Generic placeholder image

Letters in Drug Design & Discovery


ISSN (Print): 1570-1808
ISSN (Online): 1875-628X

Research Article

Synthetic Transformation of 4-fluorobenzoic Acid to 4-fluorobenzohydrazide Schiff Bases and 1,3,4-Oxadiazole Analogs having DPPH Radical Scavenging Potential

Author(s): Momin Khan*, Zala Fazal, Aftab Alam, Mohammad Ibrahim, Tehseen Ali, Mahboob Ali and Hafiz Danyal Khan

Volume 20, Issue 12, 2023

Published on: 23 November, 2022

Page: [2018 - 2024] Pages: 7

DOI: 10.2174/1570180820666221031091246

Price: $65


Aims: Synthesis of 4-fluorobenzohydrazide Schiff bases and 1,3,4-oxadiazole analogs has a DPPH radical scavenging potential.

Background: Synthetic antioxidants are widely used because they are effective and cheaper than natural antioxidants. Based on the literature survey, this present study is mainly focused on the study of the free radical scavenging activity of the Schiff base and oxadiazole motifs.

Methods: In this research work, Schiff’s base (4a-4g) and 1,3,4-oxadiazole (5a-5g) derivatives based on 4-fluorobenzoic acid were synthesized through multistep reactions. Initially, 4-fluorobenzoic acid was esterified in the presence of sulphuric acid (H2SO4) in ethanol solvent, and then it was reacted with an excess of hydrazine hydrate to obtain the desired 4-fluorobenzohydrazide. Various aromatic aldehydes were reacted with 4-fluorobenzo hydrazide in the presence of a catalytic amount of acetic acid to obtain the desired hydrazones. Finally, different substituted hydrazones were cyclized in the presence of iodine and potassium carbonate in DMSO to obtain substituted 1,3,4-oxadiazoles. The progress of all reactions was checked using thin-layer chromatography. The compounds were recrystallized from ethanol with good yield. The synthesized compounds were characterized with the help of EI-MS and 1H-NMR spectroscopy.

Results: The synthesized Schiff bases (4a-4g) and oxadiazole derivatives (5a-5g) of 4-fluorobenzoic acid demonstrated good free radical scavenging activity. Among the series, Compound 4f (IC50 = 25.57 ± 7.41 μM), showed comparable activity when compared with the standard Vitamin C (IC50 = 19.39 ± 12.57 μM). Similarly Compound 4a (IC50 = 40.90 ± 1.92 μM), 4b (IC50 = 34.77 ± 1.03 μM), 4c (IC50 = 90.2 ± 2.90 μM), 4e (IC50 = 78.62 ± 9.64 μM), 4g (IC50 = 80.65 ± 1.80 μM), 5a (IC50 = 52.67 ± 4.98 μM) and 5f (IC50 = 89.45 ± 9.11 μM) showed moderate antioxidant activity. Furthermore compounds, 4d (IC50 = 102.55 ± 10.4 μM), 5b (IC50 = 123.76 ± 12.34 μM), 5d (IC50 = 701.62 ± 1.06 μM), and 5e (IC50 = 102.87 ± 7.98 μM) displayed less significant anti-oxidant potential, while compounds 5c and 5g were found inactive.

Conclusion: Schiff’s base (4a-4g) and substituted 1,3,4-oxadiazole (5a-5g) derivatives based on 4- fluorobenzoic acid scaffolds were synthesized using standard pathways. All compounds were structurally characterized through EI-MS and 1H-NMR spectroscopy and evaluated for their in vitro DPPH free radical scavenging activity. In-vitro study reveals that the newly prepared derivatives of 4-fluorobenzoic acid have potent antioxidant potential. Whereas compound 5c and 5g were found inactive, this study has recognized a series of potential molecules as antioxidant agents and is useful in the field of medicinal chemistry.

Keywords: 4-Fluorobenzoic acid, 4-Fluorobenzohydrazide, schiff base, 1, 3, 4-oxadiazoles, DPPH radical scavengers, spectral analysis.

Graphical Abstract
Kajal, A.; Bala, S.; Kamboj, S.; Sharma, N.; Saini, V. Schiff bases: A versatile pharmacophore. J. Catalysts, 2013, 2013, 893512.
Uddin, N.; Rashid, F.; Ali, S.; Tirmizi, S.A.; Ahmad, I.; Zaib, S.; Zubair, M.; Diaconescu, P.L.; Tahir, M.N.; Iqbal, J.; Haider, A. Synthesis, characterization, and anticancer activity of Schiff bases. J. Biomol. Struct. Dyn., 2020, 38(11), 3246-3259.
[] [PMID: 31411114]
Al Zoubi, W.; Al-Hamdani, A.A.S.; Ahmed, S.D.; Ko, Y.G. Synthesis, characterization, and biological activity of Schiff bases metal complexes. J. Phys. Org. Chem., 2018, 31(2), e3752.
Ceramella, J.; Iacopetta, D.; Catalano, A.; Cirillo, F.; Lappano, R.; Sinicropi, M.S. A review on the antimicrobial activity of schiff bases: Data collection and recent studies. Antibiotics, 2022, 11(2), 191.
[] [PMID: 35203793]
Beyazit, N.; Çakran, H.S.; Cabir, A.; Akışcan, Y.; Demetgül, C. Synthesis, characterization and antioxidant activity of chitosan Schiff base derivatives bearing (−)-gossypol. Carbohydr. Polym., 2020, 240, 116333.
[] [PMID: 32475591]
Buldurun, K.; Turan, N.; Bursal, E.; Aras, A.; Mantarcı, A.; Çolak, N.; Türkan, F.; Gülçin, İ. Synthesis, characterization, powder X-ray diffraction analysis, thermal stability, antioxidant properties and enzyme inhibitions of M(II)-Schiff base ligand complexes. J. Biomol. Struct. Dyn., 2021, 39(17), 6480-6487.
[] [PMID: 32752945]
Kizilkaya, H.; Dag, B.; Aral, T.; Genc, N.; Erenler, R. Synthesis, characterization, and antioxidant activity of heterocyclic Schiff bases. J. Chin. Chem. Soc., 2020, 67(9), 1696-1701.
Mi, Y.; Li, Q.; Miao, Q.; Tan, W.; Zhang, J.; Guo, Z. Enhanced antifungal and antioxidant activities of new chitosan derivatives modified with Schiff base bearing benzenoid/heterocyclic moieties. Int. J. Biol. Macromol., 2022, 208, 586-595.
[] [PMID: 35346683]
Yadav, M.; Sharma, S.; Devi, J. Designing, spectroscopic characterization, biological screening and antioxidant activity of mononuclear transition metal complexes of bidentate Schiff base hydrazones. J. Chem. Sci., 2021, 133(1), 21.
Muhammad Yousaf, M.Y.; Momin Khan, M.K.; Mumtaz Ali, M.A.; Abdul Wadood, A.W.; Ashfaq Ur Rehman, A.U.R.; Muhammad Saeed Jan, M.S.J. Abdul Sadiq and Faima Alam, A.S.F.A. 2-Mercaptobenzimidazole derivatives as novel butyrylcholinesterase inhibitors: Biology-oriented drug synthesis (BIODS), in-vitro and in-silico evaluation. J. Chem. Soc. Pak., 2020, 42(2), 263-273.
Khan, M.; Ali, U.; Ur Rahman, A.; Ibrahim, M.; Hameed, A.; Asif, M.; Hussain, Z.; Kanwal; Khan, K.M.; Perveen, S.; Rehman, M. Green synthesis, characterization, DPPH and Ferrous Ion-chelating (FIC) activity of Tetrakis-Schiff’s bases of terephthalaldehyde. Lett. Drug Des. Discov., 2019, 16(3), 249-255.
Ahad, G.; Khan, M.; Khan, A.; Ibrahim, M.; Salar, U.; Khan, K.M. Synthesis, structural characterization, and antioxidant activities of 2, 4-dinitrophenyl-hydrazone derivatives. J. Chem. Soc. Pak., 2018, 40, 961.
Antony, R.; Arun, T.; Manickam, S.T.D. A review on applications of chitosan-based Schiff bases. Int. J. Biol. Macromol., 2019, 129, 615-633.
[] [PMID: 30753877]
Bakır, T.K.; Lawag, J.B. Preparation, characterization, antioxidant properties of novel Schiff bases including 5-chloroisatin-thiocarbohydrazone. Res. Chem. Intermed., 2020, 46(5), 2541-2557.
Khan, M.; Ahad, G.; Manaf, A.; Naz, R.; Hussain, S.R.; Deeba, F.; Shah, S.; Khan, A.; Ali, M.; Zaman, K.; Zafar, S.; Salar, U.; Hameed, A.; Khan, K.M. Synthesis, in vitro urease inhibitory activity, and molecular docking studies of (perfluorophenyl)hydrazone derivatives. Med. Chem. Res., 2019, 28(6), 873-883.
Wei, L.; Tan, W.; Wang, G.; Li, Q.; Dong, F.; Guo, Z. The antioxidant and antifungal activity of chitosan derivatives bearing Schiff bases and quaternary ammonium salts. Carbohydr. Polym., 2019, 226, 115256.
[] [PMID: 31582056]
Çavuş, M.S.; Yakan, H.; Muğlu, H.; Bakır, T. Novel carbohydrazones including 5-substituted isatin: Synthesis, characterization, and quantum-chemical studies on the relationship between electronic and antioxidant properties. J. Phys. Chem. Solids, 2020, 140, 109362.
Ahmed, W.S.; Mahmood, A.A.R.; Al-Bayati, R.I. Synthesis and evaluation of antimicrobial activity of new imides and schiff bases derived from ethyl-4-amino benzoate. Orient. J. Chem., 2018, 34, 2477.
Khan, M.; Alam, A.; Khan, K.M.; Salar, U.; Chigurupati, S.; Wadood, A.; Ali, F.; Mohammad, J.I.; Riaz, M.; Perveen, S. Flurbiprofen derivatives as novel α-amylase inhibitors: Biology-oriented drug synthesis (BIODS), in vitro, and in silico evaluation. Bioorg. Chem., 2018, 81, 157-167.
[] [PMID: 30125730]
Verma, S.K.; Verma, R.; Verma, S.; Vaishnav, Y.; Tiwari, S.P.; Rakesh, K.P. Anti-tuberculosis activity and its structure-activity relationship (SAR) studies of oxadiazole derivatives: A key review. Eur. J. Med. Chem., 2021, 209, 112886.
[] [PMID: 33032083]
Zabiulla; Nagesh Khadri, M.J.; Bushra Begum, A.; Sunil, M.K.; Khanum, S.A. Synthesis, docking and biological evaluation of thiadiazole and oxadiazole derivatives as antimicrobial and antioxidant agents. Results in Chemistry, 2020, 2, 100045.
Shah, S.; Khan, M.; Ali, M.; Wadood, A.; Ur Rehman, A.; Shah, Z.; Yousaf, M.; Salar, U.; Khan, K.M. Bis -1,3,4-oxadiazole derivatives as novel and potential urease inhibitors; Synthesis, in vitro, and in silico studies. Med. Chem., 2022, 18(7), 820-830.
[] [PMID: 35232342]
Izgi, S.; Sengul, I.F.; Şahin, E.; Koca, M.S.; Cebeci, F.; Kandemir, H. Synthesis of 7-azaindole based carbohydrazides and 1,3,4-oxadiazoles; Antioxidant activity, α-glucosidase inhibition properties and docking study. J. Mol. Struct., 2022, 1247, 131343.
Luczynski, M.; Kudelko, A. Synthesis and biological activity of 1,3,4-oxadiazoles used in medicine and agriculture. Appl. Sci., 2022, 12(8), 3756.
D'souza, AS; D’Souza, A; Mendonca, AP; Noronha, B A short review on 1, 3, 4–oxadiazole and its pharmacological activities. J. Xian Shiyou Uni., 17(12), 126-137.
Bingul, M.; Saglam, M.F.; Kandemir, H.; Boga, M.; Sengul, I.F. Synthesis of indole-2-carbohydrazides and 2-(indol-2-yl)-1,3,4-oxadiazoles as antioxidants and their acetylcholinesterase inhibition properties. Monatsh. Chem., 2019, 150(8), 1553-1560.
Demurtas, M.; Baldisserotto, A.; Lampronti, I.; Moi, D.; Balboni, G.; Pacifico, S.; Vertuani, S.; Manfredini, S.; Onnis, V. Indole derivatives as multifunctional drugs: Synthesis and evaluation of antioxidant, photoprotective and antiproliferative activity of indole hydrazones. Bioorg. Chem., 2019, 85, 568-576.
[] [PMID: 30825715]
Dixit, D.; Verma, P.K.; Marwaha, R.K. A review on ‘triazoles’: Their chemistry, synthesis and pharmacological potentials. J. Indian Chem. Soc., 2021, 18, 2535-2565.
Faramarzi, Z.; Kiyani, H. Steglich’s base catalyzed three-component synthesis of isoxazol-5-ones. Polycycl. Aromat. Compd., 2022, 1-23.
Hayat, M.; Khan, K.M.; Saeed, S.; Salar, U.; Khan, M.; Baig, T.; Ahmad, A.; Parveen, S.; Taha, M. Antimicrobial activities of synthetic arylidine nicotinic and isonicotinic hydrazones. Lett. Drug Des. Discov., 2018, 15(10), 1057-1067.
Nesaragi, A.R.; Kamble, R.R.; Dixit, S.; Kodasi, B.; Hoolageri, S.R.; Bayannavar, P.K.; Dasappa, J.P.; Vootla, S.; Joshi, S.D.; Kumbar, V.M. Green synthesis of therapeutically active 1,3,4-oxadiazoles as antioxidants, selective COX-2 inhibitors and their in silico studies. Bioorg. Med. Chem. Lett., 2021, 43, 128112.
[] [PMID: 33991632]
Shah, S.S.; Shah, D.; Khan, I.; Ahmad, S.; Ali, U. Synthesis and antioxidant activities of Schiff bases and their complexes: An updated review. Biointerface Res. Appl. Chem., 2020, 10, 6936-6963.
Shaikh, M.; Siddiqui, S.; Zafar, H.; Naqeeb, U.; Subzwari, F.; Imad, R.; Khan, K.M.; Choudhary, M.I. Antiglycation activity of triazole Schiff’s bases against fructosemediated glycation: In vitro and in silico study. Med. Chem., 2020, 16(4), 575-591.
[] [PMID: 30747076]
Stasevych, M.; Zvarych, V.; Novikov, V. Study of the antifungal action of the lacquer based on the GABA derivative of 2-chloro-N-(9, 10-dioxo-9, 10-dihydroanthracen-1-yl) acetamide. Biointerface Res. Appl. Chem., 2021, 11, 8818-8824.
Shakir, R.M.; Ariffin, A. Abdulla, MA Synthesis of new 2, 5-di-substituted 1, 3, 4-oxadiazoles bearing 2, 6-di-tert-butylphenol moieties and evaluation of their antioxidant activity. Molecules, 2014, 19, 3436-3449.
Cheng, L.X.; Tang, J.J.; Luo, H.; Jin, X.L.; Dai, F.; Yang, J.; Qian, Y.P.; Li, X.Z.; Zhou, B. Antioxidant and antiproliferative activities of hydroxyl-substituted Schiff bases. Bioorg. Med. Chem. Lett., 2010, 20(8), 2417-2420.
[] [PMID: 20346660]
Mishra, K.; Ojha, H.; Chaudhury, N.K. Estimation of antiradical properties of antioxidants using DPPH assay: A critical review and results. Food Chem., 2012, 130(4), 1036-1043.

Rights & Permissions Print Cite
© 2024 Bentham Science Publishers | Privacy Policy