European Journal of Chemistry

Synthesis and structural depiction of the isomeric benzimidazole pair and its in-silico anti-SARS-CoV-2 activities


Main Article Content

Ananya Debnath
Shreya Mahato
Abhranil De
Himanshu Verma
Om Silakari
Bhaskar Biswas


The present work presents a straightforward synthesis, spectroscopic and structural depiction, and in silico anti-SARS-CoV-2 activity of an isomeric monosubstituted benzimidazole pair, 2-(1H-benzo[d]imidazol-2-yl)-6-methoxyphenol (L1O) and 4-(1H-benzo[d]imidazol-2-yl)-2-methoxyphenol (L1P). The derivatives were synthesized by a coupling of aromatic aldehydes and o-phenylenediamine in ethanol under reflux. Different spectroscopic methods and X-ray structural analysis were employed to characterize the compounds. The crystal structure of L1O reveals that the o-vanillin substituted benzimidazole compound crystallizes in a monoclinic system and adopts a planar geometry. In silico anti-SARS-CoV-2 proficiencies of synthetic derivatives were evaluated against the main protease (Mpro) and nonstructural proteins (nsp2 and nsp7) of SARS-CoV-2. Molecular docking reveals the binding scores for the L1O-Mpro, L1O-nsp2 and L1O-nsp7 complexes as -11.31, -6.06 and -8.13 kcal/mol, respectively, while the binding scores for the L1P-Mpro, L1P-nsp2 and L1P-nsp7 complexes as -10.62, -5.09 and -6.91 kcal/mol, respectively, attributing the excellent conformational stability for both the isomeric benzimidazole derivatives.

icon graph This Abstract was viewed 273 times | icon graph Article PDF downloaded 81 times icon graph Article CIF FILE downloaded 0 times

How to Cite
Debnath, A.; Mahato, S.; De, A.; Verma, H.; Silakari, O.; Biswas, B. Synthesis and Structural Depiction of the Isomeric Benzimidazole Pair and Its in-Silico Anti-SARS-CoV-2 Activities. Eur. J. Chem. 2024, 15, 39-49.

Article Details

Crossref - Scopus - Google - European PMC

[1]. Behera, B. C.; Mishra, R. R.; Thatoi, H. Recent biotechnological tools for diagnosis of corona virus disease: A review. Biotechnol. Prog. 2021, 37, e3078.

[2]. Kahn, J. S.; McIntosh, K. History and recent advances in Coronavirus discovery. Pediatr. Infect. Dis. J. 2005, 24, S223-S227.

[3]. Monto, A. S. Medical reviews. Coronaviruses. Yale J. Biol. Med. 1974, 47, 234-251.

[4]. Coelho, C.; Gallo, G.; Campos, C. B.; Hardy, L.; Würtele, M. Biochemical screening for SARS-CoV-2 main protease inhibitors. PLoS One 2020, 15, e0240079.

[5]. Yuan, Y.; Zhao, Y.-J.; Zhang, Q.-E.; Zhang, L.; Cheung, T.; Jackson, T.; Jiang, G.-Q.; Xiang, Y.-T. COVID-19-related stigma and its sociodemographic correlates: a comparative study. Global. Health 2021, 17, 54.

[6]. Pedersen, S. F.; Ho, Y.-C. SARS-CoV-2: a storm is raging. J. Clin. Invest. 2020, 130, 2202-2205.

[7]. Huang, C.; Wang, Y.; Li, X.; Ren, L.; Zhao, J.; Hu, Y.; Zhang, L.; Fan, G.; Xu, J.; Gu, X.; Cheng, Z.; Yu, T.; Xia, J.; Wei, Y.; Wu, W.; Xie, X.; Yin, W.; Li, H.; Liu, M.; Xiao, Y.; Gao, H.; Guo, L.; Xie, J.; Wang, G.; Jiang, R.; Gao, Z.; Jin, Q.; Wang, J.; Cao, B. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet 2020, 395, 497-506.

[8]. Li, R.; Pei, S.; Chen, B.; Song, Y.; Zhang, T.; Yang, W.; Shaman, J. Substantial undocumented infection facilitates the rapid dissemination of novel coronavirus (SARS-CoV-2). Science 2020, 368, 489-493.

[9]. Peiris, J. S. M.; Yuen, K. Y.; Osterhaus, A. D. M. E.; Stöhr, K. The severe acute respiratory syndrome. N. Engl. J. Med. 2003, 349, 2431-2441.

[10]. Wang, F.; Hou, H.; Luo, Y.; Tang, G.; Wu, S.; Huang, M.; Liu, W.; Zhu, Y.; Lin, Q.; Mao, L.; Fang, M.; Zhang, H.; Sun, Z. The laboratory tests and host immunity of COVID-19 patients with different severity of illness. JCI Insight 2020, 5, e137799.

[11]. Yan, R.; Zhang, Y.; Li, Y.; Xia, L.; Guo, Y.; Zhou, Q. Structural basis for the recognition of SARS-CoV-2 by full-length human ACE2. Science 2020, 367, 1444-1448.

[12]. Hadjadj, J.; Yatim, N.; Barnabei, L.; Corneau, A.; Boussier, J.; Smith, N.; Péré, H.; Charbit, B.; Bondet, V.; Chenevier-Gobeaux, C.; Breillat, P.; Carlier, N.; Gauzit, R.; Morbieu, C.; Pène, F.; Marin, N.; Roche, N.; Szwebel, T.-A.; Merkling, S. H.; Treluyer, J.-M.; Veyer, D.; Mouthon, L.; Blanc, C.; Tharaux, P.-L.; Rozenberg, F.; Fischer, A.; Duffy, D.; Rieux-Laucat, F.; Kernéis, S.; Terrier, B. Impaired type I interferon activity and inflammatory responses in severe COVID-19 patients. Science 2020, 369, 718-724.

[13]. Olagnier, D.; Farahani, E.; Thyrsted, J.; Blay-Cadanet, J.; Herengt, A.; Idorn, M.; Hait, A.; Hernaez, B.; Knudsen, A.; Iversen, M. B.; Schilling, M.; Jørgensen, S. E.; Thomsen, M.; Reinert, L. S.; Lappe, M.; Hoang, H.-D.; Gilchrist, V. H.; Hansen, A. L.; Ottosen, R.; Nielsen, C. G.; Møller, C.; van der Horst, D.; Peri, S.; Balachandran, S.; Huang, J.; Jakobsen, M.; Svenningsen, E. B.; Poulsen, T. B.; Bartsch, L.; Thielke, A. L.; Luo, Y.; Alain, T.; Rehwinkel, J.; Alcamí, A.; Hiscott, J.; Mogensen, T. H.; Paludan, S. R.; Holm, C. K. SARS-CoV2-mediated suppression of NRF2-signaling reveals potent antiviral and anti-inflammatory activity of 4-octyl-itaconate and dimethyl fumarate. Nat. Commun. 2020, 11, 4938.

[14]. Saichi, M.; Ladjemi, M. Z.; Korniotis, S.; Rousseau, C.; Ait Hamou, Z.; Massenet-Regad, L.; Amblard, E.; Noel, F.; Marie, Y.; Bouteiller, D.; Medvedovic, J.; Pène, F.; Soumelis, V. Single-cell RNA sequencing of blood antigen-presenting cells in severe COVID-19 reveals multi-process defects in antiviral immunity. Nat. Cell Biol. 2021, 23, 538-551.

[15]. Mahato, R. K.; Mahanty, A. K.; Kotakonda, M.; Prasad, S.; Bhattacharyya, S.; Biswas, B. A hydrated 2,3-diaminophenazinium chloride as a promising building block against SARS-CoV-2. Sci. Rep. 2021, 11, 23122.

[16]. Kobayashi, S.; Mori, Y.; Fossey, J. S.; Salter, M. M. Catalytic enantioselective formation of C−C bonds by addition to imines and hydrazones: A ten-year update. Chem. Rev. 2011, 111, 2626-2704.

[17]. Layer, R. W. The chemistry of imines. Chem. Rev. 1963, 63, 489-510.

[18]. Gnanaprakasam, B.; Zhang, J.; Milstein, D. Direct synthesis of imines from alcohols and amines with liberation of H2. Angew. Chem. Int. Ed Engl. 2010, 49, 1468-1471.

[19]. Cano, R.; Ramón, D. J.; Yus, M. Transition-metal-free O-, S-, and N-arylation of alcohols, thiols, amides, amines, and related heterocycles. J. Org. Chem. 2011, 76, 654-660.

[20]. Chen, B.; Wang, L.; Gao, S. Recent advances in aerobic oxidation of alcohols and amines to imines. ACS Catal. 2015, 5, 5851-5876.

[21]. Wang, J.; Lu, S.; Cao, X.; Gu, H. Common metal of copper(0) as an efficient catalyst for preparation of nitriles and imines by controlling additives. Chem. Commun. (Camb.) 2014, 50, 5637-3640.

[22]. Sonobe, T.; Oisaki, K.; Kanai, M. Catalytic aerobic production of imines en route to mild, green, and concise derivatizations of amines. Chem. Sci. 2012, 3, 3249-3255.

[23]. Mudi, P. K.; Mahato, R. K.; Joshi, M.; Shit, M.; Choudhury, A. R.; Das, H. S.; Biswas, B. Copper(II) complexes with a benzimidazole functionalized Schiff base: Synthesis, crystal structures, and role of ancillary ions in phenoxazinone synthase activity. Appl. Organomet. Chem. 2021, 35, e6211.

[24]. Mudi, P. K.; Mahanty, A. K.; Kotakonda, M.; Prasad, S.; Bhattacharyya, S.; Biswas, B. A benzimidazole scaffold as a promising inhibitor against SARS-CoV-2. J. Biomol. Struct. Dyn. 2023, 41, 1798-1810.

[25]. Mudi, P. K.; Mahato, R. K.; Verma, H.; Panda, S. J.; Purohit, C. S.; Silakari, O.; Biswas, B. In silico anti-SARS-CoV-2 activities of five-membered heterocycle-substituted benzimidazoles. J. Mol. Struct. 2022, 1261, 132869.

[26]. Bruker (2009). SMART (Version 5.0) and SAINT (Version 6.02). Bruker AXS Inc., Madison, Wisconsin, USA.

[27]. Sheldrick, G. M. (1996). SADABS. University of Göttingen, Germany.

[28]. Sheldrick, G. M. (1996). SHELXS97 and SHELXL97. University of Göttingen, Germany.

[29]. Dolomanov, O. V.; Bourhis, L. J.; Gildea, R. J.; Howard, J. A. K.; Puschmann, H. OLEX2: a complete structure solution, refinement and analysis program. J. Appl. Crystallogr. 2009, 42, 339-341.

[30]. Zhang, D.; Hamdoun, S.; Chen, R.; Yang, L.; Ip, C. K.; Qu, Y.; Li, R.; Jiang, H.; Yang, Z.; Chung, S. K.; Liu, L.; Wong, V. K. W. Identification of natural compounds as SARS-CoV-2 entry inhibitors by molecular docking-based virtual screening with bio-layer interferometry. Pharmacol. Res. 2021, 172, 105820.

[31]. Yi, Y.; Li, J.; Lai, X.; Zhang, M.; Kuang, Y.; Bao, Y.-O.; Yu, R.; Hong, W.; Muturi, E.; Xue, H.; Wei, H.; Li, T.; Zhuang, H.; Qiao, X.; Xiang, K.; Yang, H.; Ye, M. Natural triterpenoids from licorice potently inhibit SARS-CoV-2 infection. J. Adv. Res. 2022, 36, 201-210.

[32]. Ma, J.; Chen, Y.; Wu, W.; Chen, Z. Structure and function of N-terminal zinc finger domain of SARS-CoV-2 NSP2. Virol. Sin. 2021, 36, 1104-1112.

[33]. Thuy, B. T. P.; My, T. T. A.; Hai, N. T. T.; Hieu, L. T.; Hoa, T. T.; Thi Phuong Loan, H.; Triet, N. T.; Van Anh, T. T.; Quy, P. T.; Van Tat, P.; Van Hue, N.; Quang, D. T.; Trung, N. T.; Tung, V. T.; Huynh, L. K.; Nhung, N. T. A. Investigation into SARS-CoV-2 resistance of compounds in garlic essential oil. ACS Omega 2020, 5, 8312-8320.

[34]. Bauer, M. R.; Mackey, M. D. Electrostatic complementarity as a fast and effective tool to optimize binding and selectivity of protein-ligand complexes. J. Med. Chem. 2019, 62, 3036-3050.

[35]. Du, X.; Li, Y.; Xia, Y.-L.; Ai, S.-M.; Liang, J.; Sang, P.; Ji, X.-L.; Liu, S.-Q. Insights into protein-ligand interactions: Mechanisms, models, and methods. Int. J. Mol. Sci. 2016, 17, 144.

[36]. He, X.; Man, V. H.; Yang, W.; Lee, T.-S.; Wang, J. A fast and high-quality charge model for the next generation general AMBER force field. J. Chem. Phys. 2020, 153, 114502.

[37]. Jakalian, A.; Bush, B. L.; Jack, D. B.; Bayly, C. I. Fast, efficient generation of high-quality atomic charges. AM1-BCC model: I. Method. J. Comput. Chem. 2000, 21, 132-146.<132::AID-JCC5>3.0.CO;2-P

[38]. Kelly, B. D.; Smith, W. R. A simple method for including polarization effects in solvation free energy calculations when using fixed-charge force fields: Alchemically polarized charges. ACS Omega 2020, 5, 17170-17181.

[39]. Eastman, P.; Swails, J.; Chodera, J. D.; McGibbon, R. T.; Zhao, Y.; Beauchamp, K. A.; Wang, L.-P.; Simmonett, A. C.; Harrigan, M. P.; Stern, C. D.; Wiewiora, R. P.; Brooks, B. R.; Pande, V. S. OpenMM 7: Rapid development of high performance algorithms for molecular dynamics. PLoS Comput. Biol. 2017, 13, e1005659.

[40]. Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.; Robb, M. A.; Cheeseman, J. R.; Montgomery, J. A.; Vreven, T.; Kudin, K. N.; Burant, J. C.; Millam, J. M.; Iyengar, S. S.; Tomasi, J.; Barone, V.; Mennucci, B.; Cossi, M.; Scalmani, G.; Rega, N.; Petersson, G. A.; Nakatsuji, H.; Hada, M.; Ehara, M.; Toyota, K.; Fukuda, R.; Hasegawa, J.; Ishida, M.; Nakajima, T.; Honda, Y.; Kitao, O.; Nakai, H.; Klene, M.; Li, X.; Knox, J. E.; Hratchian, H. P.; Cross, J. B.; Adamo, C.; Jaramillo, J.; Gomperts, R.; Stratmann, R. E.; Yazyev, O.; Austin, A. J.; Cammi, R.; Pomelli, C.; Ochterski, J. W.; Ayala, P. Y.; Morokuma, K.; Voth, G. A.; Salvador, P.; Dannenberg, J. J.; Zakrzewski, V. G.; Dapprich, S.; Daniels, A. D.; Strain, M. C.; Farkas, O.; Malick, D. K.; Rabuck, A. D.; Raghavachari, K; Foresman, J. B.; Ortiz, J. V.; Cui, Q.; Baboul, A. G.; Clifford, S.; Cioslowski, J.; Stefanov, B. B.; Liu, G.; Liashenko, A.; Piskorz, P.; Komaromi, I.; Martin, R. L.; Fox, D. J.; Keith, T.; Al-Laham, M. A.; Peng, C. Y.; Nanayakkara, A.; Challacombe, M.; Gill, P. M. W.; Johnson, B.; Chen, W.; Wong, M. W.; Gonzalez, C.; Pople, J. A. Gaussian 09 (Revision A.02), Gaussian, Inc., Wallingford CT, 2009.

[41]. Zhao, Y.; Truhlar, D. G. A new local density functional for main-group thermochemistry, transition metal bonding, thermochemical kinetics, and noncovalent interactions. J. Chem. Phys. 2006, 125, 194101.

[42]. De, A.; Sahu, A.; Paul, S.; Joshi, M.; Choudhury, A. R.; Biswas, B. Structural and luminescent properties of a new 1D Cadmium(II) coordination polymer: A combined effort with experiment & theory. J. Mol. Struct. 2018, 1167, 187-193.

[43]. Roy, S.; Paul, P.; Karar, M.; Joshi, M.; Paul, S.; Choudhury, A. R.; Biswas, B. Cascade detection of fluoride and bisulphate ions by newly developed hydrazine functionalised Schiff bases. J. Mol. Liq. 2021, 326, 115293.

[44]. Mahato, S.; Meheta, N.; Kotakonda, M.; Joshi, M.; Shit, M.; Choudhury, A. R.; Biswas, B. Synthesis, structure, polyphenol oxidase mimicking and bactericidal activity of a zinc-schiff base complex. Polyhedron 2021, 194, 114933.

[45]. Rajani, K. M.; Prafullya, K. M.; Mayukh, D.; Bhaskar, B. A direct metal‐free synthetic approach for the efficient production of privileged benzimidazoles in water medium under aerobic condition. Asian J. Org. Chem. 2021, 10, 2954-2963.

[46]. Culletta, G.; Gulotta, M. R.; Perricone, U.; Zappalà, M.; Almerico, A. M.; Tutone, M. Exploring the SARS-CoV-2 proteome in the search of potential inhibitors via structure-based pharmacophore modeling/docking approach. Computation (Basel) 2020, 8, 77.

[47]. Badavath, V. N.; Kumar, A.; Samanta, P. K.; Maji, S.; Das, A.; Blum, G.; Jha, A.; Sen, A. Determination of potential inhibitors based on isatin derivatives against SARS-CoV-2 main protease (mpro): a molecular docking, molecular dynamics and structure-activity relationship studies. J. Biomol. Struct. Dyn. 2022, 40, 3110-3128.

[48]. Purwati; Miatmoko, A.; Nasronudin; Hendrianto, E.; Karsari, D.; Dinaryanti, A.; Ertanti, N.; Ihsan, I. S.; Purnama, D. S.; Asmarawati, T. P.; Marfiani, E.; Yulistiani; Rosyid, A. N.; Wulaningrum, P. A.; Setiawan, H. W.; Siswanto, I.; Tri Puspaningsih, N. N. An in vitro study of dual drug combinations of anti-viral agents, antibiotics, and/or hydroxychloroquine against the SARS-CoV-2 virus isolated from hospitalized patients in Surabaya, Indonesia. PLoS One 2021, 16, e0252302.

Supporting Agencies

University of North Bengal, Darjeeling, 734013, India

Dimensions - Altmetric - scite_ - PlumX

Downloads and views


Download data is not yet available.


Metrics Loading ...
License Terms
Creative Commons License

This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License.

License Terms


Copyright © 2024 by Authors. This work is published and licensed by Atlanta Publishing House LLC, Atlanta, GA, USA. The full terms of this license are available at and incorporate the Creative Commons Attribution-Non Commercial (CC BY NC) (International, v4.0) License ( By accessing the work, you hereby accept the Terms. This is an open access article distributed under the terms and conditions of the CC BY NC License, which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited without any further permission from Atlanta Publishing House LLC (European Journal of Chemistry). No use, distribution, or reproduction is permitted which does not comply with these terms. Permissions for commercial use of this work beyond the scope of the License ( are administered by Atlanta Publishing House LLC (European Journal of Chemistry).