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CHEMICAL PROBLEMS 2023 no. 4 (21) ISSN 2221-8688
343
UDC 615.31:547.792].014
SYNTHESIS, CHARACTERIZATION IN SILICO AND IN VITRO STUDY OF NEW 1,2,3- TRIAZOLE DERIVATIVES AS ANTIOXIDANT AGENTS
Nabeel A. Abdul-Reda*, Islam H.Tarrad
Department of Chemistry, College of Science, University of Al-Qadisiyha,
Diwanyiah, 58002, Iraq *e-mail: nabeel.a.alradha@qu.edu.iq
Received 17.07.2023 Accepted 11.10.2023
Abstract: By the region-selective, a click one-pot reaction a series of new 1,2,3-triazole derivatives were successfully synthesized and evaluated in vitro as antioxidant agents. The molecular structures of synthesized derivatives were characterized using spectral analysis (IR, 1H NMR, and 13C NMR) in addition to elements analysis (C.H.N). The products obtained were investigated in vitro for their antioxidant activity. The results of the DPPH test revealed that 1,2,3-triazole derivatives possess a good selectivity index to capture free radicals. It was found among these compounds that the 5a, 5c and 5d exhibited potent levels of activity with inhibition percentages of82.25, 80.42, and 75.36%, respectively compared to that of standard ascorbic acid. In addition, the molecular docking study confirmed the biological activity results of the tested compounds and determined their interactions nature with the active site of the protein. Keyword: 1,2,3-triazole, click chemistry, antioxidant, molecular docking, diazotization reaction. DOI: 10.32737/2221-8688-2023-4-343-352
Introduction
Oxidative stress is one of the most complex processes that occur in biological systems because of an imbalance between the production of oxidants, such as reactive oxygen species, and the ability to eliminate these oxidants by antioxidant systems [1]. Oxidants are unstable active molecules with one or more of unpaired electrons, e.g., hydroxyl radical OH-, superoxide ion O2-, and hydrogen peroxide H2O2, and are known as free radicals that are by-products of enzymatic reactions [2]. Among the effects, it was found that free radicals can interact with proteins, nucleic acids, lipids, and carbohydrates, and thus affect their structure and function. These effects can damage the cells and lead to different pathologies including early aging, atherosclerosis, cancer, and Alzheimer's disease, etc.[3,4]. Antioxidants are active molecules that affect on deactivating or eliminating free radicals by mechanism allowing reduction the oxidative stress and prevention of cellular damage, thus they contribute greatly to
maintaining human health [5,6]. It was also found that the overproduction of oxidants in the biological system depletes the antioxidants in the body and thus increases the risk of disease, for this reason, exogenous antioxidants were used to compensate of the lack and protect the body from diseases [7]. Natural and synthetic chemical compounds, e.g., vitamins C, phenolic compounds, and some minerals (Se and Zn), etc., are one of the most important sources of exogenous antioxidants that can be obtained through medicines or nutritional supplements [8]. 1,2,3-triazole and their derivatives are one of the important synthetic compounds in nitrogen-containing, heterocyclic systems, characterized by a range of biological activities and low toxicity parameters [9-11]. Next to their antioxidant activity [12], triazole derivatives exhibited a broad spectrum of biological activities, such as antibacterial [13], anti-fungal [14], anti-inflammatory [15], anti- HIV [16,17], anti-Alzheimer [18], anti-cancer [19,20], and other pharmacological activities [21,22].
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CHEMICAL PROBLEMS 2023 no. 4 ( 21)
Besides, they are used in the industrial field as excellent anti-corrosion agents in acidic environments [23, 24]. In this work, we
synthesized a number of 1, 2, 3-triazole derivatives and their activity evaluation in vitro and in silico as antioxidant agents.
Experimental part
General information
Melting points are uncorrected and were measured on SMP apparatus (Gallenkamp). IR spectra were measured with IR spectrophotometer (BRUKER). NMR measurements ^H NMR, 13C NMR) were recorded on Bruker AMX 400 and 100 instruments using TMS as a reference and DMSO-d6 as a solvent. Microelements (C.H.N.) were measured using Vario Elemental Analyzer 3000 (Shimadzu, Japan). Analyses TLC were carried out on Merck 60 F254. The chemicals were supplied from commercial sources and utilized as received without further purification. Synthesis
General procedure for preparation of azide compounds 2a-b [23]
One of the aniline compounds (5mmol), anthranilic acid 1a (0.69gm) or 4-nitroaniline 1b (0.685gm) was individually dissolved with sodium nitrite NaNO2 (6mmol, 0.2gm) in an acidic solution (10%HCl) and stirred for 30 min at 0°C. Then, the solution of NaN3 (5mmol, 0.326gm in 5 mL water) was gradually added and again stirred for another 1h. Following the completion of the reaction (check by TLC), the solution was treated with 5%NaOH (10mL) and then extracted with chloroform. The organic liquid obtained was dried with Na2SO4 and then concentrated to a solid by a vacuum. The final products were recrystallized from absolute ethanol.
2-azidobenzoc acid 2a: white crystals,
yeild79%, m.p165-167. IR (KBr,cm-1): v 3354 (OH), 3274,3157 (NH2), 3025(C-H), 2214 (N=N), 1732 (C=O). 1H NMR (DMSO-d6, ppm): 5 10.74 (s,1H,OH), 7.92-7.38(d,4H,H-Ar). 13C NMR (DMSO-d6, ppm): 5 161.41 (C=O), 129.51-122.93 (C-arom.). Anal. calculated for C7H5N3O2: C, 51.34; H, 3.09; N, 25.76. Found; C, 52.05; H, 3.28; N, 25.92. 1-azido-4-nitrobenzene 2b: yellow crystals, yeild 87%, m.p 132-134. IR (KBr,cm-1): v 3032(C-H), 2126 (N=N), 1585, 1328 (NO2), . 1H NMR (DMSO-d6, ppm): 5 7.92-
7.48(d,4H,H-arom.). 13C NMR (DMSO-d6, ppm): 5 145.12(C-Nb), 141.23 (C-NO2), 121.34, 123.65 (C-arom.). Anal. calculated for C6H4N4O2: C, 43.91; H, 2.46; N, 34.14. Found; C, 43.35; H, 2.18; N, 33.72. General method for synthesis of propargyl derivatives 3a and 3b [25].
Potassium carbonate (0.552 g, 4mmol), was dissolved with one of the derivatives 3a-d (2mmol) in 30 mL of acetone and stirred for 15 min, and then propargyl bromide (2 mmol) was slowly added to the mixture and refluxed for 15-18 h until finish of the reaction (check by TLC). The solution was diluted with H2O and then extracted with dichloromethane. The organic liquid was dried with anhydrous Na2SO4 and the solvent was evaporated with vacuum. Products obtained were purified on short column of SiO2 using methanol- chloroform as eluent.
N-(4-(prop-2-yn-1-yloxy)phenyl)acetamide
3a: white crystals, yeild 74%, m.p 187-185. IR (KBr,cm-1): v 3126(N-H), 2115 (C=C), 1689(C=O). 1H-NMR(DMSO-J^,ppm): 5 9.45(s,1H, NH), 7.50-6.67(d,4H,H-arom.), 4.74(s,2H,CH2), 3.53(s,1H,Hacetylene),
2.08(t,8H,Me). 13C-NMR (DMSO-d6, ppm): 5 168.3(C=O), 153.5(C-O), 133.6-115.3(C-arom.), 79.3, 78.5(C=C), 56.0(C-O), 46.7(CH2), 24.2(CHs). Anal. calculated for C11H11NO2: C, 69.83; H, 5.86; N, 7.40. Found; C, 68.75; H, 5.41; N, 7.05.
1-((4-chlorophenyl)(phenyl)methyl)-4-(prop-
2-yn-1-yl)piperazine 3b: yellow crystals, yeild 78%, m.p 117-115. IR (KBr,cm-1): v 2111(C=C), 835(C-Cl). 1H-NMR(DMSO-d6,ppm): 5 7.73-7.23(d,9H,H-arom.), 5.25(s,1H,Htertiary, 4.65(s,2H,CH2), 3.45(s,1H,HaCetylene), 2.08-1.96 (t,8H,CH2piprazine). 13C-NMR (DMSO-d6, ppm): 5 135.1-118.6(C-arom.), 79.5(C-tertiary), 76.3, 70.8(C=C), 52.7, 51.4(C-piprazine), 47.9(CH2). Anal. calculated for C20H21ClN2: C, 73.95; H, 6.52; N, 8.62. Found; C, 72.66; H, 5.98; N, 8.11.
General procedure for synthesis of 1,2,3-triazole 5a-d derivatives [26]
A mixture of one of the azido compounds 2a-b (2mmol), one of alkynes 3a-b (2mmol), sodium ascorbate, aqueous copper sulfate CuSO4.5H2O as a catalyst were dissolved in 30 mL of DMF/H2O (2:1) and refluxed for 14-18h at 60°C, and then was monitored by TLC until the end of the reaction. The reaction mixture was cooled to room temperature and treated with brine solution. Next step, a solution was extracted with chloroform and the product obtained was dried with anhydrous Na2SO4 and vacuumed to evaporation of the solvent. Products obtained were purified on short column of SiO2 using methanol-dichloromethane as eluent. N-(4-((1-(4-nitrophenyl)-1H-1,2,3-triazol-4-yl)methoxy)phenyl)acetamide 5a: white crystals, yield;76%, m.p.;186-184. IR (KBr,cm-1): v 3369(N-H), 1696 (C=O), 1625 (N=N), 1609 (C=Ctriazole), 1515, 1318 (NO2). 1H-NMR (DMSO-^6, ppm): 5 9.48(s,1H,NH), 8.12 (s,1H, H-5triazole), 7.95-6.60(d,8H,Ar-H), 4.70 (s,2H,CH2), 2.72(s,3H, CH3). 13C-NMR (DMSO-^6, ppm): 5 167.6(C=O), 156.3 (C-O), 139.8(C-4triazole), 113.2(C-5triazole), 137.5-119.4 (C-arom.), 63.8 (CH2), 24.4 (CH3). Anal. calculated for C17H15N5O4: C, 57.79; H, 4.28; N, 19.82. Found; C, 56.31; H, 3.88; N, 18.92.
1-((4-chlorophenyl)(phenyl)methyl)-4-((1-(4-nitrophenyl)-1H-1,2,3-triazol-4-yl)methyl)piperazine 5b: yellow crystals, yield;61%, m.p.;214-212. IR (KBr,cm-1): v 1637 (N=N), 1588 (C=Ctriazole), 1510, 1345 (NO2), 864(C-Cl). 1H-NMR (DMSO-J6, ppm): 5 8.26 (s,1H, H-5triazole), 7.98-6.72(d,13H,Ar-H), 3.87 (s,1H,CH), 3.37(s,2H, CH2), 2.85-2.80 (t,8H,CH2piprazine). 13C-NMR (DMSO-J6, ppm): 5 139.1-124.2 (C-arom.), 118.5(C-41riazole), 116.8(C-5triazole), 79.4(C-tertiary), 58.8 (CH2) 57.3, 55.8(C-piprazine). Anal. calculated for C26H25ClN6O2: C, 63.87; H, 5.15; N, 17.19. Found; C, 62.67; H, 4.73; N, 16.65.
2-(4-((4-acetamidophenoxy)methyl)-1H-1,2,3-triazol-1-yl)benzoic acid 5c: dark brown crystals, yield;68%, m.p.;151-149. IR (KBr,cm-1): v 3416(OH), 3235(N-H), 1736,1668 (C=O), 1612 (N=N).1459, 1571(C=C), 1722, 1687(C=O), 1625(N=N). 1H-NMR (DMSO-J6, ppm): 5 12.89(s,1H,OH),
9.85(s,1H,NH), 7.96 (s,1H, H-5triazole), 7.78-6.76(d,8H,Ar-H), 5.16 (s,2H,CH2), 2.50(s,3H, CH3). 13C-NMR (DMSO-J6, ppm): 5 168.3, 166,2(C=O), 154.2 (C-O), 144.7(C-4triazole), 118.5(C-5triazole), 132.9-121.2 (C-arom.), 76.3 (CH2), 24.6 (CH3). Anal. calculated for C18H16N4O4: C, 61.36; H, 4.58; N, 15.90. Found; C, 60.42; H, 4.06; N, 15.11.
2-(4-((4-((4-
chlorophenyl)(phenyl)methyl)piperazin-1-yl)methyl)-1H-1,2,3-triazol-1-yl)benzoic acid
5d: orange crystals, yield;65%, m.p.;228-226. IR (KBr,cm-1): v 3337(OH), 1747 (C=O), 1631 (N=N), 1495 (C=Ctriaz.), 829(C-Cl). 1H-NMR (dMSO-^6, ppm): 5 11.75(s,1H,OH), 8.22 (s,1H, H-5triazole), 8.10-6.78(d,13H,Ar-H), 4.70 (s,1H,CH), 3.40(s,2H, CH2), 2.79-2.75 (t,8H,CH2piprazine). 13C-NMR (DMSO-J6, ppm): 5 168.7 (C=O), 139.8-119.6 (C-arom.), 119.1(C-4triazole), 115.3(C-5triazole), 79.0(C-tertiary), 59.7 (CH2) 58.4, 57.9(C-piprazine). Anal. calculated for C27H26ClN5O2: C, 66.46; H, 5.37; N, 14.35. Found; C, 65.42; H, 4.96; N, 13.76. Antioxidant Screening Assay [27]
The antioxidant activity of derivatives 5a-d was screened using the DPPH (1,1-diphenyl-2-picryl hydrazyl) assay to determine the radical scavenging potential of under-study compounds. Briefly, a solution of DPPH (60pM in 2ml of ethanol) was added to a solution of the tested compound at 12.5, 25, 50, 100, 250, and 500^M concentrations. Following the addition and homogenizing, the mixture was incubated in the dark for 30 min. The absorbance of the sample was determined at wavelength 515nm on a UV/Vis spectrophotometer "Amersham Biospectro". The same steps were applied with ascorbic acid for comparison, as all results obtained were utilized to calculate the percentage of inhibition according to the following formula:
Antioxidant effect as % = [(Ac-As) -^Ac] x 100
where AC = the control absorbance, while AS = the sample absorbance. Docking study analysis [28]
Four compounds with good antioxidant activity underwent molecular docking studies to identify the potential binding with the protein of cytochrome c peroxidase enzyme (PDB: 2X08) obtained from the protein data bank. The
compounds were structured and converted to PBD format and then used as ligands. Autodock 4.2.6 program was employed to calculate the binding energy of the ligand with the protein
pocket (2X08). Discovery studio software was utilized to set the receptor and visualize the binding modes that occur theoretically by 2D and 3D interaction poses.
Results and Discussion
By the diazotization reaction, the azide compounds 2a and 2b were individually synthesized from anthranilic acid 1a and 4-nitroaniline 1b, respectively in an acidic
medium (10%HCl) containing sodium nitrite and sodium azide and at 0°C, as shown in Scheme 1.
NH,
la-b
10%HC1 / NaNOz 30min / 0C°
© © N=N CI
SV
R
NaN,
Diazonium Salt
N,
lh / 0C°
R
2a-b
where R = la: 2-COOH, lb: 4-NOz Scheme 1. Experimental steps for synthesis of compounds (2a, 2b)
In the second step, the alkyne derivatives 4a and 4b were synthesized through reaction propargyl bromide with N-(4-hydroxyphenyl)acetamide 3a, 1 -((4-chlorophenyl)(phenyl)methyl)
Br>
piperazine 3b, individually in the presence of potassium carbonate and acetone as solvent as shown in Scheme 2.
3a, 3b +
K2C03/ acetone
reflux 16-24h
4a, 4b
H
4a
Scheme 2. Experimental steps
In the next step and by the region-selective click reaction, 1,2,3-triazole derivatives 5a-d were synthesized from reaction of the azide derivatives 2a, 2b with different alkynes 4a and 4b using sodium ascorbate and hydrated copper sulfate as catalytic agents. This reaction occurs according to the cyclo-addition 1,3-dipolar mechanism that leads to the
for synthesis of compounds (4a, 4b)
formation of 5-membered hetero-cycles, as shown in scheme 3. The structures of all newly synthesized derivatives were determined utilizing different spectroscopic methods (IR, 1H-NMR, 13C-NMR) in addition to microelements analysis. The data of spectral and micro-elements analysis were included in the experimental section.
Biological activity Antioxidant activity study
The antioxidant activities of under-study compounds 5a-d were evaluated in vitro using DPPH assay, and the ascorbic acid was used as a reference. The radicals scavenging test depends
on a mechanism that make it possible to reduce the DPPH radical solution by a hydrogen donor antioxidant which leads to the formation of the non-radical form of DPPH-H. Generally, the results revealed that tested compounds showed potent activity as antioxidants.
Na.Asco/CuS04.5H20
DMF/H20 (2:1) sterring, 60 °C , 14-18h
N=N
R
2a-b
4a, 4b
5a-d
Where G =
H
I
N. -CH
^XX T
3
5a, 5c
04-
5b, 5d
Scheme 3. Experimental steps for synthesis of compounds (5-d)
Moreover, compounds 5a, 5c and 5d have the most potent levels of activity as compared to that of standard ascorbic acid at all the used concentrations, while the activity of compound 5b was less effective than with increased concentration. At a concentration 500^M, it was found that the percentage inhibition of
compounds 5a, 5c and 5d potency of 82.25, 80.42 and 75.36%, respectively as shown in Table 1. In addition, our results indicated that some of synthesized compounds possess structural properties that help in capturing free radicals; this was confirmed in a molecular docking study.
Table 1. Results of DPPH assay of compounds 5a-d at wavelength 515nm and concentration
500^M.
Compounds Absorbance of Sample % Inhibition
5a 0.178 82.25±4.52
5b 0.218 29.5±1.25
5c 0.086 80.42±4.14
5d 0.112 75.36±3.98
Ascorbic-acid 0.065 85.88±4.72
Antioxidant activity
-*-5d
control
Fig. 1. Antioxidant activity results of compounds 5a-d by DPPH assay.
Molecular Docking study
In silico, a molecular docking study of compounds 5a-d was performed to identify their antioxidant activity results. The target compounds were docked as ligands with the protein of cytochrome c peroxidase enzyme (PDB: 2X08) and attained favorable conformation. According to the docking calculations, the binding energy of 1,2,3-triazole derivatives 5a-d were -2.8, 3.7, -4.1 and -3.6 [kcal/mol], respectively. The docking results
revealed that 1,2,3-triazole derivatives 5a, 5c, and 5d were bound with the active site of the protein selectively and acceptably via different types of interactions such as hydrogen bond, hydrophobic, and electrostatic interactions. A summary of the binding energies and types of interactions is shown in Table 2, while the binding pose of compounds 5a, 5c and 5d with the active pocket of the target protein was shown as 2D, 3D representations in Fig. 2, 3 and 4.
Fig 2. Conformations for 5-a simulations with the active site of cytochrome c peroxidase enzyme
Fig 3. Conformations for 5-c simulations with the active site of cytochrome c peroxidase enzyme
A371
Fig 4. Conformations for 5-d simulations with active site of cytochrome c peroxidase enzyme
Table 2. Docking results, types of interactions and the binding energy of 1,2,3-triazole derivatives with the
catalytic site of cytochrome c peroxidase enzyme
Compound Ligand moiety Site(A.A) Interaction E (kcal/mol)
NH GLU 273(A) H- Bond
C=O GLU 469(A) H- Bond
5a N=N GLU 282(A) Pi-Anion -2.8
LYS 150(A) Pi-Amid
ALA 351(A) Pi-Alkyl
6-ring LYS 150(A) Pi-Alkyl
Other Electrostatic
NH GLU 273(A) H- Bond
OH LEU 202(A) H- Bond
5c ARG 259(A) H- Bond -4.1
N=N PRO 155(A) Pi-Alkyl
ARG 259(A) Pi-Cat ion
6-ring ALA 151(A) Pi-Alkyl
LEU 202(A) Pi-Alkyl
other Electrostatic
5-ring GLY 399(A) Pi- Amid
PRO 368(A) Pi-Alkyl
5d N=N ASN 75(A) H- Bond -3.6
6-ring LYS 473(A) Pi-Alkyl
ARG 400(A) Pi-Alkyl
C-N ARG 400(A) C-H-Bond
TYR 366(A) C-H-Bond
other Electrostatic
Conclusions
In the current work, we focused on the synthesis of a series of 1, 2, 3-triazole derivatives by the 3,1-dipole cyclo-addition mechanism and their in vitro evaluation as antioxidants. The results of the test indicated that some synthesized compounds had a good selectivity index as radicals scavenging agents, among those compounds, N-(4-((1-(4-
nitrophenyl)- 1H-1,2,3 -triazol-4-yl)methoxy)phenyl) acetamide showed higher inhibition level with percentage potency of 80.15% as compared to other compounds. In addition, molecular docking simulation confirmed the biological activity results by determining the interactions nature that spontaneously occurs between the compound
and the active site of the protein. Generally, compounds are able to capture free radicals; this results obtained indicated that some synthesized was confirmed in a molecular docking study. Acknowledgements
Authors are thankful to the Department of Chemistry - College of Science - University of Al Qadisiyah for providing facilities. We also extend our thanks to Dr. Qassim A.H. Jaber, for helping us.
Conflict of Interest: The authors acknowledge that there is no conflict of interest.
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СИНТЕЗ, ХАРАКТЕРИСТИКА IN SILICO И ИССЛЕДОВАНИЕ IN VITRO НОВЫХ ПРОИЗВОДНЫХ 1,2,3-ТРИАЗОЛА В КАЧЕСТВЕ АНТИОКСИДАНТОВ
Набиль А. Абдул-Реда*, Ислам Х.Таррад
Кафедра химии, Университет Аль-Кадисия, Дивания, 58002, Ирак *e-mail: nabeel.a.alradha@qu.edu.iq
Аннотация: С помощью региоселективной реакции был успешно синтезирован ряд новых производных 1,2,3-триазола. Молекулярную структуру синтезированных производных охарактеризовали с помощью спектрального анализа (ИК, ЯМР 1Н и ЯМР 13С), а также элементного анализа. Полученные продукты исследовали in vitro на предмет их антиоксидантной активности. Результаты ДФРГ теста показали, что производные 1,2,3-триазола обладают хорошим показателем селективности по захвату свободных радикалов. Было обнаружено, что соединения 5a, 5c и 5d проявляют высокие уровни активности с процентами ингибирования 82,25, 80,42 и 75,36% соответственно по сравнению с таковым стандартной аскорбиновой кислоты. Кроме того, исследование молекулярного докинга подтвердило результаты биологической активности тестируемых соединений и определило характер их взаимодействия с активным центром белка.
Ключевые слова: 1,2,3-триазол, клик-химия, антиоксидант, молекулярный докинг, реакция диазотирования
ANTiOKSiDANLAR KiMi 1,2,3-TRiAZOLUN YENi TÖR9M9L9RiNIN IN VITRO TODQiQi V9 IN SILICO SiNTEZi, XARAKTERiSTiKASI
Nabil A. Abdul-Reda*, islam H. Tarrad
dl-Qadisiyyd Universitetinin Kimya fakültasi, Divaniyya, 58002, Iraq *e-mail: nabeel.a.alradha@qu.edu.iq
Xülasa: Regioselektiv reaksiyadan istifada edarak 1,2,3-triazolun bir sira yeni töramalari ugurla sintez edilmi§dir. Sintez edilmi§ töramalarin molekulyar strukturu spektral (iQ, 1H NMR va 13C NMR), ham9inin element analizdan istifada etmakla xarakteriza olunmu§dur. 9lda edilan mahsullar antioksidant kimi tatbiqina göra in vitro tadqiq edilmi§dir. DFPH testinin naticalari göstarmi§dir ki, 1,2,3-triazol töramalari sarbast radikallari tamizlamak ü9ün yax§i se9iciliya malikdir. 5a, 5c va 5d birla§malarinin standart askorbin tur§usu ila müqayisada müvafiq olaraq 82. 25, 80.42 va 75.36 % inhibitorla§ma faizi ila yüksak aktivlik nümayi§ etdirdiyi a§kar edilmi§dir. Bundan alava, molekulyar dokinq tadqiqati naticasinda birla§malarin bioloji aktivliyinin olmasi tasdiqlanmi§ va onlarin zülalin aktiv sahasi ila qar§iliqli tasirinin xarakteri tayin edilmi§dir. A?ar sözlar: 1,2,3-triazol, klik kimyasi, antioksidant, molekulyar dokinq, diazotla§ma reaksiyasi
