Benzohydrazide as a good precursor for the synthesis of novel bioactive and anti-oxidant 2-phenyl-1,3,4-oxadiazol-aminoacid derivatives: Structural determination, biological and anti-oxidant activity - Arabian Journal of Chemistry (2025)

Table of Contents

1 Introduction 2 Experimental 2.1 Material and methods 3 Results and discussion 3.1 Chemistry 3.2 Structural determination by spectroscopic methods 3.3 Biological activity 4 Conclusion CRediT authorship contribution statement References

Khaled Briki^a,⁎, Talal Lahreche^b, Mouna Souad Abbassi^a, Mokhtar Boualem Lahrech^a, Adil Ali Othman^c, Ahmed M. Elissawy^d,e, Abdel Nasser B. Singab^d,e

1 Introduction

One of the groups of heterocyclic compounds with a wide spectrum of biological activity is oxadiazoles (Kawale et al., 2023; Berillo and Dyusebaeva, 2022; Di Franco et al., 2021; Parrino et al., 2021; Queiroz et al., 2020; Mustafa, 2018). 1,3,4-oxadiazole has applications in diverse areas of medicine, including antibacterial antibacterial (Wang et al., 2023; AL-Sharabi et al., 2023; Abbassi et al., 2021; Briki et al., 2020; Yang et al., 2021; Othman et al., 2019; Desai and Dodiya, 2014), antifungal (Glomb and Świątek, 2021; Wen et al., 2023; Patil et al., 2021; Capoci et al., 2019), antioxidant (Mahi et al., 2023; Bhandari et al., 2023; Shridhar et al., 2016), anticonvulsant (Fakhrioliaei et al., 2023; Nazar et al., 2020), antidepressant (Singh et al., 2020), antiviral (Chaudhary et al., 2023; Hassan et al., 2010; Li et al., 2011), antidiabetic (Qazi et al., 2023; Radia et al., 2021; Wang et al., 2022; Kavitha et al., 2017), antiinflammatory (Dewangan et al., 2018; Chawla et al., 2018; Rahul et al., 2023), anticancer (Chen et al., 2024; Carbone et al., 2023; Afzal et al., 2023; Nayak et al., 2021; Vaidya et al., 2021; Morsy et al., 2017; Gudipati et al., 2011), Antiseizure (Rasool et al., 2023) and anti-Alzheimer's (Naseem et al., 2023).

Several examples containing the 1,3,4-oxadiazole group used in clinical medicine (Fig. 1) such as raltegravir 1 for the treatment of HIV infection (Chaudhary and Upadhyay, 2023), tiodazosin 2 for antihypertensive agents (Desai et al., 2022), zibotentan 3 as an investigational anticancer drug candidate (Bajaj et al., 2021), nesapidil is a vasodilator, that is used as an antiarrythmic and antihypertensive therapy (Paruch et al., 2020) and furamizole 4 for antimicrobial (Siwach and Verma, 2020).

Benzohydrazide as a good precursor for the synthesis of novel bioactive and anti-oxidant 2-phenyl-1,3,4-oxadiazol-aminoacid derivatives: Structural determination, biological and anti-oxidant activity - Arabian Journal of Chemistry (1)

Another sub-class of 2,5-disubstituted-1,3,4-oxadiazole derivatives represented by the general formula (Fig. 2):

Some of these compounds were capable of suppressing and/or inhibiting the programmed cell death 1 (PD-1) signally pathway (Aksenov et al., 2022; Brotschi,et al., 2020; Sasikumar et al., 2018). Our interest is to synthesize some derivatives of the 2,5(R)-disubstituted-1,3,4-oxadiazole in different way other than what was reported.

There are several strategies for the synthesis of 2,5- disubstituted -1,3,4-oxadiazole derivatives by treating hydrazide derivatives with carboxylic acid in one or two steps. For one step synthesis, 1,3,4-oxadiazole can be prepared by reacting hydrazide derivatives with: ketones in the presence of I₂ and K₂CO₃ (Chen et al., 2024; Gao et al., 2015), ClF₂COONa with K₃PO₄ (Yan et al., 2012), nucleophilic addition of carbon disulfide (CS₂) in the presence of a basic KOH (Wang et al., 2024; Rana et al., 2023), 1,10-carbonyldiimidazole (CDI) (Savariz et al., 2014), CO₂ with paraformaldehyde in the presence NaI and t-BuOK (Yang et al., 2016), derivatives of carboxylic acid with polyphosphoric acid (PPA) (Luczynski and Kudelko, 2022), 1,1′-carbonyldiimidazole (CDI) with triphenylphosphine (Ph₃P) and tetrabroomethane (CBr₄) (Rajapakse et al., 2006), hexafluorophosphate azabenzotriazole tetramethyl uronium (HATU) with N,N-diisopropylethylamine (DIPEA) (Li and Dickson, 2009), sulfuryl chloride (SO₂Cl₂) (De Oliveira et al., 2012; Mihailović et al., 2017) or phosphorus oxychloride (POCl₃) as the cyclization agent (Dong et al., 2022; Salama, 2020; Faraz et al., 2017; Amarouche et al., 2022). In this study, we used the POCl₃ method by adding a hydrazide derived from benzoic acid with a series of aminoacids.

As for the preparation of 1,3,4-oxadiazole in two steps, the reactant isothiocyanate is used to obtain thiosomicarbazide and then one of the following catalysts is added: mercuric acetate (Hg(AcO)₂) (Liu et al., 2014), iodobenzene diacetate (PhI(AcO)₂) (Hassan and Rauf, 2016), N-ethyl-N′-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDC. HCl) (Naaz et al., 2020), 1,3-dibromo-5,5-dimethylhydantoin (DBDMH) (Hamdy et al., 2017; He et al., 2009), N,N-diisopropylethylamine (DIEA) (Maghari et al., 2013), potassium bisulfate (KHSO₄) (Long et al., 2021).

In the present paper, we have explored the synthesis of some 2-phenyl- 1,3,4-oxadiazole-5(R)-amino acid derivatives and testing their antioxidant and antimicrobial activity. All the synthesized compounds were primarily detected by careful TLC, melting point, and characterized by spectroscopic methods (UV–Visible, IR, ¹HNMR, ¹³CNMR).

2 Experimental

2.1

2.1 Material and methods

2.1.1

2.1.1 Chemistry

The reagent and solvents used were obtained from commercial sources. Analytical thin layer chromatography was carried out on TLC plates of 3×15cm coated with silica gel G for reaction monitoring and for the determination of retardation factor. Spots of TLC were located by the iodine chamber. The final products were purified by recrystallization. Melting points of newly synthesized derivatives were determined on a digital melting point apparatus (BÜCHI 540). The λ_max was calculated by using UV–Visible 1800 Shimadzu spectrophotometer. The IR spectra were recorded on a FTIR-Shimadzu spectrometer (University of Laghouat, Amar Telidji, Algeria), ν units of cm⁻¹. The ¹H and ¹³C NMR spectra recorded on a Bruker AC 400MHz spectrometer in DMSO‑d₆ and referenced to TMS (University of AinShamss, Department of Pharmacy, Egypt). Chemical shift values are expressed in ppm and are abbreviated as follows: s (singlet), d (doublet), t (triplet), q (quadruplet), m (multiplet), o (ortho), m (meta), p (para) and ph ((linking phenyl group). Numbering 1,2,..etc for oxadiazole ring, while 1′,2′, …etc for amino acid moiety (see scheme 3).

2.1.1.1

2.1.1.1 Synthesis of compounds 2–3 and 5(a-j)

Methyl benzoate (2):

To a mixture of benzoic acid 1 (10g, 0,081mol) in methanol (80ml), H₂SO₄ (2,5 ml) was added dropwise with stirring. The mixture refluxed on a water bath at 80°C for 3h. TLC eluted with ethanol/Chloroform (1/1) showed R_f=0,62 for trace of starting acid 1 and R_f=0,77 for methyl benzoate 2. After cooling the solution to room temperature, the solution was neutralized with 5% aqueous NaHCO₃ (110ml) until pH 7. The solution was washed and extracted again with chloroform several times. The organic layers were dried over anhydrous MgSO₄ and filtered. The filtrate evaporated to dryness to give product 2 with a yield of 81%.

Benzohydrazide (3):

Methyl benzoate 2 (11g, 0.080mol), ethanol (83ml) and hydrazine hydrate (64%, 40ml) were mixed and heated under reflux at 80°C for 2h. TLC eluted with ethyl acetate/hexane 1:1 showed R_f=0.15 for hydrazide 3 and R_f=0.73 for trace of starting ester 2. Aqueous ethanol evaporated under reduced pressure and a product was recrystallized from ethanol to give benzohydrazide 3 with a yield of 84%.

2.1.1.2

2.1.1.2 General procedures for the synthesis of 2,5-disubstitued-1,3,4-oxadiazole 5(a-j)

The mixture of benzohydrazide (3, 0.01mol) and the amino acid [4(a-j), 0.01mol] were dissolved in 7ml of phosphorus oxychloride POCl₃ and allowed to stand at room temperature for 30min. The mixture was refluxed for 4–7h at 80°C, and then concentrated by evaporation in a rotary evaporator under reduced pressure. The rest of the mixture was slowly poured onto crushed ice and kept overnight. The solid was separated and washed by warm water and the filtrate was basified with saturated sodium hydroxide. The precipitate was filtered and recrystallized from ethanol several times to give the white solid compounds 5(a-j).

1-(5-Phenyl-1,3,4-oxadiazol-2-yl)methanamine (46182–58-5) 5a

TLC (ethanol/chloroform 1:4): R_f (5a)=0.43; Yield 58% (0.99g); m.p: 200°C; UV (H₂O), λ (nm): 3.108 (226, π - π*), 0.435 (269, n - π*); IR (ν_max, cm⁻¹): 3248.1, 3001.2 (NH₂, NH), 2900.9 (CH_arom), 1604.7 (C=N), 1489.0 (C=C), 1165 (C-O-C); ¹HNMR (400MHz, DMSO‑d₆) δ: 8.14 (s, 3H, ⁺NH₃-1′), 7.57–7.31 (m, 5H, -ph), 3.88–3.81 (m, 2H, H1′). ¹³CNMR (400MHz, DMSO‑d₆) δ: 169.2 (C5), 166.0 (C2), 132.5 (p-ph), 127.5 (m-ph), 122.0 (o-ph), 117.0 (C1-ph), 16.4 (C1′).

(1R)-3-Methyl-1-(5-phenyl-1,3,4-oxadiazol-2-yl)butan-1-amine 5b

TLC (ethanol/chloroform 1:4): R_f (5b)=0.41; Yield 68% (1,57g); m.p: 206°C; UV (H₂O), λ (nm): 1.00 (229, π - π*), 0.34 (257, n - π*); IR (ν_max, cm⁻¹): 3248.1, 3001.2 (NH₂, NH), 2900.9 (CH_arom), 1604 (C⚌N), 1489 (C⚌C), 1165 (C-O-C); ¹HNMR (400MHz, DMSO‑d₆) δ: 8.48–8.45 (s, 3H, ⁺NH₃-1′), 7.90–7.30 (m, 5H, -ph), 3.86 (m, 1H, H1′), 1.95 (m, 2H, H2′), 1.6 (m, 1H, H3′), 1.15 (m, 6H, H4′, H5′); ¹³CNMR (400MHz, DMSO‑d₆) δ: 165.9 (C5), 157.6 (C2), 134.9 (p-ph), 130.2 (m-ph), 120.10 (o-ph), 117.4 (C1-ph), 62.6 (C1′), 16. 5 (C2′-C5′).

(2R)-2-Amino-2-(5-phenyl-1,3,4-oxadiazol-2-yl)ethanethiol 5c

TLC (ethanol/chloroform 1:1): R_f (5c)=0.51; Yield 72% (1.59g); m.p: 202°C; UV (H₂O), λ (nm): 3.035 (229, π - π*), 0.412 (262, n - π*); IR (ν_max, cm⁻¹): 3147.8 (NH), 2985.8 (CH_arom), 2893.2 (CH₂) 2630.9 (SH), 1635.6 (C⚌N), 1489 (C⚌C), 1203.5 (C-O-C); ¹HNMR (400MHz, DMSO‑d₆) δ: 8.74 (m, 3H, ⁺NH₃-1′), 7.82–7.31 (m, 5H, -ph), 4.15 (m, 1H, H1′), 3.31 (m, 2H, H2′), 2.51 (s, 1H, SH); ¹³CNMR (400MHz, DMSO‑d₆) δ: 169.4 (C5), 133.31 (C2), 131.0 (p-ph), 130.0 (m-ph), 129.5 (o-ph), 62.3 (C1′), 16.5 (C2′).

(1R)-3-(Methylsulfanyl)-1-(5-phenyl-1,3,4-oxadiazol-2-yl)propan-1-amine 5d

TLC (ethanol/chloroform 1:1): R_f (5d)=0.48; Yield 55% (1,36g); m.p: 135°C; UV (H₂O), λ (nm): 1.031 (231, π - π*), 0.185 (262, n - π*); IR (ν_max, cm⁻¹): 3248.13, 3140.1 (NH), 2893.22 (CH_arom), 2831.5, 2708.0 (CH₂, CH₃); 1481.3 (C⚌N), 149.61 (C⚌C), 1249.8 (S-CH₃); 1087.6 (C-O-C); ¹HNMR (400MHz, DMSO‑d₆) δ: 8.69 (m, 3H, ⁺NH₃-1′), 7.93 (t, 1H, J=0.9Hz, p-ph), 7.59, (t, 2H, J=2.5Hz, m-ph), 7.49 (d, 2H, J=7.5Hz, o-ph), 3.87 (m, 2H, H1′), 3.41 (m, 2H, H2′), 2.56 (m, 2H, H3′), 2.05 (s, 3H, H4′); ¹³CNMR (400MHz, DMSO‑d₆) δ: 166.6 (C5), 159.2 (C2), 135.0 (p-ph), 129.5 (m-ph), 119.8 (o-ph), 117.6 (C1-ph), 62.6 (C1′), 62.5 (C2′), 61.8 (C3′), 16.5 (C4′).

1-[(4R)-4-Amino-4-(5-phenyl-1,3,4-oxadiazol-2-yl)butyl]guanidine 5e

TLC (ethanol/chloroform 1:1): R_f (5e)=0.42; Yield 63% (1,72g); m.p: 187°C; UV (H₂O), λ (nm): 3.435 (228, π - π*), 0.441 (262, n - π*); IR (ν_max, cm⁻¹): 3332.9 (NH), 3171 (CH_arom), 2893 (CH₂); 1651 (C⚌N), 1481 (C⚌C), 1211 (C-O-C); ¹HNMR (400MHz, DMSO‑d₆) δ: 8.72 (s, 2H, C5′=⁺NH₂), 8.55 (s, 2H, H₂N⁺-C5′), 8.54 (s, 3H, C5-⁺NH₃), 7.96 (t, 1H, J=1.5Hz, p-ph), 7.60 (t, 2H, J=2Hz, m-ph), 7.50 (d, 2H, J=7.5Hz, o-ph), 4.18 (m, H1′), 3.86 (m, H2′), 3.13 (m, H3′), 1.83 (m, 1H, C5′=NH), 1.63 (m, 2H, C5′–NH₂), 1.54 (m, 2H, C1′–NH₂); ¹³CNMR (400MHz, DMSO‑d₆) δ: 165.3 (C5), 158.6 (C2), 134.5 (p-ph), 129.6 (C5′), 129.5 (m-ph), 119.5 (o-ph), 117.5 (C1-ph), 61.6 (C1′), 61.5 (C4′), 16.5 (C2′, C3′).

(1R)-1-(5-Phenyl-1,3,4-oxadiazol-2-yl)pentane-1,5-diamine 5f

TLC (ethanol/chloroform 1:4): R_f (5f)=0.37; Yield 73% (1,79g); m.p: 204°C; UV (H₂O), λ (nm): 2.67 (224, π - π*), 0.25 (273, n - π*); IR (ν_max, cm⁻¹): 3132.4 (NH), 3093.8 (CH_arom), 2978.0 (CH₂); 1620.2 (C⚌N), 1481.3 (C⚌C), 1219.0 (C-O-C); ¹HNMR (400MHz, DMSO‑d₆) δ: 14.93 (m, 3H, C1′-⁺NH₃), 14.65 (m, 3H, C5′-⁺NH₃), 7.51 (m, 5H, -ph), 4.36 (m, 1H, H1′), 3.94–3.84 (m, 2H, H5′), 3.35–3.25 (m, 6H, H2′-H4′), 1,20 (m, 2H, C5′–NH₂); ¹³CNMR (400MHz, DMSO‑d₆) δ: 170.0 (C5),169.7 (C2), 154.4 (p-ph), 134.0 (m-ph), 128(o-ph), 127.4 (C1-ph), 51.6 (C1′, C4′), 25.6 (C2′), 25.0 (C3′).

(3R)-3-Amino-3-(5-phenyl-1,3,4-oxadiazol-2-yl)propanamide (1518828-37-9) 5g

TLC (ethanol/chloroform 1:4): R_f (5g)=0.46; Yield 55% (1.27g); m.p: 184°C; UV (H₂O), λ (nm): 3.556 (227, π - π*), 0.608 (273, n - π*); IR (ν_max, cm⁻¹): 3439.4 (NH₂), 3038.3 (CH_arom), 1618.9 (C⚌O), 1482.0 (C⚌N), 1402 (C⚌C), 1092.4 (C-O-C); ¹HNMR (400MHz, DMSO‑d₆) δ: 10.94 (s, 3H, C1′-⁺NH₃), 7.70–7.20 (m, 5H, -ph), 4.1 (m, H1′), 2.90 (d, H2′); ¹³CNMR (400MHz, DMSO‑d₆) δ: 171.5 (C3′), 170.1 (C5), 165 (C2), 151.0 (p-ph), 129.5 (m-ph), 129.0 (o-ph), 119.0 (C1-ph), 116.0 (C2′), 48.3 (C1′).

(1R)-2-(1H-indol-3-yl)-1-(5-phenyl-1,3,4-oxadiazol-2-yl)ethanamine 5h

TLC (ethanol/chloroform 1:4): R_f (5h)=0.43; Yield 53% (1,61g); m.p: 198°C; UV (H₂O), λ (nm): 3.624 (226, π - π*), 2.446 (276, n - π*); IR (ν_max, cm⁻¹): 3425.9 (NH₂), 3288.0 (NH), 2982.3 (CH_arom), 1578.5 (C=N), 1436.7 (C⚌C), 1206.2 (C-O-C); ¹HNMR (400MHz, DMSO‑d₆) δ: 11.90 (s, 2H, ⁺NH₂), 11.17 (s, 3H, C1′-⁺NH₃), 8.76 (s, =N⁺H), 7.97 (m, 1H, C4′), 7.60 (t, 1H, J=1.5Hz, p-ph), 7.53 (t, 2H, J=1.5Hz, m-ph), 7.36 (d, 2H, J=4Hz, o-ph), 7.25 (d, 2H, J=1.5Hz, H8′), 7.07 (t, 1H, J=3.5Hz, H10′), 7.05 (t, 1H, J=4Hz, H9′), 7.00 (t, 1H, J=2.5Hz, H11′), 6.81 (m, 1H, H7′), 4.13–3.89 (m, 3H, H1′, H2′); ¹³CNMR (400MHz, DMSO‑d₆) δ: 171.11 (C5), 169.69 (C2), 138.0 (C4′), 136.6 (C1-ph), 136.0 (C8′), 130.0 (C10′), 129.7 (C7′), 129.2 (C11′), 127.5 (C6′), 127.4 (C9′), 127.4 (p-ph), 125.4 (m-ph), 119.1 (o-ph), 62.5 (C1′), 118.7 (C11′), 111.7 (C3′), 33.1 (C2′).

(1R)-2-(1H-imidazol-4-yl)-1-(5-phenyl-1,3,4-oxadiazol-2-yl)ethanamine 5i

TLC (ethanol/chloroform 1:4): R_f (5i)=0.46; Yield 78% (1.98g); m.p: 180°C; UV (H₂O), λ (nm): 3.613 (227, π - π*), 0.425 (263, n - π*); IR (ν_max, cm⁻¹): 3424.9 (NH₂), 2930.3 (CH_arom), 1620.8 (C⚌N), 1422.2 (C⚌C), 1143.3 (C-O-C); ¹HNMR (400MHz, DMSO‑d₆) δ: 14.67 (s, 3H, -⁺NH₃), 9.05 (s, 2H, -⁺NH₂), 8.73 (s, 1H, -⁺NH), 8.20–7.32 (m, 5H+2H, ph & diazole), 4.30 (m, H1′), 3.30 (m, H2′); ¹³CNMR (400MHz, DMSO‑d₆) δ: 169.6 (C5), 158.0 (C2), 148.0 (C6′), 134.0 (C4′), 133.0 (p-ph), 129.7 (m-ph), 129.1 (o-ph), 116.4 (C1-ph), 62.0 (C1′), 51.6 (C2′).

2-phenyl-5-[(2R)-(pyrrolidin-2-yl)]-1,3,4-oxadiazole (1201915–88-9) 5j

TLC (ethanol/chloroform 1:4): R_f (5j)=0.33; Yield 63% (1,35g); m.p: 188°C; UV (H₂O), λ (nm): 3.393 (229, π - π*), 0.618 (264, n - π*); IR (ν_max, cm⁻¹): 3248.1 (NH), 2893.2 (CH_arom), 1573.91 (C⚌N), 1481.3 (C⚌C), 1087.8 (C-O-C); ¹HNMR (400MHz, DMSO‑d₆) δ: 8.61 (s, 2H, -⁺NH2), 7.57–7.32 (m, 5H, -ph), 3.85 (m, H1′), 3.81 (m, 2H, H3′), 1.92 (m, 4H, H4′, H5′); ¹³CNMR (400MHz, DMSO‑d₆) δ: 172.3 (C5), 165.7 (C2), 157.5 (o-ph), 135.0 (m-ph), 157.5 (o-ph), 119.8 (C1-ph), 61.9 (C1′), 59.7 (C3′), 45.8 (C5′), 28.3 (C4′).

2.1.2

2.1.2 Biological activity

2.1.2.1

2.1.2.1 Antibacterial activity

Microbial strains

The antibacterial activity of the different compounds 2, 3 and 5(a-j) was assessed using three Gram-positive bacteria, viz. Bacillus cereus ATCC 14579, Staphylococcus aureus ATCC 25923, Listeria innocua ATCC 33090, and two Gram-negative bacteria, viz. Escherichia coli ATCC 25922, Pseudomonas aeruginosa ATCC 27853. The antifungal activity of the different compounds was also assessed using Candida albicans ATCC 10231. The inhibition zones were compared with the controls AX 25: Amoxicillin, TE 30: Tetracycline, CN 120: Gentamicin OX 1: Oxacillin. All bacterial strains (KWIK-STIK format) were purchased from Micro Biologics, MN, USA.

Disc diffusion method

The antibacterial and antifungal activities of different compounds were evaluated by determining the zone of inhibition using the disc diffusion method, as reported by the Clinical and Laboratory Standards Institute CLSI (CLSI, 2012a; CLSI, 2004). Microbial suspensions, prepared from young cultures (18–24h), were standardized at 0.5 Mc Farland using a densitometer and spread over Mueller Hinton (MH) agar medium. Sterile paper discs (6mm in diameter, Whatman no.1), impregnated with 10µL of compound diluted in water to a concentration of 10mg/ml, and were placed on the surface of the inoculated agars. After incubation at 37°C for 24h, the antimicrobial activities were assessed by measuring the diameter of the inhibition zones against the tested microorganism.

Minimal inhibitory concentration

The minimal inhibitory concentration (MIC) of compounds that showed good antibacterial activity was determined using the method described by CLSI (CLSI, 2012b). MH plates containing different concentrations (100, 50, 25, 12.5, 6.25 and 3.12µg/ml) of compounds were prepared and spread on the surface with standardized bacterial suspension (0.5 McFarland) in order to visualize no bacterial growth after incubation at 37°C for 24h in the case of bacteria and 48h in the case of fungi. Control plates prepared under the same procedure without the bacterial inoculums were assessed simultaneously. The MIC corresponded to the lowest concentration preventing visible growth.

2.1.2.2

2.1.2.2 Antioxidant activity

All used chemicals, reagents, solvents, and reference standards are of the purest analytical quality available on the market. 2,2-diphenyl-1-picrylhydrazyl radical (DPPH), butylated hydroxytoluene (BHT), ascorbic acid (AA), dipotassium hydrogen phosphate (K₂HPO₄), potassium dihydrogen phosphate (KH₂PO₄), potassium ferricyanide (K₃Fe(CN)₆), trichloroacetic acid (TCA), iron (III) chloride (FeCl₃), sodium phosphate (Na₃PO₄), ammonium molybdate ((NH₄)₆Mo₇O₂₄), and sulfuric acid were the materials obtained from Sigma-Aldrich. Mueller Hinton (MH) agar medium was obtained from Merck.

Free radical scavenging activity

Blois was used to evaluate the DPPH radical scavenging activity (Blois, 1958). Solutions of compounds 2, 3 and 5(a–j) in different concentrations (8, 16, 32, 62.5, 125, and 250μg/ml) were prepared in water. 1000µL of DPPH methanolic solution (0.2mM) was mixed with 500µL of samples at different concentrations in water. The mixture was well shaken and then allowed to settle at room temperature for 30min. The absorbance was then measured in a UV–Vis spectrophotometer at 517nm 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]x100, 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/references. The concentration providing 50% inhibition (IC ₅₀) was calculated from the graph of RSA percentage against compound concentration. RSA of AA and BHT were also estimated for reference.

Ferric-reducing antioxidant power (FRAP)

The ferric-reducing antioxidant power (FRAP) was determined using the Oyaizu method (Oyaizu, 1986). Solutions of compounds 2, 3 and 5(a–j) in different concentrations (8, 16, 32, 62.5, 125, and 250μg/ml) were prepared in water. Samples at varying concentrations were combined with 500μL of 1% potassium ferricyanide [K₃Fe(CN)₆] and 1000μL phosphate buffer (2mM, pH 6.6). For 20min, the mixture was incubated at 50°C. After adding 1000μL of 10% trichloroacetic acid (TCA), the mixture was centrifuged for 10min at 3000rpm. After filtering the supernatant, 500μL of it was combined with 1.5ml of distilled water and 500μL of 0.1% FeCl₃. After giving the mixture a good shake, it was left to sit at room temperature for 30min. In a UV–Vis spectrophotometer, the absorbance was measured at 700nm against the control and compared to the references (AA and BHT).

Total antioxidant capacity (TAC) by phosphomolybdenum method

Total antioxidant activity (TAC) was measured as described by Prieto (Prieto et al., 1999). Solutions of compounds 2, 3 and 5(a–j) in different concentrations (8, 16, 32, 62.5, 125, and 250μg/ml) were prepared in water. 1000µL of molybdate reagent containing 28mM sodium phosphate, 4mM ammonium molybdate and 6mM sulphuric acid was added to100 μL of different concentrations of the samples. The tubes were incubated at 95°C for 90min and then the mixture was cooled at room temperature. The absorbance was recorded at 695nm against the control using a UV–Vis spectrophotometer.

Statistical analyses

The averages and standard deviations were obtained in triplicate. One-way analysis of variance (ANOVA) followed by Tukey’s multiple range tests was performed to establish the significant differences at p-value<0.05 using the Statistical Package for Social Science (SPSS 20.0 for windows, SPSS Inc., Chicago, IL, USA).

3 Results and discussion

3.1

3.1 Chemistry

The final heterocyclic products 2,5-disubstituted-1,3,4-oxadiazole 5(a-j) have been synthesized from benzohydrazide 3 and amino acids 4(a-j) as summarized in Scheme 1.

Methyl benzoate 2 was prepared by esterification of benzoic acid 1 in the presence of H₂SO₄ in methanol. Hydrazide 3 was obtained by the reaction of esters 2 with hydrazine hydrate in ethanol. The hydrazide 3 was utilized as starting material with ten amino acids for the synthesis of 2,5-disubstituted-1,3,4-oxadiazole 5(a-j) by using POCl₃ as the cyclization agent. The amino acids were selected: glycine 4a, l-leucine 4b, l-cysteine 4c, l-methionine 4d, l-arginine 4e, l-lysine 4f, l-asparagine 4g, l-tryptophan 4h, l-histidine 4i and l-proline 4j.

The proposed reaction mechanism is shown in Scheme 2.

3.2

3.2 Structural determination by spectroscopic methods

The determination of the ten synthetic compounds 5(a-j) were based upon the characteristic functional groups as following:

The methyl benzoate (2) was obtained and detected by the IR spectrum, which showed two bands at 1722 and 1278cm⁻¹ for the C⚌O and C-O-C respectively of group ester. The ester 2 refluxed with hydrazine hydrate 64% to produce hydrazide 3 in yield 84%. IR spectrum showed bands at 3327.89–3009.3cm⁻¹ for NH₂ and 1659.44cm⁻¹ for NC⚌O stretching. The yields of the compounds 2,5-disbstituted-1,3,4-oxadiazole 5(a-j) ranged from 53 to 78%, and they were all produced as white solids. The molecules have a melting point that ranges from 135 to 206°C. In the UV spectrum, all compounds have an absorption maximum ((λmax, abs) which indicates the presence of electronic transitions of the type n→π* and π→π*. The maximum wavelengths appeared very close for the 1,3,4-oxadiazole derivatives 5(a-j), this is between 224 and 231nm (Costaet al., 2016; Oliveira et al., 2023). IR spectrum showed bands for NH₂ at 3267cm⁻¹, and CO-N stretching’s at 1586cm⁻¹. The characteristic C⚌N band (1651–1512cm⁻¹) of medium intensity and a medium-strong band at 1242,16–1163cm⁻¹ were identified in each IR spectra, the latter could be attributed to the C–O–C vibration or heteroatom ring deformation of the oxadiazole ring.

The characteristic C⚌N band (1651–1481cm⁻¹) of medium intensity and a medium-strong band at 1219–1087cm⁻¹ were identified in each IR spectra, the latter could be attributed to the C–O–C vibration or heteroatom ring deformation of the oxadiazole ring. This difference is due to the type of radical of the amino acid attached at position 5 in the oxadiazole ring.

The 5-phenyl-1,3,4-oxadiazol-2-yl moiety is the common fragment which is repeated in all the ten synthetic compounds 5(a-j) is designated as in the following general structure:

The NMR of 5-Phenyl-1,3,4-oxadiazol-2-yl moiety is as following:

¹H NMR showed the characteristic signals in ppm: Phenyl group: 2-(o-H) between 9→7; 1-(p-H) between 8.5→7.5; 2-(m-H) between 7.5→7. Oxadiazole: Non. Amino acid moiety: H1′, 4.5→3.5. For rest of amino acid, see experimental part.

¹³C NMR showed the characteristic signals in ppm: Phenyl locations: 1-ph, between 135→125; para-C, between 130→129; ortho-C, between 130→116; meta-C, between 117 and 105. Oxadiazole: C5, 171→165; C2, 165→130. Amino acid moiety locations, C1′, between 62.5→61.6, and so on (See experimental part).

3.3

3.3 Biological activity

3.3.1

3.3.1 Antibacterial activity of synthetic compounds 2, 3 and 5(a-j) at concentration 10 and 0.1mg/ml

All synthetic compounds 2, 3 and 5(a-j) were assessed in vitro using the paper-disk diffusion method for their antibacterial activity against Gram-negative bacteria (E. coli ATCC 25922, P. aeruginosa ATCC 27853), Gram-positive bacteria (S. aureus ATCC 25923, B. cereus ATCC 14579, L. innocua ATCC 33090), and was also assessed for the antifungal activity using C. albicans ATCC 10231 (Table 1 and Fig. 3). The disk diffusion results were compared against a panel of control antibiotics belonging to three different classes (penicillins, tetracycline and aminoglycosides).

Table 1 Antibacterial and antifungal activities of synthesized compounds 2, 3 and 5(a-j) at concentrations C₁=10 and C₂=0.1mg/ml.

Inhibition Zone IZ in mm
Comp	Gram-positive bacteria						Gram- negative bacteria				Fungi
Comp	S. aureus		B. cereus		L. innocua		E. Coli		P. aeruginosa		C. albicans
	C₁	C₂	C₁	C₂	C₁	C₂	C₁	C₂	C₁	C₂	C₁	C₂
2	−	−	−	−	−	−	13	−	−	−	−	−
3	−	−	25	8	−	−	11	−	−	−	10	−
5a	14	−	29	12	−	−	23	9	−	−	−	−
5b	21	8	31	8	14	8	25	9	−	−	−	−
5c	25	8	33	15	−	−	28	9	30	8	34	8
5d	23	8	34	15	−	−	30	9	32	10	33	8
5e	21	8	32	15	−	−	27	9	−	−	−	−
5f	−	−	20	7	−	−	−	−	−	−	−	−
5g	22	9	33	15	−	−	19	9	32	11	31	10
5h	−	−	24	7	−	−	−	−	−	−	−	−
5i	24	9	34	15	22	8	23	9	−	−	−	−
5j	25	8	32	16	−	−	25	9	33	11	34	8
T1	16		24		−		12		25		−
T2	08		30		−		11		20		19
T3	29		27		−		31		26		29
T4	18		21		−		09		−		−

Staphylococcus aureus ATCC 25923, Bacillus cereus ATCC 14579, Listeria innocua ATCC 33090, Escherichia coli ATCC 25922, Pseudomonas aeruginosa ATCC 27853, Candida albicans ATCC 10231; IZ: Inhibition Zone in mm; T1: AX 25 Amoxicillin, T2: TE 30 Tetracycline, T3: CN 120 Gentamicin, T4: OX 1 Oxacillin

In primary screening 10mg/ml concentrations were used, and then we used concentrations of 0.1mg/ml (Table 1). The only compound found to be active in this primary screening was further tested in a second set of dilution 100μg.ml⁻¹ against all microorganisms, the results are presented in Table 2. The disk diffusion results were compared against a panel of control antibiotics belonging to three different classes (penicillins, tetracycline and aminoglycosides). The results of the antimicrobial activity (Table 1, Fig. 3 and supplementary file) demonstrated variation in the potency against the different microbial strains for each compound tested. Most of the compounds have excellent efficacy, and some of them, such as 5i, 5g, 5d, 5c, and 5j can inhibit their activity better or very close to that of the antibiotics used as standards (T_1-4).

Table 2 Minimum inhibitory concentrations (μg/ml) for compounds that have good antibacterial and antifungal activities.

No Comp	Gram-positive bacteria			Gram- negative bacteria		Fungi
No Comp	S. aureus	B. cereus	L. innocua	E. Coli	P. aeruginosa	C. albicans
3	−	100	−	−	−	−
5a	−	50	−	100	−	−
5b	100	100	100	100	−	−
5c	100	25	−	100	100	100
5d	100	25	−	100	50	100
5e	100	25	−	100	−	−
5f	−	100	−	−	−	−
5g	100	25	−	100	50	50
5h	−	100	−	−	−	−
5i	100	25	100	100	−	−
5j	100	25	−	100	50	100

Staphylococcus aureus ATCC 25923, Bacillus cereus ATCC 14579, Listeria innocua ATCC 33090, Escherichia coli ATCC 25922, Pseudomonas aeruginosa ATCC 27853, Candida albicans ATCC 10231.

In general, most prepared 2-phenyl-1,3,4-oxadiazol-aminoacid derivatives have shown to be susceptible to excellent potency against Gram-positive (14mm $\leq$ IZ $\leq$ 34mm), Gram-negative bacteria (11mm $\leq$ IZ $\leq$ 33mm), and Fungi (31mm $\leq$ IZ $\leq$ 34mm). The results were better or comparable to those of the reference antibiotics Amoxicillin, Tetracycline, Gentamicin and Oxacillin.

At concentration C₁=10mg/ml (Table 1), only two compounds 5b (IZ=14mm) and 5i (IZ=22mm) presented good results against L. innocua (Table 1 and Fig. 3A), as the rest of the compounds and antibiotics were unable to inhibit it. They also presented a good to excellent inhibition zone (21mm $\leq$ IZ $\leq$ 34mm) against S. aureus, B. cereus, E. coli (Table 1 and Fig. 3(B, C, D). Compounds 5(b-e), 5g, and 5(i-j) revealed superior antibacterial activity against S. aureus (14mm $\leq$ IZ $\leq$ 25mm) compared to all the used control antibiotics expect for Gentamycin (IZ=34mm). Where they showed comparable inhibition zone diameter. In addition, the same compounds revealed superior activity against B. cereus compared to all the tested control antibiotics. Compounds 5c, 5d containing the sulfur radical, 5g containing the amide radical and 5j containing the pyrrolidine radical showed good to very excellent activity (19mm $\leq$ IZ $\leq$ 34mm) against all microorganisms except L. innocua. All compounds except ester 2 provided excellent activity against B. cereus (24mm $\leq$ IZ $\leq$ 34mm). As for P. aeruginosa and fungal strain C. albicans, the compounds 5c, 5d, 5g and 5j have an inhibition zone of 30mm $\leq$ IZ $\leq$ 34mm (Table 1 and Fig 0.3(E, F)) and gave better activity against results than all the standards used.

At concentration C₂=0.1mg/ml (Table 1), most of the active compounds presented an inhibition zone ranging between 8mm and 11mm for each tested microorganism except for B. cereus which was affected by compounds 5(c-e), 5g and 5i with an inhibition zone of 15mm, while the compound 5j provided the best inhibition against B. cereus with an inhibition zone of 16mm. 1,3,4-oxadiazole-aminoacid then subjected to minimum inhibition concentration (MIC) testing. Results were summarized in Table 2 and supplementary file. The MIC values for the tested compounds against S. aureus, L. innocua, E. coli, and C. albicans were 100μg/mL, which is four-fold higher than the MIC (25µg/ml) of the other derivatives 5(c-e), 5g and 5(i-j) against B. cereus representing the best activity of the tested compounds.

Also, the MIC of the compounds 5d, 5g and 5j was estimated at 50µg/ml against P. aeruginosa. These results indicated that the compounds have effective activity against all tested microorganisms and indicated also that the improved potency of the prepared compounds could be attributed to the type of amino acid moiety attached to the 1,3,4-oxadiazole.

3.3.2

3.3.2 Antioxidant activity

Phenyl-oxadiazole derivatives are known for their antioxidant activity due to their potent free radical scavenging activity that could be tolerated through the extended conjugating system composed of the phenyl group and the oxadiazole ring. The following references demonstrate this activity for oxadiazole derivatives (Mihailović et al., 2017; Rana et al., 2023).

The antioxidant activity of synthesized 2-phenyl-1,3,4-oxadiazole derivatives 5(a-j), ester 2 and hydrazide 3 are shown in Table 3.

Table 3 Free radical scavenging activity, Ferric-reducing antioxidant power and Total antioxidant capacity of synthesized 2,5-disubstituted-1,3,4-oxadiazole derivatives 5(a–j), 2, and 3 at 250µg/ml concentration and IC50 values.

	DPPH		FRAP		TAC
Com	RSA % at 250µg /ml	IC 50 value (µg)	RPA % at 250µg /ml	IC 50 value (µg)	TAC % at 250µg /ml	IC 50 value (µg)
2	36,15±0,64h	> 250 a	59,71±0,77 e	13,71±0,19h,i	90,60±0,16 a,b	2,56±0,31f
3	92,79±0,41 d,e	15,97±0,35k	89,49±1,91b	23,08±0,30g	91,20±0,02 a,b	4,00±0,31f
5a	95,01±0,31b,c	29,30±0,35h	98,25±4,03 a	35,87±0,40c	98,32±0,31 a	20,76±0,34 a
5b	80,74±0,26g	54,20±,031 d	80,02±0,70c	39,44±0,29b	96,41±3,35 a	12,76±0,35b,c,d
5c	93,71±0,02c,d	31,96±,035g	98,24±4,78 a	38,54±0,36b	94,25±3,65 a,b	13,64±0,35b
5d	80,66±0,28g	25.76±0,31 i	99,21±4,23 a	34,16±0,36c,d	93,89±3,47 a,b	7,90±0,36 e
5e	93,94±0,13c,d	16,03±0,36k	97,62±3,75 a	29,71±0,33 e	93,40±3,47 a,b	11,45±0,36c,d
5f	33,62±0,11 i	> 250 a	76,12±1,48c	15,22±0,30h	98,43±0,14 a	6,94±0,33 e
5g	91,48±0,73 e,f	73,22±0,29c	97,46±2,31 a	11,52±0,31 j	92,41±1,56 a,b	12,89±0,33b,c,d
5h	80,43±0,26g	132.59±0,29b	88,08±2,77b	25,00±0,29f	88,19±0,20b	6,05±0,31 e
5i	91,02±0,35f	50,03±0,11 e	97,93±2,18 a	12,41±0,36 i,j	88,07±0,31b	11,11±0,36 d
5j	95,47±0,09b	55,71±0,37 d	98,57±4,31 a	33,89±0,38 d	90,63±2,91 a,b	13,17±0,36b,c
BHT	93,02±0,26g	21,44±0,35 j	60,66±1,21 e	54,34±0,24 a	94,59±1,10 a,b	3,52±0,31f
AA	97,70±0,32 a	38,33±0,36f	71,49±0,71 d	10,71±0,26 j	91,69±0,03 a,b	6,19±0,34 e

RSA: Radical Scavenging Ability; RPA: Reducing Power Activity; TAC: Total antioxidant capacity.

Values are expressed as means±SD from triplicate.

a, b, c: Different letters in the same column indicate significant differences (p<0.05).

3.3.2.1

3.3.2.1 Free radical scavenging activity

The antioxidant ability of synthesized 2-phenyl-1,3,4-oxadiazole derivatives 5(a-j), ester 2 and hydrazide 3 were measured by DPPH assay using 2,6-di-tert-butyl-4-methylphenol (butylated hydroxytoluene, BHT) and Ascorbic Acid (AA) as standards. Table 3 displays the percentage of the produced compounds' radical scavenging capacity (RSA) at doses (250µg/ml, IC50). The proportion of RSA and the concentration of the compounds were shown to be positively correlated, with the percentage of RSA rising as the concentration of the compounds increased.

The results obtained for the anti-radical strength of compounds 2, 3, and 5(a-j) and of BHT and AA determined by DPPH (Table 3), showed radical activity in the trapping by electron transfer or their ability to donate hydrogen. All derivatives synthesized except 2 and 5f showed excellent activity with a concentration of 250µg/ml as an antioxidant agent (80% < RSA<95.5%), in particular 5a, 5c, 5e and 5j which gave an inhibition percentage very close to AA (RSA=97.70%) and better than BHT (RSA=93.02%). The highest inhibition percentages are 95.47% (5j), 95.01% (5a), 93.94% (5e), 93.71% (5c), 92.79% (3), 91.48% (5g), 91.02% (5i), 80.74% (5b), 80.66% (5d), 80.43% (5h), 36.15 (2), and 33.62% (5f). Because 1,3,4-oxadiazole synthesized contains donor groups such as amine: amine (NH₂ found in all compounds); pyrrolidin (in 5j); guanidine (in 5e); sulfanyl (in 5c and 5d); amide [ in 5g]; 1H-imidazol (in 5i) and 1H-indol (in 5h).

By graphing the computed inhibition percentages against various concentrations of the fractions utilized, the concentration of the produced compounds required to scavenge 50% of the free radicals is determined graphically. The lower the value of the IC50, the more effective the compounds prepared are in eliminating DPPH* free radicals which means more antioxidant activity. The results showed that compounds 3, 5e, 5d, 5a and 5c are more effective as antioxidants based on the ability to scavenge DPPH free radicals: IC50(3)=15.97µg/ml<IC50(5e)=16.03µg/ml<IC50(BHT)=21.44µg/ml<IC50(5d)=25.76µg/ml<IC50(5a)=29.30µg/ml<IC50(5c)=31.95µg/ml<IC50(AA)=38.33µg/ml<IC50(5i)=50.03µg/ml<IC50(5b)=54.20µg/ml<IC50(5j)=55.71µg/ml<IC50(5g)=73.22µg/ml<IC50(5h)=132.95µg/ml<IC50(2 and 5f).

3.3.2.2

3.3.2.2 Ferric-reducing antioxidant power (FRAP)

FRAP was used to assess the reducing power activity (RPA) of the synthesized 1,3,4-oxadiazoles derivatives 5(a-j), 2 and 3. The assay measures a compound's capacity to convert ferric ions (Fe³⁺) to ferrous ions (Fe²⁺) at a low pH. These ions then react with 2,4,6-trypyridyl-s-triazine (TPTZ) to generate a complex, vivid blue substance (Christodoulouet al., 2022; Munteanu and Apetrei, 2021; Benzie and Strain, 1996).

All synthesized compounds were shown to be good to extremely effective in reducing iron(III) to iron(II) ions in the FRAP test (Table 3). At a concentration of 250µg/ml, all derivatives synthesized except 2 showed excellent activity as an antioxidant agent (RSA>76%) better than AA (71.49%) and BHT (60.66%), in particular 5(a, c-e, g, i, j) which gave a higher inhibition percentage (>97%) because they contain sulfur, amide and amino groups. From the IC50 values of the FRAP test, It can be concluded that the effect of antioxidants followed the following order: AA>5g>5i>2>5f>3>5h>5e>5j>5d>5a>5c>5b>BHT. According to the findings, the amine group improves antioxidant capacity.

3.3.2.3

3.3.2.3 Total antioxidant capacity (TAC)

The total antioxidant capacity of synthesized 1,3,4-oxadiazoles derivatives 5(a-j), 2 and 3 were assessed against BHT and AA by phosphomolybdenum assay which is a quantitative spectroscopic method based on the reduction of Mo (VI) to Mo (V) and subsequent formation of a green phosphate Mo (V) complex at low pH (Alam et al., 2013).

The TAC of the fractions was measured spectrophotometrically by the synthesized compounds with maximum absorption at 695nm. From results (Table 3), at 250µg/ml, all synthesized compounds were shown to be excellently effective in reducing Mo (VI) to Mo (V) ions in the TAC test (>88%).

The 1,3,4-oxadiazole compounds 5(a, b, f) with aliphatic chain and amino groups have the best antioxidant activity (>96%) than BHT (94.59%), followed by other compounds that have better or close activity than AA (91.69%). From the IC50 values, the following compounds 2, 3, 5h, 5f and 5d showed excellent antioxidant activity with values of 2.56, 4.00, 6.05, 6.94 and 7.90µg/ml respectively, compared to AA and BHT, while other compounds except 5a (20.76%) presented good results: 11µg/ml<IC50<14µg/ml.

4 Conclusion

The ten 2,5-disubstituted-1,3,4-oxadiazolyl derivatives 5(a-j) were successfully synthesized and fully characterized by UV–Vis IR, ¹H NMR and ¹³C NMR.

The most derivatives synthesized showed excellent antioxidant activity with a concentration of 250µg/ml as an antioxidant agent (76% < RSA<95.5%), in particular 5a, 5c, 5e and 5j which gave an inhibition percentage very close to AA. The results of IC₅₀ values showed that compounds 3, 5e, 5d, 5a and 5c are more effective as antioxidants due to their ability to scavenge DPPH free radicals, and for the FRAP test, it can be concluded that the effect of antioxidants followed the following order: AA>5g>5i>5f>3>5h>5e>5j>5d>5a>5c>5b>BHT. TAC test showed that the following compounds 5h, 5f and 5d have excellent antioxidant activity with IC₅₀ values of 6.05, 6.94 and 7.90µg/ml respectively compared to AA and BHT.

The 1,3,4-oxadiazole derivatives 5c, 5d, 5g, 5i and 5j showed excellent antibacterial and antifungal activity better or very close to that of the antibiotics used as standards. Compounds 5b and 5i provided good results against L. innocua with inhibition values of IZ=14mm and IZ=22mm, respectively, while the rest of the compounds and antibiotics were unable to inhibit it. Compounds 5c, 5d, 5g and 5j showed excellent activity against C. albicans with values between 31mm and 34mm. These results were better than all the standards used. The MIC value (25µg/ml) for derivatives 5(c-e), 5g and 5(i-j) against B. cereus represent the best activity of the tested compounds. In light of the results obtained in this study, the potent antioxidant and antimicrobial activities of the synthesized compounds could provide a promising application in the field of food, pharmaceutical, and cosmetics industry.

CRediT authorship contribution statement

Khaled Briki: Conceptualization, Data curation, Methodology, Writing – original draft. Talal Lahreche: Conceptualization, Formal analysis, Methodology, Writing – original draft. Mouna Souad Abbassi: Conceptualization, Formal analysis, Methodology, Writing – original draft. Mokhtar Boualem Lahrech: Conceptualization, Supervision, Validation, Writing – review & editing. Adil Ali Othman: Conceptualization, Formal analysis, Methodology, Writing – original draft, Writing – review & editing. Ahmed M. Elissawy: Formal analysis, Validation, Visualization, Writing – review & editing. Abdel Nasser B. Singab: Conceptualization, Supervision, Visualization, Writing – review & editing.

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