Prediction of Antimicrobial Activities of Benzimidazole Derivatives Containing an Amide Bond Through Molecular Docking Analysis

Yıl 2025, Cilt: 21 Sayı: 3, 131 - 136, 26.09.2025

Turgay Tunç

https://doi.org/10.18466/cbayarfbe.1599076

Öz

Gram-positive and Gram-negative bacterial infections are one of the most important causes of illness and death worldwide. Although antibiotics are the primary treatment for these infections, the increase in the number of drug-resistant bacteria has posed a serious threat to public health in a global scale. Benzimidazole derivatives possess a distinctive chemical structure that exhibits a wide range of biological and therapeutic properties, including notable antimicrobial activity. In this study, we performed molecular docking analyses of four benzimidazole derivatives targeting dihydrofolate reductase, DNA gyrase, and 7,8-dihydro-6-hydroxymethylpterin-pyrophosphokinase enzymes from C. albicans, Escherichia coli, and Staphylococcus aureus. The relative binding free energy of the protein-ligand complexes were also calculated by the molecular mechanics-generalized born surface area (MM-GBSA) method. The relative binding free energy of the protein–ligand complexes were also calculated by the molecular mechanics-generalized born surface area (MM-GBSA) method. All tested compounds showed good potential as dihydrofolate reductase inhibitors and antifungal activity against Candida albicans. Notably, the compound 9A demonstrates the highest antimicrobial activity. Furthermore, all compounds are anticipated to exhibit greater activity against DNA gyrase in both E. coli and S. aureus compared to their respective cognate ligands. Compounds 9A/9B caused higher antimicrobial activity than compounds 10A/10B.

Anahtar Kelimeler

Benzimidazole derivatives , amide bonds , molecular docking , antibacterial activity

Destekleyen Kurum

Kırşehir Ahi Evran Üniversitesi

Proje Numarası

MMF.A4.22.017

Kaynakça

• [1]. Preston, PN. 1974. Synthesis, reactions, and spectroscopic properties of benzimidazoles. Chem. Rev; 74: 279–314.
• [2]. Sundberg, RJ, Martin, RB. 1974. Interactions of histidine and other imidazole derivatives with transition metal ions in chemical and biological systems. Chem. Rev; 74: 471–517.
• [3]. Nájera, C, Yus, M. 2015. Chiral benzimidazoles as hydrogen bonding organocatalysts. Tetrahedron Lett; 56: 2623–2633.
• [4]. Khose, VN, John ME, Pandey AD, Karnik, AV. 2017. Chiral benziimidazoles and their applications in stereodiscrimination processes. Tetrahedron Asymmetry; 28: 1233–1289.
• [5]. Asensio, JA, Sanchez, EM, Gómez-Romero, P. 2010. Proton-conducting membranes based on benzimidazolepolymers for high-temperature PEMfuelcells. A chemical quest. Chem. Soc. Rev; 39: 3210–3239.
• [6]. Al-Muhaimeed, HS. 1997. A parallel-group comparison of Astemizole and Loratadine for the treatment of perennial allergic rhinitis. J. Int. Med. Res; 25: 175–181.
• [7]. Scott, LJ, Dunn, CJ, Mallarkey G, Sharpe, M. 2002. Esomeprazole: a review of its use in the management of acid-related disorders. Drugs; 62: 1503–1538.
• [8]. Gaba, M, Singh, S, Mohan, C. 2014. Benzimidazole: an emerging scaffold for analgesic and anti-inflammatory agents. Eur. J. Med. Chem; 76: 494–505.
• [9]. Horton, DA, Bourne, GT, Sinythe, ML. 2003. The combinatorial synthesis of bicyclic privileged structures or privileged substructures. Chem. Rev; 103: 893–930.
• [10]. Alamgir, M, Black, DSC, Kumar, N. 2007. Synthesis, reactivity and biological activity of Benzimidazoles. Heterocycl. Chem; 9: 87–118.
• [11]. Goker, H, Ozden, S, Yildiz, S, Boykin, DW. 2005. Synthesis and potent antibacterial activity against MRSA of some novel 1,2-disubstituted-1H-benzimidazole-N-alkylated-5-carboxamidines. Eur. J. Med. Chem; 40: 1062–1069.
• [12]. Abraham, R, Periakaruppan, P, Mahendran, K, Ramanathan, M. 2018. A novel series of N-acyl substituted indole-linked benzimidazoles and naphthoimidazoles as potential antiinflammatory, anti-biofilm and anti-microbial agents. Microb. Pathog; 114: 409–413.
• [13]. Zhu, Z, Lippa, B, Drach, DJ, Townsend, LB. 2000. Design, synthesis, and biological evaluation of tricyclic nucleosides (dimensional probes) as analogues of certain antiviral polyhalogenated benzimidazole ribonucleosides. J. Med. Chem; 43: 2430–2437.
• [14]. Mann, J, Baron, A, Opoku-Boahen, Y, Johansson, E, Parkinson, G, Kelland, LR, Neidle, S. 2001. A new class of symmetric bisbenzimidazole-based DNA minör groove-binding agents showing antitumor activity. J. Med. Chem; 44: 138–144.
• [15]. Sambanthamoorthy, K, Gokhale, AA, Lao, W, Parashar, V, Neiditch, MB, Semmelhack, MF, Lee, I, Waters, CM. 2011. Identification of a novel benzimidazole that inhibits bacterial biofilm formation in a broad-spectrum manner. Antimicrob. Agents Chemother; 55: 4369–4378.
• [16]. Singu, PS, Kanugal, S, Dhawale, SA, Kumar, CG, Ravindra, M, Kumbhare, RM. 2020. Synthesis and pharmacological evaluation of some amide functionalized 1H-Benzo[d]imidazole-2-thiol derivatives as anti-microbial agents. Chemistry Select; 5: 117–123.
• [17]. Reddy, NB, Grigory, V, Zyryanov, GV, Reddy GM, Balakrishna, A, Padmaja A, Padmavathi, V, Reddy, CS, Garcia, JR, Sravya, G. 2019. Design and synthesis of some new benzimidazole containing pyrazoles and pyrazolyl thiazoles as potential anti-microbial agents. J. Heterocycl. Chem; 56: 589–596.
• [18]. Shi, Y, Jiang, K, Zheng, R, Fu, J, Yan, L, Gu, Q, Zhang, Y, Lin, F. 2019. Design, microwave-assisted synthesis and in vitro antibacterial and antifungal activity of 2,5-disubstituted benzimidazole. Chem. Biodivers; 16: e1800510.
• [19]. Obaiah, N, Bodke ND, Telkar, S. 2020. Synthesis of 3-[(1H-Benzimidazol-2-ylsulfanyl)(aryl)methyl]-4-hydroxycoumarin derivatives as potent bioactive molecules, Chemistry Select; 5: 178–184.
• [20]. Feng, D, Zhang, A, Yang, Y, Yang, P. 2020. Coumarin‐containing hybrids and their antibacterial activities. Archiv Der Pharmazie; 353(6): 1900380.
• [21]. Alım, Z, Tunç, T, Demirel, N, Günel, A, Karacan, N. 2022. Synthesis of benzimidazole derivatives containing amide bond and biological evaluation as acetylcholinesterase, carbonic anhydrase I and II inhibitors. Journal of Molecular Structure; 1268: 133647.
• [22]. Basavaraju, M, Gunashree, BS. 2022. Escherichia coli: an overview of main characteristics. Escherichia coli-Old and New Insights.
• [23]. Peacock, S, 2006. Staphylococcus aureus. Principles and practice of clinical bacteriology, 2, 73-98.
• [24]. Reece, RJ, Maxwell, A. 1991. DNA gyrase: structure and function. Critical reviews in biochemistry and molecular biology, 26 (3-4), 335-375.
• [25]. Nabuurs, SB, Wagener, M, De Vlieg, J. 2007. A Flexible approach to induced fit docking. Journal of Medicinal Chemistry; 50(26): 6507–6518.
• [26]. Genheden, S, Ryde, U. 2015. The MM/PBSA and MM/GBSA methods to estimate ligand-binding affinities. Expert Opinion on Drug Discovery; 10(5): 449–461.
• [27]. Shahabadi, N, Mahdavi, M. 2023. Green synthesized silver nanoparticles obtained from Stachys schtschegleevii extract: Ct-DNA interaction and in silico and in vitro investigation of antimicrobial activity. Journal of Biomolecular Structure and Dynamics; 41(6): 2175–2188.
• [28]. Costa-de-Oliveira, S, Rodrigues, AG. 2020. Candida albicans antifungal resistance and tolerance in bloodstream infections: the triad yeast-host-antifungal. Microorganisms; 8(2): 154-173.
• [29]. Whitlow, M, Howard, AJ, Stewart, D, Hardman, KD, Kuyper, LF, Baccanari, DP, Fling, ME, Tansik, RL. 1997. X-ray crystallographic studies of candida albicans dihydrofolate reductase. Journal of Biological Chemistry; 272(48): 30289–30298.
• [30]. Krucinska, J, Lombardo, MN, Erlandsen, H, Estrada, A, Si, D, Viswanathan, K, Wright, DL. 2022. Structure-guided functional studies of plasmidencoded dihydrofolate reductases reveal a common mechanism of trimethoprim resistance in Gram-negative pathogens. Communications Biology; 5: 459.
• [31]. Dennis, ML, Lee, MD, Harjani, JR, Ahmed, M, DeBono, AJ, Pitcher, NP, Wang, Z, Chhabra, S, Barlow, N, Rahmani, R, Cleary, B, Dolezal, O, Hattarki, M, Aurelio, L, Shonberg, J, Graham, B, Peat, TS, Baell, JB, Swarbrick, JD. 2018. 8‐Mercaptoguanine derivatives as inhibitors of dihydropteroate synthase. Chemistry – A European Journal; 24(8): 1922–1930.
• [32]. Lafitte, D, Lamour, V, Tsvetkov, PO, Makarov, AA, Klich, M, Deprez, P, Moras, D, Briand, C, Gilli, R. 2002. Dna gyrase interaction with coumarin-based inhibitors: the role of the hydroxybenzoate isopentenyl moiety and the 5‘-methyl group of the noviose. Biochemistry; 41(23): 7217–7223.
• [33]. Dennis, ML, Chhabra, S, Wang, ZC, Debono, A, Dolezal, O, Newman, J, Pitcher, NP, Rahmani, R, Cleary, B, Barlow, N, Hattarki, M, Graham, B, Peat, TS, Baell, JB, Swarbrick, JD. 2014. Structure-based design and development of functionalized mercaptoguanine derivatives as inhibitors of the folate biosynthesis pathway enzyme 6-hydroxymethyl-7,8-dihydropterin pyrophosphokinase from staphylococcus aureus. Journal of Medicinal Chemistry; 57(22): 9612–9626.
• [34]. Eakin, AE, Green, O, Hales, N, Walkup, GK, Bist, S, Singh, A, Mullen, G, Bryant, J, Embrey, K, Gao, N, Breeze, A, Timms, D, Andrews, B, Uria-Nickelsen, M, Demeritt, J, Loch, JT, Hull, K, Blodgett, A, Illingworth, RN, Sherer, B. 2012. Pyrrolamide dna gyrase inhibitors: fragment-based nuclear magnetic resonance screening to identify antibacterial agents. Antimicrobial Agents and Chemotherapy; 56(3): 1240–1246.
• [35]. Heaslet, H, Harris, M, Fahnoe, K, Sarver, R, Putz, H, Chang, J, Subramanyam, C, Barreiro, G, Miller, JR. 2009. Structural comparison of chromosomal and exogenous dihydrofolate reductase from Staphylococcus aureus in complex with the potent inhibitor trimethoprim. Proteins: Structure, Function, and Bioinformatics; 76(3): 706–717.