Design, microwave-assisted synthesis, biological evaluation, molecular docking and ADME studies of pyrrole-based hydrazide-hydrazones as potential antioxidant agents
In this study, one novel N-pyrrolyl carboxylic acid (3), the corresponding N-pyrrolyl hydrazide (5), and four new hydrazide-hydrazones (5a-d) bearing electron donating moieties were designed, synthesized, and fully elucidated by 1H NMR, FT-IR, and HRMS. The hydrazide-hydrazones were produced in five steps, which were optimized by applying microwave heating. The microwave-assisted synthesis significantly decreased the reaction times and increased the yields of the title molecules. In addition, all novel compounds were assessed for their radical scavenging properties by employing DPPH and ABTS assays. The most promising agent was obtained after condensation of the title hydrazide (5) with a 3,5-dimetoxy-4-hydroxybenzaldehyde (5d). The latter compound showed better antioxidant properties than Trolox (6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid) and could serve as a prominent lead structure for future optimization as an antioxidant agent. A possible binding conformation of 5d in the active site of NADPH oxidase was also identified through molecular docking simulations. Analysis of the major interactions showed the importance of the hydroxyl moiety for the antioxidant activity. Finally, the virtual calculations of the ADME properties of the synthesized compounds displayed good drug-like properties. Overall, an optimized synthetic protocol through MW irradiation was employed. The newly synthesized ethyl (E)-5-(4-bromophenyl)-1-(1-(2-(4-hydroxy-3,5-dimethoxybenzylidene)hydrazineyl)-3-(1H-indol-3-yl)-1-oxopropan-2-yl)-2-methyl-1H-pyrrole-3-carboxylate (5d) was found to possess the most prominent radical-scavenging capacity, which identifies it as a promising lead compound for the development of novel antioxidants.
(1) Bozkurt, E.; Sıcak, Y.; Oruç-Emre, E. E.; Iyidoğan, A. K.; Öztürk, M., Design and bioevaluation of novel hydrazide-hydrazones derived from 4-acetyl-N-substituted benzenesulfonamide. Russian Journal of Bioorganic Chemistry 2020, 46, 702–714.
(2) Bolduc, J.; Collins, J.; Loeser, R., Reactive oxygen species, aging and articular cartilage homeostasis. Free Radical Biology and Medicine 2019, 132, 73–82.
(3) Butterfield, D. A.; Halliwell, B., Oxidative stress, dysfunctional glucose metabolism and Alzheimer disease. Nature Reviews Neuroscience 2019, 20, 148–160.
(4) Jasril; Juwiyatri, E.; Fauza, S. N.; Afriana, N., Synthesis, in vitro antioxidant activity, and toxicity evaluation of hydrazone derivatives naphthalene-1-ylmethylene hyd¬razine. Journal of Physics: Conference Series 2021, 2049, 012050.
(5) Shabeeb, I.; Al-Essa, L.; Shtaiwi, M.; Al-Shalabi, E.; Younes, E.; Okasha, R.; Abu Sini, M., New hydrazide-hydrazone derivatives of quinoline 3-carboxylic acid hydrazide: synthesis, theoretical modeling and antibacterial evaluation. Lett. Org. Chem. 2019, 16, 430–436.
(6) Pallapati, R. K.; Mutchu, B. R.; Khandapu, B. M. K.; Vanga, U. R.; Varala, R.; Bollikolla, H. B., Synthesis of novel gabapentin scaffold derived hydrazide-hydrazones for potential antimicrobial agents and antioxidants. Chemistry Africa 2020, 3, 881–888.
(7) 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.
(8) Gedye, R. N.; Rank, W.; Westaway, K. C., The rapid synthesis of organic compounds in microwave ovens. II. Can. J. Chem. 1991, 69, 706–711.
(9) Banerjee, B.; Kaur, G., Microwave assisted catalyst-free synthesis of bioactive heterocycles. Current Microwave Chemistry 2020, 7, 5–22.
(10) Zhao, W.; Chen, J.; Chang, X.; Guo, S.; Srinivasakannan, C.; Chen, G.; Peng, J., Effect of microwave irradiation on selective heating behavior and magnetic separation characteristics of Panzhihua ilmenite. Appl. Surf. Sci. 2014, 300, 171–177.
(11) Bijev, A., New Heterocyclic Hydrazones in the Search for Antitubercular Agents: Synthesis and In Vitro Evaluations. Lett. Drug Des. Discov. 2006, 3, 506-512.
(12) Brand-Williams, W.; Cuvelier, M. E.; Berset, C., Use of a free radical method to evaluate antioxidant activity. LWT – Food Science and Technology 1995, 28, 25–30.
(13) Arnao, M. B.; Cano, A.; Hernández-Ruiz, J.; Garcı́a- Cánovas, F.; Acosta, M., Inhibition byl-ascorbic acid and other antioxidants of the 2,2′-azino-bis(3- ethylbenzthiazoline-6-sulfonic acid) oxidation catalyzed by peroxidase: A new approach for determining total antioxidant status of foods. Anal. Biochem. 1996, 236, 255–261.
(14) Moussa, Z.; Al-Mamary, M.; Al-Juhani, S.; Ahmed, S. A., Preparation and biological assessment of some aromatic hydrazones derived from hydrazides of phenolic acids and aromatic aldehydes. Heliyon 2020, 6, e05019-e05019.
(15) Amine Khodja, I.; Boulebd, H., Synthesis, biological evaluation, theoretical investigations, docking study and ADME parameters of some 1,4-bisphenylhydrazone derivatives as potent antioxidant agents and acetylcholinesterase inhibitors. Mol. Divers. 2020, 25, 279–290.
(16) Irfan, A.; Imran, M.; Al-Sehemi, A. G.; Shah, A. T.; Hussien, M.; Mumtaz, M. W., Exploration of electronic properties, radical scavenging activity and QSAR of oxadiazole derivatives by molecular docking and first-principles approaches. Saudi J. Biol. Sci. 2021, 28, 7416–7421.
(17) Lee, C. Y.; Nanah, C. N.; Held, R. A.; Clark, A. R.; Huynh, U. G. T.; Maraskine, M. C.; Uzarski, R. L.; McCracken, J.; Sharma, A., Effect of electron donating groups on polyphenol-based antioxidant dendrimers. Biochimie 2015, 111, 125–134.
(18) Kundu, T.; Pramanik, A., Expeditious and eco-friendly synthesis of new multifunctionalized pyrrole derivatives and evaluation of their antioxidant property. Bioorg. Chem. 2020, 98, 103734.
(19) Miyata, K., Synthesis and properties of 5-pyrrolyl-cytidine and uridine derivatives. Nucleic Acids Symp. Ser. 2004, 48, 15–16.
(20) Nayak, B. N.; Buttar, H. S., Evaluation of the antioxidant properties of tryptophan and its metabolites in in vitro assay. Journal of Complementary and Integrative Medicine 2016, 13.
(21) Balakrishna, A.; Aguiar, A.; Sobral, P. J. M.; Wani, M. Y.; Almeida e Silva, J.; Sobral, A. J. F. N., Paal–Knorr synthesis of pyrroles: from conventional to green synthesis. Catalysis Reviews 2018, 61, 84–110.
(22) De la Hoz, A.; Diaz-Ortiz, A.; Moreno, A., Microwaves in organic synthesis. Thermal and non-thermal microwave effects. ChemInform 2005, 36.
(23) Shi, S.; Hwang, J.-Y., Microwave-assisted wet chemical synthesis: advantages, significance, and steps to industrialization. Journal of Minerals and Materials Characterization and Engineering 2003, 02, 101–110.
(24) Floegel, A.; Kim, D.-O.; Chung, S.-J.; Koo, S. I.; Chun, O. K., Comparison of ABTS/DPPH assays to measure antioxidant capacity in popular antioxidant-rich US foods. J. Food Compost. Anal. 2011, 24, 1043–1048.
(25) Thaipong, K.; Boonprakob, U.; Crosby, K.; Cisneros-Zevallos, L.; Hawkins Byrne, D., Comparison of ABTS, DPPH, FRAP, and ORAC assays for estimating antioxidant activity from guava fruit extracts. J. Food Compost. Anal. 2006, 19, 669–675.
(26) Tzankova, D.; Vladimirova, S.; Aluani, D.; Yordanov, Y.; Peikova, L.; Georgieva, M., Synthesis, in vitro safety and antioxidant activity of new pyrrole hydrazones. Acta Pharmaceutica 2020, 70, 303–324.
(27) Tarafdar, A.; Pula, G., The Role of NADPH oxidases and oxidative stress in neurodegenerative disorders. Int. J. Mol. Sci. 2018, 19, 3824.
(28) Hosen, S.; Dash, R.; Khatun, M.; Akter, R.; Bhuiyan, M.; Karim, M.; Mouri, N.; Ahamed, F.; Islam, K.; Afrin, S., In silico ADME/T and 3D QSAR analysis of KDR inhibitors. Journal of Applied Pharmaceutical Science 2017, 120–128.
(29) Costa, J. d. S.; Ramos, R. d. S.; Costa, K. d. S. L.; Brasil, D. d. S. B.; Silva, C. H. T. d. P. d.; Ferreira, E. F. B.; Borges, R. D. S.; Campos, J. M.; Macêdo, W. J. d. C.; Santos, C. B. R. D., An in silico study of the antioxidant ability for two caffeine analogs using molecular docking and quantum chemical methods. Molecules (Basel, Switzerland) 2018, 23, 2801.
(30) Vadabingi, N.; Avula, V. K. R.; Zyryanov, G. V.; Vallela, S.; Anireddy, J. S.; Pasupuleti, V. R.; Mallepogu, V.; Chamarthi, N. R.; Ponne, V. C., Multiple molecular targets mediated antioxidant activity, molecular docking, ADMET, QSAR and bioactivity studies of halo substituted urea derivatives of α-Methyl- -DOPA. Bioorg. Chem. 2020, 97, 103708.
- 2022-12-30 (2)
- 2022-12-11 (1)
How to Cite
Copyright (c) 2022 Emilio Mateev, Maya Georgieva, Alexander Zlatkov
This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License.
The authors agree to the following licence: Attribution-NonCommercial 4.0 International (CC BY-NC 4.0)
- Share — copy and redistribute the material in any medium or format
- Adapt — remix, transform, and build upon the material
- for any purpose, even commercially.
Under the following terms:
Attribution — You must give appropriate credit, provide a link to the license, and indicate if changes were made. You may do so in any reasonable manner, but not in any way that suggests the licensor endorses you or your use.
- NonCommercial — You may not use the material for commercial purposes.