)
4a	Dark brown solid	0.88 (n-hexane/EtOAc. 1:3)	224-226	72	40
4b	Brown solid	0.76 (n-hexane/EtOAc. 1:3)	128-130	82	30
4c	Brown solid	0.92 (n-hexane/EtOAc. 1:3)	233-235	79	30
4d	Brown solid	0.90 (n-hexane/EtOAc. 1:3)	124-126	83	30
4e	Brown solid	0.91 (n-hexane/EtOAc. 1:3)	179-181	80	30
4f	Brown solid	0.86 (n-hexane/EtOAc. 1:3)	165-167	62	33
4g	Dark brown solid	0.82 (n-hexane/EtOAc. 1:3)	169-171	85	35
5a	Brown solid	0.96 (n-hexane/EtOAc. 1:1)	233-235	74	40
5b	Brown solid	0.93 (n-hexane/EtOAc. 1:1)	184-186	61	30
5c	Dark brown solid	0.94 (n-hexane/EtOAc. 1:1)	199-201	83	30
5d	Brown solid	0.95 (n-hexane/EtOAc. 1:1)	177-179	95	30
5e	Brown solid	0.92 (n-hexane/EtOAc. 1:1)	138-140	94	30
5f	Brown solid	0.86 (n-hexane/EtOAc. 1:1)	135-137	89	30
5g	Dark brown solid	0.82 (n-hexane/EtOAc. 1:1)	191-193	88	35

2.7. Preliminary antibacterial action athwart Staphylococcus aurous and Escherichia coli using Gentamycin as standard drug:

All prepared 1,3-benzoxazepine-1,5-diones (5a–g) have been tested athwart Staphylococcus aurous and Escherichia coli bacteria using diffusion method⁵⁰. Both isolated germs have been pollinated using (MHA) sanitizes via autoclave through dousing a cotton wipe in suspension and striping on agar surface.

Table 2: The activities of benzoxazepines (5a-g) athwart bacteria

Entry	*Staphylococcus aurous*	*Escherichia coli*
5a	13	17
5b	20	17
5c	18	17
5d	20	20
5e	20	14
5f	19	15
5g	20	18
DMSO	0	0
Gentamycin	15	15

After that, seven pits have been done (6mm) in solidified medium,. 0.5ml taken from each compound (10mg in 1 mL of dimethyl sulfoxide) put in pits. All dishes have been embosomed around 37^oC and inhibition areas recorded after (24 h). (Table 2).

Figure1 Synthetic scheme for new 1,3-benzoxazepine-1,5-diones, (i) CS₂, KOH, EtOH, 70^oC, 24 h; (ii) Conc. HCl; (iii) NaNO₂, HCl, 0-5^oC; (iv) 2-hydroxybenzaldehyde, NaOH 10% , 5^oC; (v) Ar-NH₂, EtOH, MW (330W), (30-35 min); (vi) phthalic anhydride, benzene, MW (330W), (30-40 min).

3. RESULTS AND DISCUSSION:

5-(4-aminophenyl)-2-thiol-1,3,4-oxadiazole (2) have been synthesized by treatment of 4-aminobenzoyl hydrazide (1) with (CS₂) and potassium hydroxide in absolute ethanol⁴⁸. compound (2) was reacted with (HCl/ NaNO₂) to produce diazonium salt which reacted with salicylaldehyde to give azoaldehyde (3)⁴⁹. compound (3) was condensed with (4-nitroaniline, 3-nitrroaniline, 2-nitroaniline, 4-chloroaniline, 2-chloroaniline, 2,4-dichloroaniline and 4-bromoaniline) using (MW) method in ethanol to yield seven Schiff bases (4a–g). Reaction of Schiff bases (4a-g) with phthalic anhydride by (MW) irradiation afforded 1,3-benzoxazepine-1,5-diones (5a–g), Figure (1).

Structures of newly synthesized compounds were proven by elemental analysis, infrared, and (¹H NMR) spectra.

The IR spectrum of oxadiazole derivative (2) indicated the disappearance of the sharp doublet band for hydrazide group (-NHNH₂) around (3307, 3236) cm^-1 and the strong band at 1627 cm^-1attributed to (C=O)str. in compound (1), additionally the appearance of the following characteristic bands: the doublet band at 3450 cm^-1 and 3352 cm^-1assigned to (-NH₂)str. substituted in benzene ring, the strong band at 1606 cm^-1belong to the oxadiazolic (C=N)str. and (-NH₂)bend. due to the vibration coupling interaction.

The weak and strong bands at 2592 cm^-1 and 1068 cm^-1due to (S-H)str. and (C=S)str. in thioenol and thioketone forms, respectively. The IR spectrum of azo-oxadiazole derivative (3) showed the absence of a doublet band at 3450 cm^-1 and 3352 cm^-1 for (-NH₂)str. and appearance of the following characteristic bands: the weak band at 1417 cm^-1assigned to azo group (N=N)str., the broad band at 3074 cm^-1due to (O-H)str., the peak around 1658 cm^-1belong to carbonyl stretching., the oxadiazolic imine stretching. appeared at 1599 cm^-1. Compounds (4a–g) pointed absence the band at 1658 cm^-1assigned to (C=O) absorption, also disappearance absorptions of (-NH₂) around (3400-3250) cm^-1, meanwhile appearance band at (1604-1626) cm^-1attributed to imine group. 1,3-benzoxazepine-1,5-diones (5a–g) appeared band at 1597-1612 cm^-1 due to imine function of oxadiazole, in addition to appearance peak around 1703-1722 cm^-1assigned to (O=C-N and O=C-O) functions of oxazepine. (Table 3).

The structures of benzoxazepine compounds (5a-g) were deduced by their¹H NMR spectra (500 MHz, DMSO-d₆) which showed the (N-H) proton for thione form as a singlet at 11.61, 11.23, 11.44, 12.19, 12.19, 12.66 and 10.93 ppm, respectively^51,52. The thiolic (S-H) hydrogen around δ 11.44, 11.07, 10.85, 11.45, 11.45, 11.45 and 10.64 ppm. Phenolic proton around δ 10.32, 9.40, 10.56, 10.92, 10.16, 10.31 and 9.98 ppm, respectively. The signals of aromatic protons and hydrogen of oxazepine appeared at δ 6.53-8.42 ppm. Elemental analysis consequences appeared very good concordance with proposed constitutions (Table 4).

Table 3: FT-IR Data of compounds (4a–g) and (5a–g) in cm^-1

Compound Code	IR Spectral Study
4a	3335 (νO-H), 3215 (νN-H, thione), 3059 νC-H, benzene), 1626 (νC=N, imine), 1597 (νC=N, oxadiazole), 1558 and 1498 (νC=C, benzene), 1541 (νas.NO₂), 1413 (νN=N), 1329 (νs.NO₂), 1109 (νC=S, thione), 839 (δo.o.p.C-H, benzene).
4b	3329 (νO-H), 3209 (νN-H), 3076 (νC-H, benzene), 1608 (νC=N, imine and νC=N, oxadiazole, overlapped), 1506 (νC=C, benzene and νas.NO₂, overlapped), 1419 (νN=N), 1346 (νs.NO₂), 1064 (νC=S, thione), 734 (δo.o.p.C-H, benzene).
4c	3468 (νO-H), 3363 (νN-H, thione), 3047 (νC-H, benzene), 1610 (νC=N, imine and νC=N, oxadiazole, overlapped), 1562 and 1498 (νC=C, benzene), 1539 (νas.NO₂), 1421 (νN=N), 1336 (νs.NO₂), 1053 (νC=S, thione), 736 (δo.o.p.C-H, benzene).
4d	3352 (νO-H), 3230 (νN-H, thione form) 3055 (νC-H, benzene), 1624 (νC=N, imine), 1606 (νC=N, oxadiazole), 1541 and 1491 (νC=C, benzene), 1413 (νN=N), 1091 (νC=S, thione form), 829 (δo.o.p.C-H, benzene).
4e	3350 (νO-H), 3211 (νN-H, thione form), 3063 (νC-H, benzene), 1604 (νC=N, imine and νC=N, oxadiazole, overlapped), 1566, 1531 and 1498 (νC=C, benzene), 1417 (νN=N), 1060 (νC=S, thione), 748 (δo.o.p.C-H, benzene).
4f	3335 (νO-H), 3200 (νN-H,), 3091 (νC-H, benzene), 1606 (νC=N, imine and νC=N, oxadiazole), 1568, 1504 and 1483 (νC=C, benzene), 1415 (νN=N), 1066 (νC=S,), 839 (δo.o.p.C-H, benzene).
4g	3174 (νO-H and νN-H, thione, overlapped), 3049 (νC-H, benzene), 1610 (νC=N, imine and νC=N, oxadiazole, overlapped), 1568, 1537 and 1491 (νC=C, benzene), 1408 (νN=N), 1070 (νC=S, thione), 825 (δo.o.p.C-H, benzene).
5a	3317 (νO-H), 3211 (νN-H, thione form), 3068 (νC-H, benzene), 1718 (νC=O, O=C-O and O=C-N, oxazepine, overlapped), 1597 (νC=N, oxadiazole), 1506 (νas.NO₂and νC=C, benzene, overlapped), 1419 (νN=N), 1334 (νs.NO₂),1111 (νC=S, thione), 839 (δo.o.p.C-H, benzene).
5b	3460 and 3342 (νO-H), 3217 (νN-H, thione), 3088 (νC-H, benzene), 1716 (νC=O, O=C-O and O=C-N, oxazepine, vib. coupling), 1604 (νC=N, oxadiazole), 1525 (νas.NO₂and νC=C, benzene, overlapped), 1419 (νN=N), 1346 (νs.NO₂),1070 (νC=S, thione), 729 (δo.o.p.C-H, benzene).
5c	3279 (νO-H), 3190 (νN-H, thione), 3064 (νC-H, benzene), 1714 (νC=O, O=C-O and O=C-N, oxazepine, overlapped), 1602 (νC=N, oxadiazole), 1568 and 1533 (νC=C, benzene), 1500 (νas.NO₂), 1421 (νN=N), 1373 (νs.NO₂),1076 (νC=S, thione), 711 (δo.o.p.C-H, benzene).
5d	3483 and 3410 (νO-H), 3269 (νN-H, thione), 3064 (νC-H, benzene), 1714 (νC=O, O=C-O and O=C-N, oxazepine, overlapped), 1612 (νC=N, oxadiazole), 1550 and 1492 (νC=C, benzene),1082 (νC=S, thione), 713 (δo.o.p.C-H, benzene).
5e	3383 (νO-H), 3244 (νN-H, thione), 3064 (νC-H, benzene), 1714 (νC=O, O=C-O and O=C-N, oxazepine, overlapped), 1604 (νC=N, oxadiazole), 1566, 1533 and 1496 (νC=C, benzene), 1423 (νN=N), 1072 (νC=S, thione), 715 (δo.o.p.C-H, benzene);
5f	3470 (νO-H), 3308 (νN-H, thione), 3059 (νC-H, benzene), 2922 (νasC-H, CH₃), 2864 (νsC-H, CH₃), 1718 (νC=O, O=C-O and O=C-N, oxazepine, overlapped), 1600 (νC=N, oxadiazole), 1543 and 1500 (νC=C, benzene), 1076 (νC=S, thione), 715 (δo.o.p.C-H, benzene.
5g	3468 (νO-H), 3294 (νN-H, thione), 3064 (νC-H, benzene), 1714 (νC=O, O=C-O and O=C-N, oxazepine, overlapped), 1668 (νC=O, amide), 1606 (νC=N, oxadiazole), 1512 (νC=C, benzene), 1408 (νN=N),1074 (νC=S, thione), 713 (δo.o.p.C-H, benzene.

Table 4: (CHNS) Elemental analysis of compounds (5a–g)

Entry	Calculated %				Found %
Entry	C	H	N	S	C	H	N	S
5a	58.58	3.05	14.13	5.39	58.96	3.37	14.50	5.07
5b	58.58	3.05	14.13	5.39	58.25	3.36	14.47	5.72
5c	58.58	3.05	14.13	5.39	58.46	3.44	14.49	5.75
5d	59.64	3.11	11.99	5.49	59.57	3.46	12.06	5.11
5e	59.64	3.11	11.99	5.49	59.40	3.48	12.38	5.10
5f	56.32	2.77	11.32	5.18	56.61	3.02	10.94	4.83
5g	55.42	2.89	11.14	5.10	55.08	3.28	11.51	5.46

Antibacterial activity performed at concentration (10mg/mL) using gentamycin as reference antibiotic against Staphylococcus aurous and Escherichia coli. Compounds 5b, 5c, 5d, 5e, 5f and 5g have more action than gentamycin athwart Staphylococcus aurous. Meanwhile, the 1,3-oxazepine-1,5-diones (compounds 5a, 5b, 5c, 5d, and 5g) appeared higher effect against Escherichia coli comparably with the standard antibiotic.

4. CONCLUSIONS:

Most of synthesized 1,3-benzoxazepine-1,5-diones showed greater effect against positive and negative bacteria than that of control drug. Compounds 5b, 5c, 5d, 5e, 5f and 5g have better effect than standard antibiotic against positive germ, whereas benzoxazepines 5a, 5b, 5c, 5d, and 5g appeared better activity to standard antibiotic against negative germ.

5. ACKNOWLEDGEMENTS:

Thanks to staff of central lab., University of Tahran, Iran for recording ¹H NMR and elemental analysis for the target compounds.

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Received on 09.01.2020 Modified on 16.05.2020

Research J. Pharm. and Tech. 2021; 14(4):1837-1841.

DOI: 10.52711/0974-360X.2021.00416