Their activities against bacteria and fungi are interesting. They also have used as anticonvulsant and anti-tuberculosis (Al Adhreai et al., 2022; Ibrahim et al., 2012; Salman, 2019).

Various methods have been used for the synthesis of nitrone derivatives (Murahashi & Imada, 2019), but their preparation by condensation reaction between derivatives of N- monosubstituted hydroxyamines and different substituted aldehydes or ketones is the most common method (Mahieddine et al., 2016; West & Davis, 1989).

The aim of the present study includes the synthesis of some new biologically active nitrone derivatives, because, the development of novel antimicrobial drugs is still in demand as there is increasing resistance of microorganisms to currently available antimicrobial drug.

MATERIALS AND METHODS

The substances and solvents used in this study as well as the characterization were as follows:

NH₄Cl, sodium sulphate anhydrous and zinc dust (SDFCL), diethyl ether (Scharlau), ethyl acetate (Licrosolv), ethanol (Hongwell), and all aldehyde and nitro compounds were obtained from commercial lab in China. All materials and solvents were utilized without purification.

The progress of the reactions and purity of the synthesized nitrones were monitored by thin layer chromatography (TLC) plate (60F-254-Buchs, Switzerland) in which the aluminum plate was pre-coated with silica gel. Ethyl acetate and toluene (3:1) were used as the developing solvent, and the results were observed by UV light.

¹H-NMR and ¹³C NMR characterization were done by 500 and 126 MHz (Ascend) respectively in Kurd Central Research Facilities (KCRF) in Iran. FT-IR spectrometer was determined by Shimadzu, KBr disk in Salahaddin University-Erbil. Melting points were also measured in Salahaddin University-Erbil by Stuart Scientific melting point apparatus (SMP3).

2.1. Synthesis of phenylhydroxylamine derivatives

All procedures were modified and derived from (Mahieddine et al., 2016; West & Davis, 1989).

In a (500 mL) beaker was added (0.033 mol) of substituted nitrobenzene to (240 mL) distilled water, then added (0.087 mol) of Zn dust and stirring for (20) minutes. The temperature was in the ranges of (60-65) °C. At the end of 20 minutes, the solution was stirred for another 15 minutes. The mixture was filtered and washed with hot distilled water. The filtrate was supersaturated with NaCl and kept in an ice container for 2 hr in a dark place, then extracted with (3*70 mL) of diethyl ether.

Diethyl ether part dried with sodium sulphate anhydrous, and then evaporated to obtain the desired corresponding phyneylhydroxylamine. The product was unstable and was put directly into the next reaction.

2.2. Procedure A: Synthesis of Nitrone (N1-N8)

In a (50 mL) round bottom flask, a mixture of (0.0046 mol) of phenylhydroxyamine derivatives and (0.0046 mol) of one of the substituted benzaldehydes in (15 mL) of the pure ethanol was refluxed for 2-3 hr in the range of (50-55) °C. The progress of the reaction was monitored by TLC plate. Then the mixture was stirred at r.t in the dark for 18 hr. The desired product (figure

1), was filtered, recrystallized with ethanol, and then washed with diethyl ether.

2.3. Procedure B: Synthesis of nitrone (N9)

In a (100 mL) conical flask, (0.0046 mol) of 4-nitrobenzyl bromide with (35 mL) of ethanol 85% and (0.0046 mol) of NH₄Cl were mixed. The temperature was set in the range of (7-10) ^oC, and then (0.0184 mol) of zinc dust was added gradually over 2 hr with stirring. After the addition was complete, the mixture was filtered and 3-methylbenzaldehyde was added to the filtrate and then refluxed in the range of (50-55) ^oC. The progress of the reaction was monitored by TLC plate, and after 2 hr the mixture was stirred overnight in the dark at r.t. The desired nitrone (figure 2) was filtered, and then recrystallized with ethanol and washed with diethyl ether.

2.4. -(3,4-dichlorophenyl)-1-phenylmethanimine oxide (N1)

White crystal, m.p= 140-141 ⁰C, yield= 65%, R_f= 0.64

IR (KBr/ v_max/ cm^-1): 3099.61 (Ar-H) stretching, 1577.77 (C=N), 1463.97-1546.91 (C=C), 1068.56 (N⁺-O^-), 761.88 (Ar-H) out-of-plane/ bending. ¹H-NMR [500 MHz, CDCl₃, δ (ppm)]: 8.3701(s, 1H, H-C₁₂), 7.9306 (s, 1H, H-C₅), 7.9266 (d, 1H, H-C₂), 7.8962 (d, 1H, H-C₁), 7.4748-7.6387 (m, 5H, H-C₁₆, H-C₁₅ and H-C₁₇, H-C₁₄ and H-C₁₈) H-C₁₅ and H-C₁₇ have a same chemical shifting, ¹³C NMR [126 MHz, CDCl₃, δ (ppm)]: 147.79, 134.82, 134.17, 133.32, 131.51, 130.77, 130.17, 129.25, 128.77, 123.93, 120.81.

Figure 2Structure of N-(4-(bromomethyl) phenyl)-1-(p-tolyl) methanimine oxide

2.5. N

2.6. N-(3,4-dichlorophenyl)-1-(p-tolyl)methanimine (N2)

White, m.p = 165-167 ⁰C, yield=56.0 % , R_f = 0.61

IR (KBr/ v_max/ cm^-1): 3099.61 (Ar-H) stretching, 2835.66 aliphatic (C-H), 1575.84 (C=N), 1544.98-1415.75, (C=C), 1070.49 (N⁺-O^-), 725.23 (Ar-H) out-of-plane/ bending. ¹H-NMR [500 MHz, CDCl₃, δ (ppm)]: 8.2898 (s, 1H, H-C₁₂), 8.0305-7.7869 (m, 4H, H-C₁₄, H-C₁₅, H-C₁₇, H-C₁₈₎, 7.7548-7.3017 (m, 3H, H-C₁, H-C₂, H-C₅), 2.4286 (s, 3H, H-C₁₉). ¹³C NMR [126 MHz, CDCl₃, δ (ppm)]: 163.05, 134.87, 134.01, 133.28, 130.75, 130.72, 129.59, 129.35, 127.55, 123.91, 120.86, 21.93.

2.7. N-(3,4-dichlorophenyl)-1-(2-nitrophenyl) methanimine oxide (N3)

Yellow powder, m.p= 117-119 ⁰C, yield= 74%, Rf= 0.71

IR (KBr/ v_max/ cm^-1): 3097.68 (Ar-H) stretching, 1568.13 (C=N), 1568.13-1419.61(C=C), 1078.43 (N⁺-O^-), 731.02 (Ar-H) out-of-plane/ bending. ¹H-NMR [500 MHz, CDCl₃, δ (ppm)]: 8.5897 (d, 1H, H-C₁₈), 8.5781 (s,1H, H-C₁₂), 8.4090 (d, 1H, H-C₁), 8.4067 (d, 1H, H-C₁₅), 8.1339 (t, 1H, H-C₁₆), 7.9961 (t,1H, H-C₁₇), 7.5387 (d, 1H, H-C₂), 7.5299 (s, 1H, H-C₅). ¹³C NMR [126 MHz, CDCl₃, δ (ppm)]: 147.85, 147.52, 135.06, 133.66, 133.65, 130.98, 130.92, 129.52, 128.80, 125.19, 124.13, 124.06, 120.81.

2.8. N-(3,4-dichlorophenyl)-1-(3,4-dimethoxyphenyl)methanimine oxide (N4)

yellow powder, m.p=78-80 ⁰C, yield= 49%, R_f= 0.57

IR (KBr/ v_max/ cm^-1): 3080.32 (Ar-H) stretching, 2935.66 and 2833.43 aliphatic (C-H), 1587.42 (C=N), 1575.84-1456.26 (C=C), 1070.64 (N⁺-O^-), 740.67 (Ar-H) out-of-plane/ bending. ¹H-NMR [500 MHz, CDCl₃, δ (ppm)]: 8.4517 (s,1H, H-C₁₂), 7.9204 (s,1H, H-C₅), 7.8333 (s, 1H, H-C₁₈), 7.6338 (d, 1H, H-C₁), 7.5028 (d, 1H, H-C₂), 6.9198 (d, 2H, H_14,H-C₁₅), 3.9409 (s, 3H, H-C₂₀ in methoxy), 3.9532 (s, 3H, H-C₂₀ in methoxy). ¹³C NMR [126 MHz, CDCl₃, δ (ppm)]: 151.68, 148.54, 147.52, 134.85, 133.84, 133.26, 130.73, 124.52, 123.66, 123.41, 120.57, 111.16, 110.73, 55.99.

So far, in practical work, nitrobenzene containing electron withdrawing groups (two chlorine groups) have been studied, and from this section to 2.11 the nitrobenzene with electron donating groups (two methyl groups) have been considered.

2.9. N-(3,4-dimethylphenyl)-1-phenylmethanimine oxide (N5)

Pale yellow powder, m.p=66-68 ⁰C, yield= 69.3%, R_f= 0.76.

IR (KBr/ v_max/ cm^-1): 3064.89 (Ar-H) stretching, 2839.22 Aliphatic (C-H), 1581.63 (C=N), 1517.98-1456.26 (C=C), 1078.14 (N⁺-O^-), 775.38 (Ar-H) out-of-plane/ bending. ¹H-NMR [500 MHz, CDCl₃, δ (ppm)]: 8.3888 (d,1H, H-C₁), 7.8911 (s,1H, H-C₁₂), 7.8525 (s, 1H, H-C₅), 7.5719-7.4603 (m, 5H, H-C₁₄, H-C₁₅, H-C₁₆, H-C₁₇, H-C₁₈), 7.2052 (d, 1H, H-C₂), 2.3301 (s, 3H, H-C₈), 2.3108 (s, 3H, H-C₉). ¹³C NMR [300 MHz, CDCl₃, δ (ppm)]: 147.02, 138.83, 137.76, 134.21, 130.81, 130.461, 130.03, 129.02, 128.61, 122.73, 118.79, 19.91, 19.53.

2.10. N-(3,4-dimethylphenyl)-1-(p-tolyl)methanimine oxide (N6)

Yellow crystal, m.p=101-102 ⁰C, yield= 61.9%, R_f= 0.73.

IR (KBr/ v_max/ cm^-1): 3022.45 (Ar-H) stretching, 2976.16-2918.30 Aliphatic (C-H), 1598.99 (C=N), 1564.27-1417.68 (C=C), 1070.49 (N⁺-O^-), 768.32 (Ar-H) out-of-plane/ bending. ¹H-NMR [500 MHz, CDCl₃, δ (ppm)]: 8.2928 (d,2H, H-C_14,H-C₁₈) 7.8429 (s, 1H, H-C₁₂), 7.5725 (s, 1H, H-C₅), 7.4646 (d,1H, H-C₁ ) 7.2889 (d, 2H, H-C₁₅, H-C₁₇), 7.1872 (d, 1H, H-C₂), 2.4035 (s, 3H, H-C₁₉), 2.3196 (s, 3H, H-C₈), 2.2989 (s, 3H, H-C9). ¹³C NMR [126 MHz, CDCl₃, δ (ppm)]: 147.03, 141.25, 138.58, 137.67, 134.04, 129.97, 129.57, 129.31, 129.06, 128.26, 122.69, 118.72, 21.76, 19.90, 19.51

c

.

2.11. N-(3,4-dimethylphenyl)-1-

(2-nitrophenyl)methanimine oxide (N7) yellow powder, m.p=116-118 ⁰C, yield= 81%, R_f= 0.72.

IR (KBr/ v_max/ cm^-1): 3032.10 (Ar-H) stretching, 2935.66-2914.44 Aliphatic (C-H), 1564.27 (C=N), 1516.05 (C=C), 1072.42 (N⁺-O^-), 790.81(Ar-H) out-of-plane/ bending. ¹H-NMR [500 MHz, CDCl₃, δ (ppm)]: 8.5507 (s,1H, H-C₁₂), 8.0700 (d,1H, H-C₁), 7.7466 (t, 1H, H-C₁₇), 7.5529 (d, 1H, H-C₁₅), 7.4973 (d, 1H, H-C₁₈), 7.2402 (t,1H, H-C₁₆), 7.2322 (d, 1H, H-C₂), 7.1063 (s,1H, H-C₅),2.3455 (s,3H, H-C₉), 2.3276 (s, 3H, H-C₈). ¹³C NMR [126 MHz, CDCl₃, δ (ppm)]: 154.57, 147.51, 147.22, 139.66, 137.97, 130.24, 129.42, 127.79, 124.97, 124.75, 122.70, 118.89, 106.83, 19.93, 19.60.

2.12. 1-(3,4-dimethoxyphenyl)-N-(3,4-dimethylphenyl)methanimine (N8)

Light-yellow powder, m.p=108-110 ⁰C, yield= 58% , R_f= 0.78.

IR (KBr/ v_max/ cm^-1): 3020.53 (Ar-H) stretching, 2964.59-2918.30 Aliphatic (C-H), 1577.77 (C=N), 1508.33 (C=C),

1076.27 (N⁺-O^-), 759.96 (Ar-H) out-of-plane/ bending. ¹H-NMR [500 MHz, CDCl₃, δ (ppm)]: 8.3551(s,1H, H-C₁₂), 8.0723 (s, 1H, H-C₅), 8.0099 (d, 1H, H-C₁), 7.9977 (s, 1H, H-C₁₄), 7.2410 (d, 1H, H-C₂), 7.1565 (d, 1H, H-C₁₇), 6.9371 (d, 1H, H-C₁₈), 4.0098 (s, 3H, H-C₁₉), 3.9598 (s, 3H, H-C₂₀), 2.3667 (s, 3H, H-C₉), 2.3364 (s, 3H, H-C₈). ¹³C NMR [126 MHz, CDCl₃, δ (ppm)]: 159.04, 140.55, 137.27, 136.84, 130.31, 129.71, 126.85, 123.08, 122.99, 122.24, 119.61, 118.10, 110.47, 56.04, 19.90, 19.72.

2.13. N-(4-(bromomethyl) phenyl)-1-(p-tolyl) methanimine oxide (N9)

Yellow powder, m.p=176-178 ⁰C, yield= 38.5%, R_f= 0.72.

IR (KBr/ v_max/ cm^-1): 3010.88 (Ar-H) stretching, 2956.87-2866.22 Aliphatic (C-H), 1597.06 (C=N), 1419.81-1577.77 (C=C), 1076.14 (N⁺-O^-), 759.95(Ar-H) out-of-plane/ bending. ¹H-NMR [300 MHz, CDCl₃, δ (ppm)]: 8.5353(s,1H, H-C₁₀), 8.3316-7.9014 (m, 4H, H-C_1,H-C_2,H-C_4,H-C₅), 7.8721- 7.6776 (m, 4H, H-C_12,H-C_13,H-C_15,H-C₁₆), 3.0569 (s, 2H, H-C18), 2.4448 (s, 3H, H-C17). ¹³C NMR [126 MHz, CDCl₃, δ (ppm)] 136.84, 130.96, 130.39, 126.84, 124.51, 123.08, 122.98, 122.53, 119.61, 57.18, 19.90.

2.14. Antibacterial and antifungal activity of nitrone derivatives

Activities of nitrones (N1-N9) were studied with two concentrations (1000 and 500) µg/ mL in dimethyl sulfoxide (DMSO) as antibacterial against E. coli as Gram-negative bacteria and S.aureus as Gram-positive bacteria and also as an antifungal Candida albicans fungi. Agar well diffusion method was used for the antibacterial activity of synthesized nitrones. After autoclaving of Mueller-Hinton Agar (MHA) was cooled to 55°C and poured onto petri dishes. Then, with sterilized swabs, E. coli and S.aureus bacteria were completely streaked on them until they solidified and left for half an hour. After that, four wells of 8 mm were made on agar and (100 μL) of dimethyl sulfoxide, two different concentrations of synthesized nitrones and levofloxacin as a standard drug were placed. After incubation at 37°C for 28 hr, the zones of inhibition were determined in mm (Lino & Deogracious, 2006).

Antifungal activities of synthesized nitrones were compared with clotrimazole as a standard drug against Candida albicans. Sabouraud dextrose was used as the growth medium. 8 mm wells were cut and (100 μL) of two different concentrations of synthesized nitrone, DMSO and standard drug were placed. After incubation at 37°C for 28 hr, the zones of inhibition were determined in mm (Salman & Majeed, 2013) .

RESULTS AND DISCUSSION

In this study, the starting materials for the synthesis of these nitrones (N1-N9) were nitrobenzene compounds in which bearing electron donating and electron withdrawing groups. Both types converted to corresponding phenylhydroxyl amine by Zn dust in aqueous solution and 85% of ethanol in presence of NH₄Cl as a weak acid. Synthesized phenylhydroxylamines were converted to new nitrones after condensation reaction with various substituted benzaldehydes (scheme 3 and scheme 4).

In the (N1-N4), the aromatic nitro compounds that had two Cl groups, after converted to corresponding phenylhydroxylamine and condensation reaction with four types of substituted benzaldehydes (benzaldehyde, 3-chloro benzaldehyde, 2-nitrobenzaldehyde and 3,4-dimethoxybenz aldehyde), the higher yields were obtained when benzaldehyde was (2-nitrobenzaldehyde). The reason for this was the presence of the nitro group in the ortho position of benzaldehyde. It was an electron withdrawing group and increased electrophilicity of benzaldehyde and when a nucleophile (exist pair of electron on N atom) such as N-(3,4-dichlorophenylhydroxylamine) reacted with this benzaldehyde, the yield was higher than other three substituents of benzaldehydes (section 2.6, N3).

The lowest yield in this reaction was observed when N- (3,4-dichlorophenylhydroxylamine) reacted with (3,4-dimethoxy benzaldehyde) due to the electron donating of methoxy groups (-OCH₃) in the benzaldehyde, which reduced the electrophilicity of the benzaldehyde and slower reaction occurred when attacked by nucleophile (section 2.7, N4).

In N5, N6, N7 and N8 all the topics described for (N1-N4), were applied to these synthesized nitrones, and therefore, it had the highest yield in N7 (section 2.10).

In these reactions when used two starting materials, one of them 1,2-dichloro-4-nitrobenzene and the other 1,2-dimethyl-4-nitrobenzene (scheme 3), their differences were in the types of substitutitionsa. In 1,2-dichloro-4-nitrobenzene there were two Cl groups, which were electron withdrawing groups. These groups were causes a lower yield when compared to 1,2-dimethyl-4-nitrobenzene (compare yields of N1 and N5, N2 and N6, N3 and N7, N4 and N8). Due to the presence of two electron donating groups CH₃ in 1,2-dimethyl-4-nitrobenzene with the same substituted benzaldehydes, the yield of synthesized nitrones was higher compared to 1,2-dichloro-4-nitrobenzene (West & Davis, 1989) .

Although N9 could not be prepared by method A and was prepared by method B, its yield was lower than other nitrones (scheme 4).

According to the studies of HK Kim (Kim et al., 1970) and Mariana C. Ferraz (Ferraz et al., 2017) on nitrone derivatives, it has been clearly shown that substitutions have a significant effect on the biological activities of nitrones. Their activities were considered accordingly, for two types of bacteria: E. coli as Gram negative bacteria, S. aureus as Gram-positive bacteria and also were considered as antifungal against Candida albicans fungi. The results were interesting. In general, the activity of synthesized nitrones in these two concentrations against Candida albicans was better than their activity against the mentioned bacteria. In nitrones (N1-N4), the presence of two methoxy groups in (Ar-CH=N) moiety caused inactivation of (N4) against E.coli, and when NO₂ was present in (Ar-CH=N) moiety, the activity of nitrone was improved against E.coli bacteria and fungi (N3). The presence of CH₃ in mentioned moiety prevented the growth of E.coli and S. aureus bacteria and Candida albicans in nitrone (N2).

In nitrones (N5-N8), their activity was better than the previous nitrones, and the presence of two methoxy groups in (Ar-CH=N) moiety caused the activity of nitrone (N8) to be high against both bacteria, and the presence of CH₃ in the (Ar-CH=N) moity decreased the activity of nitrone (N6) against E.oli bacteria.

Nitron (N9) was inactive against E.coli and also did not appear inhibition zone against S.aureus at the lower concentration. This nitrone was resistant only against fungus Candida albicans (table 1).

Table 1: Antibacterial and antifungal of synthesized nitrones in different zone (mm)

N	microorganism	500 µg / mL in (DMSO)	1000 µg / mL in (DMSO)
N1	Escherichia coli	20	22
	Staphylococcus aureus	20	23
	Candida albicans	19	20
N2	Escherichia coli	16	18
	Staphylococcus aureus	16	17
	Candida albicans	25	26
N3	Escherichia coli	15	22
	Staphylococcus aureus	16	25
	Candida albicans	25	28
N4	Escherichia coli	NI	NI
	Staphylococcus aureus	19	20
	Candida albicans	15	20
N5	Escherichia coli	20	25
	Staphylococcus aureus	26	35
	Candida albicans	22	23
N6	Escherichia coli	12	13
	Staphylococcus aureus	15	16
	Candida albicans	15	26
N7	Escherichia coli	18	20
	Staphylococcus aureus	20	22
	Candida albicans	25	30
N8	Escherichia coli	25	30
	Staphylococcus aureus	28	30
	Candida albicans	20	22
N9	Escherichia coli	NI	NI
	Staphylococcus aureus	NI	12
	Candida albicans	12	13
The inhibition zone of levofloxacin against E.coli bacteria= 36 mm and against S.aureus= 34 mm. The inhibition zone of clotrimazole against Candida albicans= 33 mm NI: not inhibition

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INTRODUCTION