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Synthesis, characterization, antimicrobial and antioxidant activity of 2- (2′-

hydroxyphenyl) -1,3,4-oxadiazolyl-5-amino acid derivatives

Article in Journal of Saudi Chemical Society · April 2024

DOI: 10.1016/[Link].2024.101866

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Synthesis, characterization, antimicrobial and antioxidant activity of 2-

(2′-hydroxyphenyl) -1,3,4-oxadiazolyl-5-amino acid derivatives
Mouna Souad Abbassi a, *, Talal Lahreche b, Khaled Briki a, Mokhtar Boualem Lahrech a, b, Adil Ali
Othman c, Ahmed M. Elissawy d, e, Abdel Nasser B. Singab d, e
a
Laboratory of Organic Chemistry and Natural Substance, University Ziane Achour, AinEchih, Djelfa, Algeria
b
Department of Biology, Faculty of Sciences of Nature and Life, Ziane Achour University of Djelfa, Algeria
c
Laboratoire de Synthèse Organique Bioactive, Département de Chimie Organique Industrielle, Faculté de Chimie, Université des Sciences et de la Technologie d’Oran,
Mohamed Boudiaf-USTO-MB, BP. 1505, El-M’naouer, 31003 Oran, Algeria
d
Department of Pharmacognosy, Faculty of Pharmacy, Ain Shams University Abbassia, 11156 Cairo, Egypt
e
Centre of Drug Discovery Research and Development, Ain Shams University Abbasia, 11156 Cairo, Egypt

A R T I C L E I N F O A B S T R A C T

Keywords: The synthesis and biological assessment of 2,5-disubstituted-1,3,4-oxadiazoles derivatives from amino acids as
Synthesis new potential antibacterial and antioxidant agents have been reported. The structures of the new synthesized
Salicylic acid compounds were characterized based on physicochemical and spectral data UV–Visible, IR, 1HNMR, 13CNMR. All
1,3,4-oxadiazole
the target compounds were screened for their in vitro antibacterial activity against three Gram-positive bacterial
Amino acids
Antibacterial and antifungal activity
strains, namely Staphylococcus aureus ATCC 25923, Bacillus cereus ATCC 14579, Listeria innocua ATCC 33090, and
Antioxidant two Gram-negative bacterial strains, namely Pseudomonas aeruginosa ATCC 27853, Escherichia coli ATCC 25922,
and antifungal activity against Candida albicans ATCC 10231 in comparison with Amoxicillin, Tetracycline,
Gentamicin and Oxacillin. The only compound 1-{(4S)-4-amino-4-[5-(2-hydroxyphenyl)-1,3,4-oxadiazol-2-yl]
butyl}guanidine 5e with the amine radical that showed excellent results against all bacteria, particularly against
L. innocua (IZ = 12 mm), has excellent antifungal activity (IZ = 32 mm). The compounds 2-[5-(1-amino-3-meth­
ylbutyl)-1,3,4-oxadiazol-2-yl]phenol 5b and 2-[5-(pyrrolidin-2-yl)-1,3,4-oxadiazol-2-yl]phenol 5j have excellent
activities (IZ = 27 and IZ = 28 mm, respectively) against B. cereus and P. aeruginosa. Compounds 2-{5-[(1R)-1-
amino-2-sulfanylethyl]-1,3,4-oxadiazol-2-yl}phenol 5c, 2-{5-[(1S)-1-amino-3-(methylsulfanyl)propyl]-1,3,4-
oxadiazol-2-yl}phenol 5d with the sulfur radical, 3–[5-(2-3-amino hydroxyphenyl)-1,3,4-oxadiazol-2-yl]
propanamide 5g with the amide radical, 5j with the amino radical, and 4-amino-4-[5-(2-hydroxyphenyl)-
1,3,4-oxadiazol-2-yl]butanoic acid 5k gave good results against B. cereus, where 19 mm < IZ < 23 mm. We
also found that compound 5j has the greatest activity (IZ = 33 mm) against C. albicans, followed by compounds
5e (IZ = 32 mm) and 5b (IZ = 30 mm). The synthesized compounds were also screened for radical scavenging
antioxidant activities by DPPH, FRAP, and TAC assays and found to be good antioxidant agents. According to the
IC50 values, all compounds demonstrated good to excellent activity, especially 5b and 2-{5-[1-amino-2-(1H-
imidazol-4-yl)ethyl]-1,3,4-oxadiazol-2-yl}phenol 5i for DPPH, 5e and 5i for FRAP and methyl 2-hydroxyben­
zoate 2, 2-{5-[1-amino-2-(1H-indol-3-yl)ethyl]-1,3,4-oxadiazol-2-yl}phenol 5h with the imidazol group and 2-
[5-(1,5-diaminopentyl)-1,3,4-oxadiazol-2-yl]phenol 5f with the imidazol group for TAC. All these compounds
showed better activity than AA and BHT.

1. Introduction [1–5], antioxidant [6–8], antifungal [9–13], antiviral [14], anticonvul­

sant [15,16], antidiabetic [17,18], anticancer [19–22], antiin­
Most recently, 2,5-disubstituted-1,3,4-oxadiazole derivatives have flammatory [23–25], potent inhibitors of a-glucosidase and urease [26].
comprised a ubiquitous library of drug categories such as antibacterial 1,3,4-oxadiazole derivatives are also found in several clinical drugs such

* Corresponding author.
E-mail addresses: mouna0717@[Link] (M. Souad Abbassi), talal_lahreche@[Link] (T. Lahreche), brkhch28@[Link] (K. Briki), lahrechmokhtarboualem@yahoo.
fr (M. Boualem Lahrech), adelaliothman@[Link] (A. Ali Othman), aelissawy@[Link] (A.M. Elissawy), Dean@[Link] (A.N.B. Singab).

[Link]
Received 24 January 2024; Received in revised form 19 April 2024; Accepted 28 April 2024
Available online 30 April 2024
1319-6103/© 2024 The Author(s). Published by Elsevier B.V. on behalf of King Saud University. This is an open access article under the CC BY-NC-ND license
([Link]
M. Souad Abbassi et al. Journal of Saudi Chemical Society 28 (2024) 101866

as Raltegravir (a) to treat HIV infection [27], Tiodazosin (b) for anti­ 2. Experimental
hypertensive agent [28], Zibotentan (c) as an investigational anticancer
drug candidate [29], Furamizole (d) as an antimicrobial [30,31] and 2.1. Material and methods
Nesapidil (e) which is a vasodilator and is used as an antiarrhythmic and
antihypertensive therapy [32] (see Fig. 1). 2.1.1. Chemistry
There are several strategies for the synthesis of 2,5-disubstituted- All chemicals were supplied by Aldrich. All reactions were monitored
1,3,4-oxadiazole by treating the hydrazide derived from carboxylic by TLC, silica gel F254, made by Merck, Germany. The melting points
acid in one or two steps. For one step, 1,3,4-oxadiazole derivatives can were measured by a BÜCHI 540 melting point apparatus and uncor­
be prepared by condensation of acylhydrazides and carbaldehyde fol­ rected. The 1H and 13C NMR spectra (1D) were recorded on a Bruker AC
lowed by oxidative cyclization using different reagents: sodium bisulfi­ 400 MHz spectrometer in DMSO‑d6 and referenced to TMS. Symbols δ,
ite (NaHSO3) [33], nano zinc oxide and titanium dioxide ([nano(ZnO- for chemical shifts in ppm (University of AinShamss, Department of
TiO2)]) [34], phosphorus oxychloride (POCl3) [27,35–38], or from Pharmacy, Egypt). The IR spectra were recorded using KBr disks by the
cyclization of hydrazide derivatives of carboxylic acids in presence of IR Affinity-1SHIMADZU spectrophotometer in ν units of cm− 1 Univer­
1,1′-Carbonyldiimidazole (CDI) [36,39], hexafluorophosphate aza­ sity of Laghouat, Amar Telidji, Algeria. The λmax was calculated by using
benzotriazole tetramethyl uronium (HATU) [39,40–42], poly­ a double-beam UV–Visible 1800 Shimadzu spectrophotometer.
phosphoric acid (PPA) [43–45], sulfuryl chloride (SO2Cl2) [46], carbon
disulfide (CS2) in the presence of basic medium (KOH) [28,48–49]. As [Link]. Synthesis of compounds 2–3. Methyl 2-hydroxybenzoate (2):
for the preparation of 1,3,4-oxadiazole derivatives in two steps, the To a mixture of salicylic acid 1, (20g, 0.145 mol) in methanol (90
reactant is using isocyanate and then adding one of the following cata­ ml), H2SO4 (16 ml) was added dropwise with stirring. The mixture
lysts: N,N-Diisopropylethylamine (DIEA) [50], mercuric acetate (Hg refluxed on a water bath at 80 ◦ C for 5 h. TLC eluted with ethanol
(AcO)2) [51], 4-Toluenesulfonyl chloride (TsCl) [52], 1,3-dibromo-5,5- showed Rf = 0.42 for trace of starting acid 1 and Rf = 0.82 for ester 2.
dimethylhydantoin (DBDMH) [53,54], potassium bisulfate (KHSO4) After cooling the solution to room temperature, (100 ml) of cold water
[55,56], iodobenzene diacetate (PhI(AcO)2) [52,57,58], N-Ethyl-N′-(3- was added to the reaction mixture. The aqueous mixture was extracted
dimethylaminopropyl)carbodiimide hydrochloride (EDC. HCl) [59]. three times with n-hexane (25 ml × 3). The solution obtained was
Salicylic acid and their derivatives are considered as essential com­ neutralized with 10 % aqueous NaHCO3 (75 ml) until pH 7 and extracted
pounds of organic chemistry and have a variety of biological properties, again with n-hexane. The organic layers were combined, dried over
such as anti-inflammatory, anti-viral, anti-bacterial, anti-oxidant, and anhydrous MgSO4 and filtered. The filtrate evaporated to dryness to give
anti-carcinogenic properties [60–65]. In addition, amino acids are product 2.
known to play a significant role in the synthesis of new drug candidates Yield 97 %; Oily transparent liquid; UV (H2O), λ (nm): 3.9 (241,
with the use of non-proteinogenic and unnatural amino acids [66]. π-π*), 3.741 (290, n-π*); IR (νmax, cm− 1): 3189.68 (OH), 2955.37
While many biologically active compounds have been described in the (C–H), 1678.73 (C– –O), 1400 (C–O).
literature, there is still an urgent need to produce bioactive agents that 2-Hydroxybenzohydrazide (3):
can overcome all the drawbacks of reported agents because of their high Methyl 2-hydroxybenzoate 2 (5 g, 0.033 mol), ethanol (83 ml) and
cost and limited availability. 1,3,4-oxadiazole-2-thione, and 1,2,4-tria­ hydrazine hydrate 64 % (24.7 ml) mixed and heated under reflux at
zole-5-thiol derivatives from salicylic showed moderate to slight activ­ 70 ◦ C for 6 h. TLC eluted with ethanol/benzene 1:4 showed Rf = 0.36 for
ity against S. aureus and P. aeruginosa [67]. hydrazide 3 and Rf = 0.72 for trace of starting ester 2. Aqueous ethanol
In view of this, it was interesting to synthesize eleven new 2-salicylyl- evaporated under reduced pressure and the solid product was recrys­
1,3,4-oxadiazole derivatives using the coupling reaction of salicylic acid tallized from ethanol to give 2-hydroxybenzohydrazide 3.
hydrazide with eleven amino acids in the presence of POCl3 to evaluate Yield 75 % (3.75 g); brown solid; m.p: 152–155 ◦ C; UV (H2O), λ
the effect of amino acids on the bioactivity of salicylic acid hydrazide, (nm): 3.951 (225, π-π*), 2.366 (295, n-π*); IR (νmax, cm− 1): 3317.92
and thus they were tested for it is antibacterial, antifungal, and an (OH), 3267.87 (NH2), 1326.7 (NH), 1586.16 (NC– –O).
antioxidant. The structures of all synthetic compounds were proved by
spectroscopic analysis (UV–Visible, IR, 1HNMR, 13CNMR).

Fig. 1. The chemical structures of drugs used in medical practice contain 1,3,4-oxadiazole moiety..

2
M. Souad Abbassi et al. Journal of Saudi Chemical Society 28 (2024) 101866

[Link]. General procedures for the synthesis of 5-[2′-phenol-1,3,4-oxa­ (νmax, cm− 1): 3332 (NH), 3170 (CHarom), 2893 (CH2); 1651 (C– –N),
diazol-2-yl]-methanamine derivatives 5(a-k). An equimolar mixture of 2- 1481 (C– –C), 1211 (C–O–C); 1HNMR (400 MHz, DMSO‑d6) δ: 8.11 (s,
hydroxybenzohydrazide (3, 0.01 mol) and the amino acid [4(a-k), 0.01 1H, OH), 7.95–7.93 (ds, 5H, C13– –N+H2, C13-N+H3), 7.83 (t, J = 1.2
mol] in phosphorus oxychloride (7 ml) was refluxed at 80 ◦ C for 5–7 h. Hz, 1H, H4), 7.39 (d, J = 7.2 Hz, 1H, H6), 7.03 (d, J = 3.0 Hz, 1H, H3),
The reaction mixture was slowly poured onto crushed ice and kept 6.89 (t, J = 3.0 Hz, 1H, H5), 3.86–3.83 (m, 2H, H9, H12), 1.24–1.18 (m,
overnight. The solid thus separated was filtered and washed with cold 2H, H10, H11); 13CNMR (400 MHz, DMSO‑d6) δ: 166.4 (C13), 165.3
water, dried completely under vacuum and twice recrystallized by (C7), 159 (C8), 158.5 (C2), 134.4 (C4), 129.6 (C6), 119.5 (C5), 117.5
ethanol to give compounds 5(a-k). (C3), 115.5 (C1), 61.83–61.4 (C9, C12), 16.5–16.4 (C10, C11).
5-(2′-Phenol-1,3,4-oxadiazol-2-yl)-methylamine moiety, represents 2-[5-(1,5-Diaminopentyl)-1,3,4-oxadiazol-2-yl] phenol 5f
the common part of the derivatives under investigation. For tracing the TLC (ethanol): Rf (5f) = 0.38; Yield 65 % (1,71 g); White solid; m.p:
positions of the hydrogen and carbon atoms of the derivatives (R), we 204–207 ◦ C; UV (H2O), λ (nm): 3.684 (227, π-π*), 1.493 (298, n-π*); IR
propose to use the following numbering (taking in mind that they are (νmax, cm− 1): 3132 (NH), 3093 (CHarom), 2978, 2862 (CH2); 1620
different from IUPAC). (C––N), 1481 (C– –C), 1219 (C–O–C); 1HNMR (400 MHz, DMSO‑d6) δ:
9.59 (m, 3H, C13-N+H3), 9.05 (s, 1H, OH), 7.51–7.30 (m, 4H, H3-H6),
4.35 (s, 2H, C9-NH2), 4.00–3.90 (m, 1H, H12), 3.88–3.81 (m, 1H, H9),
3.7––3.6 (m, 1H, H10), 3.33–3.24 (m, 1H, H13), 1.22–1.05 (m, 1H,
H11), 13CNMR (400 MHz, DMSO‑d6) δ: 170 (C7,C8), 160.2 (C2), 134.3
(C1, C4), 127.7 (C6), 118.2 (C5), 61.8 (C9), 61.5 (C13), 61.4 (C10), 51.6
(C12), 25.6 (C11).
3-[5-(2-3-Amino hydroxyphenyl)-1,3,4-oxadiazol-2-yl]propanamide 5g
2-[5-(Aminomethyl)-1,3,4-oxadiazol-2-yl]phenol 5a TLC (ethanol): Rf (5 g) = 0.32; Yield 86 % (2,16 g); White solid; m.p:
TLC (ethanol): Rf (5a) = 0.30; Yield 75 % (1,41 g); White solid; m.p: 125–127 ◦ C; UV (H2O), λ (nm): 3.516 (234, π-π*), 1.778 (297, n-π*); IR
174–177 ◦ C; UV (H2O), λ (nm): 3.635 (226, π-π*), 2.493 (297, n-π*); IR (νmax, cm− 1): 3172 (NH), 1725 (C– –O), 1640 (C– –N), 1488 (C– –C), 1244
(νmax, cm− 1): 3248 (NH), 3140 (CHarom), 1604 (C– –N), 1489 (C– –C), (C–O–C); 1HNMR (400 MHz, DMSO‑d6) δ: 10.94 (s, 1H, OH), 8.50 (s,
1165 (C–O–C); 1HNMR (400 MHz, DMSO‑d6): δ: 10.8 (s, 1H, OH), 8.14 3H, C9-N+H3), 7.84 (t, J = 2.8 Hz, 1H, H4), 7.49 (d, J = 6.8 Hz, 1H, H6),
(t, J = 1.0 Hz, 1H, H4), 7.44 (d, J = 7.6 Hz, 1H, H6), 7.32 (d, J = 1.5 Hz, 7.42 (t, J = 1.0 Hz, 1H, H5), 7.39 (d, J = 1.2 Hz, 1H, H3), 7.31 (m, 1H,
1H, H3), 3.85 (m, 1H, H9), 3.82 (m, 2H, C9-NH2); 13CNMR (400 MHz, H10), 6.95 (m, 1H, H9); 13CNMR (400 MHz, DMSO‑d6) δ: 172.2 (C11),
DMSO‑d6) δ: 175.0 (C7), 169.1 (C8); 127.9 (C2); 116.0 (C4); 87.0 (C6); 172.1 (C7), 171.4 (C8), 170.1 (C2), 165.1 (C4), 161.3 (C6), 135.0 (C1),
63.0 (C5); 62.8 (C3); 62.5 (C1); 16.4 (C9). 130.5 (C5), 119.9 (C3), 117.6 (C10).
2-[5-(1-Amino-3-methylbutyl)-1,3,4-oxadiazol-2-yl] phenol 5b 2-{5-[1-Amino-2-(1H-indol-3-yl) ethyl] − 1,3,4-oxadiazol-2-yl} phenol
TLC (ethanol): Rf (5b) = 0.31; Yield 66 % (1,65 g); White solid; m.p: 5h
165–167 ◦ C; UV (H2O), λ (nm): 3.39 (227, π - π*), 1.845 (295, n-π*); IR TLC (ethanol): Rf (5 h) = 0.30; Yield 59 % (1,90 g); White solid; m.p:
(νmax, cm− 1): 3178 (NH), 1643 (C– –N), 1473 (C– –C), 1242 (C–O–C); 141–144 ◦ C; UV (H2O), λ (nm): 3.576 (226, π-π*), 2.24 (279, n-π*); IR
1
HNMR (400 MHz, DMSO‑d6) δ: 11.00 (s, 1H, OH), 7.88 (t, 1.5 Hz, 1H, (νmax, cm− 1): 3387 (NH), 2908 (CHarom), 1512 (C– –N), 1458 (C– –C),
1
H4), 7.45 (t, 6.8 Hz, 1H, H6), 7.44 (t, J = 1.6 Hz, 1H, H5), 7.10 (d, J = 1188 (C O C); HNMR (400 MHz, DMSO‑d6) δ: 11.17 (s, 1H, OH),
– –
1.0 Hz, 1H, H3), 3.91 (m, 1H, H9), 1.21 (m, 4H, H10, H11), 0.9 (m, 6H, 8.68 (m, C9-N+H3, C12-N+H2), 8.45 (m, C12-NH), 8.75 (d, 1H, J = 7.6
H12, H13); 13CNMR (400 MHz, DMSO‑d6) δ: 165.9 (C7), 157.6 (C8), Hz, H12), 7.59 (t, J = 3.2 Hz, 1H, H4), 7.51 (d, J = 7.6 Hz, H6), 7.43 (t, J
134.9 (C2), 130.2 (C4), 129.0 (C6), 117.0 (C5), 115.6 (C3), 16.4 (C12, = 2.8 Hz, 1H, H5), 7.39 (d, J = 3.2 Hz, 1H, H3), 7.00–7.25 (m, 4H, H15-
C13). H18), 4.13 (m, 2H, C12-N+H2), 4.00 (m, 1H, H9), 3.5 (m, 1H, C10);
13
2-{5-[(1R)-1-amino-2-sulfanylethyl]-1,3,4-oxadiazol-2-yl} phenol 5c CNMR (400 MHz, DMSO‑d6) δ: 171.1 (C7), 169.8 (C8), 165.8 (C2),
TLC (ethanol): Rf (5c) = 0.37; Yield 54 % (1.30 g); White solid; m.p: 158.0 (C12), 136.7 (C13), 134.7 (C14), 130.1 (C11), 127.4 (C15), 127.3
214–217 ◦ C; UV (H2O), λ (nm): 3.843 (228, π-π*), 2.758 (295, n-π*); IR (C16), 125.1 (C17), 121.5 (C18), 119.7 (C4), 118.9 (C6), 118.7 (C5),
(νmax, cm− 1): 3147 (NH), 2978 (CHarom), 2630 (SH), 1635 (C– –N), 1489 118.3 (C3), 115.5 (C1), 62.2 (C9), 53.1 (C10).
(C––C), 1242 (C–O–C); 1HNMR (400 MHz, DMSO‑d6) δ: 10.94 (s, 1H, 2-{5-[1-Amino-2-(1H-imidazol-4-yl)ethyl]-1,3,4-oxadiazol-2-yl}
OH), 10.8 (m, 3H, C9-N+H3), 8.14 (t, J = 1.2, H4), 7.47 (d, J = 6.8, H6), phenol 5i
7.10 (t, J = 2.8, H5), 6.9 (d, J = 1.2, H3), 4.84 (m, 2H, C9-NH2), 3.9 (m, TLC (ethanol): Rf (5i) = 0.32; Yield 82 % (2,23 g); White solid; m.p:
1H, H9); 1.2 (m, H10, SH); 13CNMR (400 MHz, DMSO‑d6) δ: 172.2 (C7), 223–225 ◦ C; UV (H2O), λ (nm): 2.576 (236, π-π*), 1.283 (299, n-π*); IR
165.8 (C8), 161.2 (C2), 158.1 (C4), 157.3 (C6), 134.7 (C5), 130.7 (C3), (νmax, cm− 1): 3413, 3240 (NH), 2926 (CHarom), 1638 (C– –N), 1484
120.2 (C1), 119.9 (C9-N+H3), 117.7 (C9-NH2), 113.2 (C9), 16.3 (C10). (C––C), 1163 (C–O–C); 1HNMR (400 MHz, DMSO‑d6) δ: 11.10 (s, 1H,
2-{5-[(1S)-1-amino-3-(methylsulfanyl)propyl]-1,3,4-oxadiazol-2-yl} OH), 7.81 (d, J = 2.0 Hz, 1H, H12), 7,79 (d, J = 2.0 Hz, 1H, H13), 7.53
phenol 5d (t, J = 1.0 Hz, 1H, H4), 7.50 (t, J = 1.6 Hz, 1H, H5), 6.95 (d, J = 8.0 Hz,
TLC (ethanol): Rf (5d) = 0.34; Yield 50 % (1,33 g); White solid; m.p: 1H, H6), 6.90 (d, J = 2.0 Hz, 1H, H3), 3.00 (m, 1H, H9), 2.54 (d, J = 2.8
135–137 ◦ C; UV (H2O), λ (nm): 3.709 (240, π-π*), 2.296 (297, n-π*); IR Hz, 2H, H10); 13CNMR (400 MHz, DMSO‑d6) δ: 172.4 (C7), 161.6 (C2,
(νmax, cm− 1): 3186 (NH), 2985 (CHarom), 2908 (CH3); 1643 (C– –N), C8), 136.0 (C4, C12), 130.0 (C6, C11), 119.6 (C1, C13), 117.5 (C5),
1481 (C– –C), 1311 (S-CH3); 1165 (C–O–C); 1HNMR (400 MHz, 113.5 (C3), 63.6 (C9).
DMSO‑d6) δ: 8.50 (s, 1H, OH), 7.84 (t, J = 1.2 Hz, 1H, H4), 7.43 (d, J = 2-[5-(Pyrrolidin-2-yl)-1,3,4-oxadiazol-2-yl]phenol 5j
7.2 Hz, 1H, H6), 7.00 (d, J = 3.4 Hz, H3), 6.92 (t, J = 3.2 Hz, H5), TLC (ethanol): Rf (5j) = 0.31; Yield 48 % (1,11 g); White solid; m.p:
3.90–3.80 (m, 2H, H6, H10), 1.24–1.18 (m, H11, H12). 13CNMR (400 173–176 ◦ C; UV (H2O), λ (nm): 3.677 (235, π-π*), 2.328 (296, n-π*); IR
MHz, DMSO‑d6) δ: 166.6 (C7), 158.2 (C8), 135.7 (C2), 134.5 (C4), 129.4 (νmax, cm− 1): 3194 (NH), 2908 (CHarom), 1643 (C– –N), 1473 (C– –C),
(C6), 119.8 (C5), 117.5 (C3), 115.5 (C1), 62.5 (C9), 61.8 (C10), 16.5 1165 (C–O–C);1HNMR (400 MHz, DMSO‑d6) δ: 11.70 (s, 1H,
(C11), 16.4 (C12). C––N+H), 10.87 (s, 1H, OH), 10.30 (m, 2H, C6-N+H2), 7.88 (d, J = 7.6
1-{(4S)-4-amino-4-[5-(2-hydroxyphenyl)-1,3,4-oxadiazol-2-yl] butyl} Hz, 1H, H6), 7.50 (t, J = 1.6 Hz, 1H, H4), 7.12 (d, J = 1.5 Hz, 1H, H3),
guanidine 5e 6.95 (t, J = 2.0 Hz, 1H, H5), 3.91–3.51 (m, 4H, H9, H12, H10, H11);
13
TLC (ethanol): Rf (5e) = 0.31; Yield 53 % (1,54 g); White solid; m.p: CNMR (400 MHz, DMSO‑d6) δ: 172.2 (C7), 170.7 (C8), 165.7 (C2),
155–158 ◦ C; UV (H2O), λ (nm): 2.774 (234, π-π*), 1.376 (295, n-π*); IR 157.4 (C4), 135.9 (C6), 130.6 (C5), 120.0 (C3), 117.5 (C1), 62.7 (C9),
59.2 (C12), 45.7 (C10), 28.2 (C11).

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M. Souad Abbassi et al. Journal of Saudi Chemical Society 28 (2024) 101866

4-Amino-4-[5-(2-hydroxyphenyl)-1,3,4-oxadiazol-2-yl]butanoic acid references. The concentration providing 50 % inhibition (IC 50) was
5k calculated from the graph of RSA percentage against compound con­
TLC (ethanol/chloroform 3/2): Rf (5k) = 0.37; Yield 56 % (1.46 g); centration. RSA of AA and BHT were also estimated for reference.
White solid; m.p: 172–175 ◦ C; UV (H2O), λ (nm): 3.491 (216, π-π*), Ferric-reducing antioxidant power (FRAP)
2.049 (296, n-π*); IR (νmax, cm− 1): 3147 (NH), 2854 (CHarom), 1674 The Oyaizu [69] approach was used to calculate the ferric-reducing
(C–
–O), 1635 (C– –N), 1481 (C– –C), 1211 (C–O–C); 1HNMR (400 MHz, antioxidant power. Solutions of compounds 5(a–k), 2, and 3 in different
DMSO‑d6) δ: 8.43 (s, 1H, OH), 7.86 (t, J = 1.2 Hz, 1H, H4), 7.42 (d, J = concentrations (8, 16, 32, 62.5, 125, and 250 μg/ml) were prepared in
8.0 Hz, 1H, H6), 7.40 (t, J = 3.2 Hz, 1H, H5), 6.92 (d, J = 2.0 Hz, 1H, water. 200 µL of compound solution at various concentrations were
H3), 3.92 (m, 1H, H9), 3.85 (m, 1H, H11), 2.39 (m, 1H, H10); 13CNMR combined with 500 μL of 1 % potassium ferricyanide [K3Fe(CN)6] and
(400 MHz, DMSO‑d6) δ: 173.8 (C12), 171.0 (C7), 166.2 (C8), 157.8 1000 μL phosphate buffer (2 mM, pH 6.6). For 20 min, the mixture was
(C2), 134.7 (C4), 129.8 (C6), 119.9 (C5), 117.4 (C3), 115.5 (C11), 61.9 incubated at 50 ◦ C. After adding 1000 μL of 10 % Trichloroacetic acid
(C9), 51.7 (C10). (TCA), the mixture was centrifuged at 3000 rpm for 10 min. After
filtering the supernatant, 500 μL of it was combined with 1.5 ml of
2.1.2. Biological activity distilled water and 500 μL of 0.1 % FeCl3. After giving the mixture a
good shake, it was let to sit at room temperature for half an hour. In a
[Link]. Antimicrobial activity. Microbiological activity was determined UV–Vis spectrophotometer (Beckman, DU520), the absorbance was
by the diffusion method against three Gram-positive bacteria namely measured at 700 nm against the control and compared to the references
Staphylococcus aureus ATCC 25923, Bacillus cereus ATCC 14579, Listeria (AA and BHT).
innocua ATCC 33090, and two Gram-negative bacteria, namely Pseudo­ Total antioxidant capacity (TAC) by phosphomolybdenium method
monas aeruginosa ATCC 27853, Escherichia coli ATCC 25922. While Total antioxidant activity (TAC) was measured as described by Prieto
antifungal activity of the different compounds was also assessed using et al. [70]. Solutions of compounds 5(a–k), 2, and 3 in different con­
Candida albicans ATCC 10231. All bacterial strains (KWIK-STIK format) centrations (8, 16, 32, 62.5, 125, and 250 μg/ml) were prepared in
were purchased from Micro Biologics, MN, USA. water. 200 µL of compound solution at various concentrations were
The synthesized compounds were prepared at a concentration of 10 added to 1000 µL of molybdate reagent containing 28 mM sodium
mg/ml. Microbial suspensions standardized at 0.5 McFarland standards phosphate, 4 mM ammonium molybdate and 6 mM sulphuric. The tubes
were placed onto the surface of sterile agar plates. The discs measuring were incubated at 95 ◦ C for 90 min and then the mixture was cooled at
5 mm in diameter were prepared and sterilized by dry heat at 120 ◦ C for room temperature. The absorbance was recorded at 695 nm against the
1 h. The sterile discs previously soaked in known concentrations of the control using a UV–Vis spectrophotometer (Beckman, DU520).
test compounds were placed in Mueller Hinton agar medium. The in­ Statistical analyses
hibition zones were measured in millimeters after incubation at 37 ◦ C The averages and standard deviations were obtained in triplicate.
for 24 and 48 h for bacterial and fungal strains, respectively, and One-way analysis of variance (ANOVA) followed by Tukey’s multiple
compared with the controls AX 25: Amoxicillin, TE 30: Tetracycline, CN range tests was performed to establish the significant differences at p-
120: Gentamicin OX 1: Oxacillin. Compounds that showed good anti­ value < 0.05 using the Statistical Package for Social Science (SPSS 20.0
bacterial activity, tested at a concentration 10 mg/ml were further for windows, SPSS Inc., Chicago, IL, USA).
evaluated by determination of the minimum inhibitory concentration
MIC (Table 3). The MIC of different compounds was determined using 3. Results and discussion
MH plates containing different concentrations (0–100 µg/ml) of com­
pounds were prepared and spread on the surface with standardized 3.1. Chemistry
bacterial suspension (0.5 McFarland) in order to visualize no bacterial
growth after incubation for 24 h at 37 ◦ C. The MIC corresponded to the The final 2,5-disubstituted-1,3,4-oxadiazolyl derivatives 5(a-k) have
lowest concentration preventing visible growth. been synthesized from salicylic acid 1 as summarized in Scheme 1 and
Table 1.
[Link]. Antioxidant activity. Every chemical, reagent, solvent, and In the present work, we converted the carboxyl function of salicylic
reference standard utilized is of the purest commercially available acid 1 to the ester function using methanol and concentrated sulfuric
analytical quality. These materials were acquired from Sigma-Aldrich: acid, where the yield was good at 97 %. Methyl 2-hydroxybenzoate 2
2,2-diphenyl-1-picrylhydrazyl radical (DPPH), butylated hydrox­ was isolated and identified using infrared spectra, which revealed two
ytoluene (BHT), ascorbic acid (AA), dipotassium hydrogen phosphate bands at 1678 and 1400 cm− 1, respectively, corresponding to the C– –O
(K2HPO4), potassium dihydrogen phosphate (KH2PO4), potassium and C–O of the group ester. The addition of aq. hydrazine solution (64
ferricyanide (K3Fe(CN)6), trichloroacetic acid (TCA), iron (III) chloride %) to the ester 2 gave the corresponding hydrazide 3, which is consid­
(FeCl3), sodium phosphate (Na3PO4), ammonium molybdate ered as the key to synthesizing 1,3,4-oxadiazole compounds.
((NH4)6Mo7O24), sulphuric acid. Mueller Hinton (MH) agar medium was IR spectrum of hydrazide showed bands at 3267 cm− 1 for NH2 and
obtained from Merck. 1586 cm− 1 for NCO stretching. The phosphorus oxychloride used as the
Free radical scavenging activity cyclization agent with eleven amino acids 4(a-k) and hydrazide 3 to
Using the Blois approach [68], the DPPH radical scavenging activity obtain eleven 2,5-disubstituted-1,3,4-oxadiazole derivatives 5(a-k). The
was assessed. Solutions of compounds 5(a–k), 2, and 3 in different amino acids were selected: aliphatic (glycine, l-Leucine), sulfur (l-
concentrations (8, 16, 32, 62.5, 125, and 250 μg/ml) were prepared in cysteine, l-methionine), amino (l-arginine, l-lysine), amide (l-aspara­
water. 500 µL of compound solution at various concentrations were gine), heterocyclic (l-tryptophan, l-histidine, l-proline) and carboxylic (l-
combined with 1000 µL of DPPH methanolic solution (0.2 mM). After
giving the mixture a good shake, it was let to sit at room temperature for
half an hour. The absorbance was then measured in a UV–Vis spectro­
photometer at 517 nm in comparison to the control. Using the following
formula, the proportion of radical-scavenging capacity was determined:
Radical-scavenging activity (%) = [(1 – A sample) / A control] × 100, where
A control is the absorbance of the control reaction (containing all reagents
except the test sample), and A sample is the absorbance of the samples/
Scheme 1. Synthesis of 2,5-disubstituted-1,3,4-oxadiazolyl derivatives 5(a-k).

4
M. Souad Abbassi et al. Journal of Saudi Chemical Society 28 (2024) 101866

Table 1
Amino acids used and the structures of 2,5-disubstituted-1,3,4-oxadiazolyl derivatives 5(a-k).

glutamic acid). Structural determination confirmed by IR, 1H- and 13C 3.2. Biological activity
NMR.
–N band (1651–1512 cm− 1) of me­
IR showed the characteristic C– 3.2.1. Antimicrobial activity of synthetic compounds 2, 3 and 5(a-k) at
dium intensity and medium-strong bands at 1242,16–1163 cm− 1 were concentration 10 mg/ml
attributed to the C–O–C vibration or heteroatom ring deformation of All synthetic compounds 2, 3 and 5(a-k) were assayed in vitro using
the oxadiazole ring. The survey of NMR spectra of compounds 5(a-k), the paper-disk diffusion method for their antibacterial activity against
revealed the expected chemical shifts signals of 1H- and 13C NMR pre­ Gram-positive bacteria, S. aureus ATCC 25923, B. cereus ATCC 14579, L.
sented in experimental section (For relevant compounds see references innocua ATCC 33090, Gram-negative bacteria, E. coli ATCC 25922,
[71–73]). P. aeruginosa ATCC 27853, also evaluated the antifungal activity of the
different compounds were also assessed using C. albicans ATCC 10231
(Table 2). The only compound found to be active in this primary

5
M. Souad Abbassi et al. Journal of Saudi Chemical Society 28 (2024) 101866

Table 2 best effect upon Gram positive B. cereus and Gram negative E. Coli
Antibacterial activity of synthesized compounds 2, 3 and 5(a-k) at concentra­ bacteria at low concentration 50 µg/ml, while. 5j which showed its ef­
tions 10 mg/ml. fect upon the same bacteria at a concentration of 100 µg/ml. The rest of
Inhibition Zone IZ (mm) synthesized compounds 5a, 5b, 5d, 5f, and 5i showed their minimum
N◦ Gram-positive bacteria Gram- negative Fungi
inhibitory concentration at greater than 100 µg/ml.
Comp bacteria
3.2.2. Antioxidant activity
S. B. L. E. Coli P. aeruginosa C. albicans
aureus cereus innocua
[Link]. Free radical scavenging activity. The antioxidant ability of syn­
2 – – – 15 – –
3 – 17 – – – – thesized 1,3,4-oxadiazoles derivatives 5(a-k), 2 and 3 were measured by
5a – 7 – – – – DPPH assay using AA and BHT as standards. The percentage of radical
5b 7 27 – 14 – 30 scavenging ability (RSA) of the synthesized compounds at different
5c 10 22 – 16 – – concentrations is shown in Table 4. A positive correlation was found
5d – 19 – 13 – –
5e 13 21 12 20 09 32
between the concentration of compounds and the percentage of RSA, as
5f – – – – – – the percentage of RSA increases with increasing concentrations of these
5g – 20 – 13 – – compounds.
5h – 14 – – – – The results obtained for the anti-radical strength of compounds 2, 3,
5i 17 22 11 11
and 5(a-k) and of AA and BHT determined by DPPH (Table 4), showed
– –
5j 13 23 – 12 28 33
5k – 20 – 17 – – radical activity in the trapping by electron transfer or their ability to
T1 16 24 – 12 25 – donate hydrogen. All derivatives synthesized except 2, 5f and 5h
T2 08 30 – 11 20 19 showed excellent activity with a concentration of 250 µg/mL as an
T3 29 27 – 31 26 29 antioxidant agent (86 % < RSA < 98 %), in particular 3, 5a and 5i which
T4 18 21 – 09 07 –
gave an inhibition percentage very close to AA (97.97 %) and better than
Staphylococcus aureus ATCC 25923, Bacillus cereus ATCC 14579, Listeria innocua BHT (93.19 %). The highest inhibition percentages are 97.94 % (5i),
ATCC 33090, Escherichia coli ATCC 25922, Pseudomonas aeruginosa ATCC 27853, 96.71 % (5a), 95.41 % (3), 94.79 % (5g), 91.50 % (5c), 90.25 % (5j),
Candida albicans ATCC 10231; IZ: Inhibition Zone in mm; T1: AX 25 Amoxicillin, 90.06 % (5d), 89.24 % (5k), 87.87 % (5b), 86.36 % (5e), 72.86 (5f),
T2: TE 30 Tetracycline, T3: CN 120 Gentamicin, T4: OX 1 Oxacillin.
64.70 % (5h) and 44.25 % (2). The presence of the heterocyclic aromatic
ring 1,3,4-oxadiazole showed the best activity as an antioxidant agent
screening was further tested in a second set of dilution 100 μg/ml (MIC) because it contained donor groups: amine (NH2 found in all com­
against all microorganisms, the results exhibited in Table 3. pounds); 1H-imidazol (5i); amide [in 5 g]; guanidine (in 5e); sulfanyl (in
From the results of activity against bacteria (Table 2 and supple­ 5c and 5d), pyrrolidin (in 5j) 1H-indol (in 5 h).
mentary file), most of the compounds showed their activity on both The concentration of the prepared compounds necessary to scavenge
types of bacteria, and were particularly effective on Gram positive 50 % free radicals, was calculated graphically by plotting the calculated
B. cereus and then on Gram negative E. Coli. We found that the only inhibition percentages against different concentrations of the fractions
compound 5e (which has many amino radicals) gave excellent results used. The lower the value of the IC50, the more effective the compounds
against all bacteria, especially against L. innocua (IZ = 12 mm). It also prepared are in eliminating DPPH* free radicals which means more
have excellent antifungal activity (IZ = 32 mm). The compounds 5b and antioxidant activity. The results showed that compounds 5b, 5i, 3, and
5j have excellent activities IZ = 27 mm and IZ = 28 mm against B. cereus 5e are more effective as antioxidants based on the ability to scavenge
and P. aeruginosa. DPPH free radicals: IC50(5b) = 2.7 µg/ml > IC50(5i) = 4.54 µg/ml >
Compounds 5c, 5d with the sulfur radical, 5 g with the amide IC50(3) = 6.25 µg/ml > IC50(5e) = 7.07 µg/ml > IC50(BHT) = 9.81 µg/
radical, 5j with the amino radical and 5k gave good results against B.s ml > IC50(5c) = 11.32 µg/ml > IC50(5a) = 12.96 µg/ml > IC50(5j) =
cereus, where 19 mm < IZ < 23 mm, while most of the compounds gave 13.98 µg/ml > IC50(AA) = 19.04 µg/ml > IC50(5d) = 33.54 µg/ml >
moderate to good activity against E. coli, where 12 mm < IZ < 22 mm. IC50(5k) = 43.94 µg/ml > IC50(5f) = 56.73 µg/ml > IC50(5 g) = 57.83
It was also found that compound 5j has the greatest activity (IZ = 33 µg/ml > IC50(5 h) = 131.56 µg/ml > IC50(2).
mm) against C. albicans, followed by compounds 5e (IZ = 32 mm) and
5b (IZ = 30 mm). From these results, it can be concluded that com­ [Link]. Ferric-reducing antioxidant power (FRAP). The reducing power
pounds with extra amino functions such as 5e and 5j have the best ac­ activity (RPA) of synthesized 1,3,4-oxadiazole derivatives 5(a-k), 2 and
tivity against the microorganism tested. 3 were estimated by FRAP. The assay is based on measuring the ability of
Results at Table 3, indicating that compound 5e showed excellent a compound to reduce at low pH the ferric ion (Fe3+) to the ferrous ion
results against all bacteria, especially against Listeria innocua and have (Fe2+) which reacts with 2,4,6-trypyridyl-s-triazine (TPTZ) to form a
an excellent antifungal activity. Also, compounds 5c and 5e showed the complex intense blue [74–76].

Table 3
Minimum inhibitory concentration for compounds that have good antibacterial activity.
Comp Concentrations (µg/ml)

0 3.12 6.25 12.5 25 50 100

B E P B E P B E P B E P B E P B E P B E P

5b + + + + + + + + + + + + + + + + + + − − +
5c + + + + + + + + + + + + + + + − + + − − +
5d + + + + + + + + + + + + + + + + + + − − +
5e + + + + + + + + + + + + + + + + − + − − +
5i + + + + + + + + + + + + + + + + + + − − +
5j + + + + + + + + + + + + + + + + + + − − −
5k + + + + + + + + + + + + + + + + + + − − +

B: B. cereus; E: E. Coli; P: P. aeruginosa; +: presence of growth of microorganisms; − : inhibition of growth of micro-organisms.

6
M. Souad Abbassi et al. Journal of Saudi Chemical Society 28 (2024) 101866

Table 4 observed that two 1,3,4-oxadiazole containing sulfur and amino-

Free radical scavenging activity, Ferric-reducing antioxidant power and Total functions 5d and 5c have the highest total antioxidant activity (96.39
antioxidant capacity of synthesized 2,5-disubstituted-1,3,4-oxadiazole de­ %, 95.97 %) followed the compounds 5a, 5g, 5f, 5k, 5b, 2, 5h (90 % <
rivatives 5(a–k), 2, and 3 at 250 µg/ml concentration and IC50 values. RSA < 93 %).
DPPH FRAP TAC The rest of the compounds showed antioxidant activity less than 90
Com RSA % at IC 50 RPA % at IC 50 TAC % IC 50 %, but they possessed a percentage better or very close to AA (88.19 %)
250 µg value 250 µg value at value and BHT (87.36 %), which are two reference standards with antioxidant
/ml (µg) /ml (µg) 250 µg (µg) activity.
/ml From the IC50 values for the TAC test, and in contrast to the DPPH
2 44,28 ± > 250 a 56,85 ± 32,18 ± 90,47 ± 2,01 ± results, ester 2, 5f and 5 h showed the highest antioxidant activity with
0,07k 0,36f 0,19 i 1,01b,c, 0,02 i values of 2.01, 2.56 and 3.24 µg/ml respectively, while compounds 5g,
d
5k, 5a, 5d and 5j presented good results 5 µg/ml < IC50 < 8 µg/ml, they
3 95,41 ± 6,25 ± 97,44 ± 80,33 ± 89,16 ± 14,74 ±
0,47b,c 0,26 j 1,84 a 0,31c 0,50b,c, 0,29c are similar almost as AA (IC50 = 6.05 µg/ml) and better than BHT (IC50
d,e = 7.90 µg/ml), while the rest of the compounds gave significant results
5a 96,71 ± 12,96 ± 87,28 ± 38,95 ± 92,80 ± 5,87 ± compared to the other compounds.
0,18 a,b 0,33 g 2,98b,c 0,31 h 3,29 a,b 0,31 e,f,
g
5b 87,87 ± 2,70 ± 80,43 ± 53,38 ± 90,24 ± 14,12 ± 4. Conclusion
0,26 g 0,14 l 2,66c,d 0,25f 0,38b,c, 0,26c,d
d The eleven novel 2,5-disubstituted-1,3,4-oxadiazolyl derivatives 5
5c 91,50 ± 11,32 ± 97,57 ± 32,66 ± 95,79 ± 18,22 ±
(a-k) were successfully synthesized and fully characterized by UV–Vis
0,61 e 0,26 h 1,02 a 0,33 i 0,44 a 0,32b
5d 90,06 ± 33,54 ± 75,34 ± 30,67 ± 96,39 ± 7,35 ± IR, 1H NMR and 13C NMR.
0,46 e,f 0,28 e 2,59 d,e 0,26 j 0,62 a 0,24 e,f The compound 5e showed excellent results against all bacteria,
5e 86,36 ± 7,07 ± 78,99 ± 16,51 ± 86,51 ± 12,96 ± especially against Listeria innocua. It also has excellent antifungal ac­
0,33 h 0,23 j 1,97 d,e 0,23m 0,45 d,e 0,30 d tivity. The compounds 5b and 5j have excellent activities against Ba­
5f 72,86 ± 56,73 ± 47,61 ± >250 a 91,08 ± 3,24 ±
0,27 i 0,14c 0,48 g 0,15b,c 0,10 a
cillus cereus and Pseudomonas aeruginosa. Compounds 5c, 5d with the
5g 94,79 ± 57,83 ± 97,60 ± 84,30 ± 87,83 ± 5,50 ± sulfur radical, 5g with the amide radical, 5j with the amino radical and
0,18c 0,31c 2,06 a 0,28b 0,30c,d,e 0,17 h 5k gave good results against Bacillus cereus. We also found that com­
5h 64,70 ± 131.56 73,58 ± 49,41 ± 90,13 ± 2,56 ± pound 5j has the greatest activity against Candida albicans. All com­
0,59 j ± 0,22b 1,89 d,e 0,21 g 0,85b,c, 0,02 i
pounds demonstrated good to excellent activity, especially 5b and 5i for
d
5i 97,94 ± 4,54 ± 70,72 ± 24,65 ± 85,66 ± 17,20 ± DPPH, 5e and 5i for FRAP and 2, 5h and 5f for TAC, All these com­
0,77 a 0,17k 3,21 e 0,22k,l 0,42 e 0,27b pounds showed a better activity as AA and BHT. The antimicrobial
5j 90,25 ± 13,98 ± 72,47 ± 66,24 ± 92,41 ± 7,69 ± mechanism of the synthesized compounds is left as a perspective work.
0,15 h 0,30 g 2,11 d,e 0,20 e 0,04 a,b 0,30 e
5k 89,24 ± 43,94 ± 56,36 ± 70,07 ± 90,84 ± 5,84 ±
0,07f,g 0,28 d 1,04f 0,19 d 0,49b,c 0,20 g,h CRediT authorship contribution statement
BHT 93,19 ± 9,81 ± 91,10 ± 23,69 ± 87,36 ± 7,90 ±
0,03 d 0,27 i 2,58 a,b 0,27 l 0,64c,d,e 0,22 e Mouna Souad Abbassi: Writing – review & editing, Methodology,
AA 97,97 ± 19,04 ± 75,97 ± 25,68 ± 88,19 ± 6,05 ±
Formal analysis, Data curation, Conceptualization. Talal Lahreche:
0,01 a 0,39f 1,70 d,e 0,25k 0,88c,d,e 0,25f,g,
h Writing – original draft, Methodology, Formal analysis, Data curation,
Conceptualization. Khaled Briki: Writing – original draft, Methodology,
RSA: Radical Scavenging Ability.
Formal analysis, Data curation, Conceptualization. Mokhtar Boualem
Values are expressed as means SD from triplicate.
Lahrech: Writing – review & editing, Supervision, Methodology, Formal
a,b,c: Different letters in the same column indicate significant differences (p <
analysis, Data curation, Conceptualization. Adil Ali Othman: Writing –
0.05).
review & editing, Writing – original draft, Supervision, Methodology,
Formal analysis, Data curation, Conceptualization. Ahmed M. Eli­
In the FRAP test (Table 4), all synthetic compounds were found to be
ssawy: . Abdel Nasser B. Singab: Writing – review & editing, Super­
good to very effective in reducing iron (III) to iron (II) ions. At a con­
vision, Formal analysis, Data curation, Conceptualization.
centration of 250 µg/ml, it was found that compounds 5 g (97.60 %), 5c
(97.57 %) and hydrazide 3 (97.44 %) have higher antioxidant activity
than BHT (91.10 %) because they contain amide, amino and sulfur Declaration of competing interest
groups. The rest of the compounds (except compounds 2, 5k and 5f)
were better or closer to the activity of AA (75.97 %). From the IC50 The authors declare that they have no known competing financial
values of the FRAP test, It can be concluded that the effect of antioxi­ interests or personal relationships that could have appeared to influence
dants followed the following order: 5e > BHT > 5i > AA > 5d > 2 > 5c the work reported in this paper.
> 5a > 5 h > 5b > 5j > 5k > 5 g > 5f. The results show that the amino-
functions enhance the antioxidant ability.
Appendix A. Supplementary material

[Link]. Total antioxidant capacity (TAC). The total antioxidant capac­ Supplementary data to this article can be found online at [Link]
ity of synthesized 1,3,4-oxadiazole derivatives 5(a-k), 2 and 3 were org/10.1016/[Link].2024.101866.
assessed against AA and BHT by phosphomolybdenum assay which is a
quantitative spectroscopic method based on the reduction of Mo (VI) to
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