Boronic Acid-substituted Benzimidazole Derivatives and Their Supramolecular Hybrid System Formed with Glutathione-functionalized Graphene Quantum Dots:Synthesis, Antimicrobial Activities and Molecular Docking Calculations

doi:10.1007/s40242-025-5040-x

Abstract

Abstract: This study presents novel functional molecules containing benzimidazole units, which are known to have biological properties, as well as phenylboronic acid units attached to the benzimidazole core. These structures were prepared for the first time and conjugated to glutathione-functionalized graphene quantum dots (G-GQDs) to form supramolecular hybrids through π-π stacking. The newly developed compounds showed varying degrees of antimicrobial activity against a panel of human pathogens:Escherichia coli, Staphylococcus aureus, Candida albicans, and Aspergillus brasiliensis. The G-GQD-functionalized derivatives were more efficient in inhibiting microbial growth, particularly against antibiotic-resistant Staphylococcus. This study introduces a new direction in antimicrobial research for G-GQD-functionalized benzimidazole derivatives as effective alternatives to conventional antibiotics. Molecular docking calculations revealed a strong correlation between antimicrobial activity and the high binding affinity of the phenylboronic acid-substituted benzimidazole derivatives to specific protein targets (5M18, 2QZX, 4LE8, 2H6T, and 2Q85). The analysis emphasized the impact of substituent positioning on enzyme inhibition, illustrating how structural modifications influenced inhibitory activity. Integrating experimental and computational findings, our study highlights key structure-activity relationships in benzimidazole derivatives and identifies promising candidates for further studies on enzyme inhibition and antimicrobial research.

Key words: Benzimidazole, Phenylboronic acid, Graphene quantum dot, Antibacterial performance, Molecular docking

Pinar SEN, Meriam BOURI, Kadir SINAN ARSLAN, Vildan Enisoglu ATALAY, Fikrettin ŞAHIN. Boronic Acid-substituted Benzimidazole Derivatives and Their Supramolecular Hybrid System Formed with Glutathione-functionalized Graphene Quantum Dots:Synthesis, Antimicrobial Activities and Molecular Docking Calculations[J]. Chemical Research in Chinese Universities, 2025, 41(4): 929-940.

References

[1] Rangappa S. K., Hiremathad A., Budagumpi S., Nagaraja B. M., Chem. Biol. Drug. Des., 2015, 86, 19.
[2] El Rashedy A. A., Aboul-Enein H. Y., Mini-Reviews in Medicinal Chemistry, 2013, 13, 399.
[3] Kavitha C. S. A., Kallappa M. H., Harisha R. S., European Journal of Medicinal Chemistry, 2010, 45,2048.
[4] Vladimir V. Z., Anatolii S. M., Liudmila N. D., Liubov A. K., Gennadii S.B., Bioorg. Med. Chem., 2016, 24, 5796.
[5] Michele T., Matteo S., Bruno T., Federica N., Vito B., Fabio S., Giuseppe P., Sabrina P., Gabriele G., Sylvain B., Cristina I., Giuseppina S., Roberta L., Paolo L. C., Bioorganic & Medicinal Chemistry, 2010, 18, 2937.
[6] Anelia T. M., Denitsa Y., Neda A., Kamelya A., Jelena Z., Aleksandra D., Dejan M., Andrija S., Bioorg. Med. Chem., 2015, 23, 6317.
[7] Fang B., Zhou C., Rao X., European Journal of Medicinal Chemistry, 2010, 45, 4388.
[8] Woods W. G., Environ. Health Perspect., 1994, 102, 5.
[9] Kırbaş O. K., Bozkurt B. T., Taşlı P. N., Hayal T. B., Özkan İ., Bülbül B., Beyaz S., Şahin F., Biological Trace Element Research, 2021, 199, 3262.
[10] Hacioglu C., Ka F., Senturk H., Kanbak G., Medical Science and Discovery, 2018, 5, 260.
[11] Melvin N. R., Elizabeth E., Alberto A., Antonio A., Marvin A. S., Current Molecular Pharmacology, 2020, 13, 57.
[12] Pasa S., Aydın S., Kalaycı S., Boğa M., Atlan M., Bingul M., Şahin F., Temel H., Journal of Pharmaceutical Analysis, 2016, 6, 39.
[13] Riehemann K., Schneider S. W., Luger T. A., Godin B., Ferrari M., Fuchs H., Angew. Chem. Int. Ed., 2009, 48, 872.
[14] Chen W., Weimin G. H., Li D., Chen S., Dai Z., Nanotechnol. Rev., 2018, 7, 157.
[15] Tian P., Tang L., Teng K. S., Lau S. P., Materials Today Chemistry, 2018, 10, 221.
[16] Zhang X. F., Shao X., J. Photochem. Photobio. A: Chem., 2014, 278, 69.
[17] Liu J., Zhang X., Cong Z., Chen Z., Yang H., Chen G., Nanoscale, 2013, 5, 1810.
[18] Majeed S. A., Nwaji N., Mack J., Nyokong T., Makhseed S., Journal of Luminescence, 2019, 213, 88.
[19] Kalaycı S., Demirci S., Sahin F., Current Psychopharmacology, 2014, 3, 195.
[20] Bouri M., Turkish Journal of Agriculture and Forestry, 2022, 46, 280.
[21] Rhouma A., Bouri M., Boubaker A., Nesme X., J. Plant. Pathol., 2008, 90, 517.
[22] Stewart J. J., Journal of Molecular Modeling, 2009, 15, 765.
[23] Spartan 14v1.1.4, Wavefunction, Inc., Irvine, CA, 2014 (https://www.wavefun.com/).
[24] Dennington R., Keith T., Millam J., GaussView, Version 5, Semichem Inc., Shawnee Mission, Kansas, 2009.
[25] Frisch M. J., Trucks G. W., Schlegel H. B., Scuseria G. E., Robb M. A., Cheeseman J. R., Scalmani G., Barone V., Mennucci B., Petersson G.A., Nakatsuji H., Caricato M., Li X., Hratchian H. P., Izmaylov A. F., Bloino J., Zheng G., Sonnenberg J. L., Hada M., Ehara M., Toyota K., Fukuda R., Hasegawa J., Ishida M., Nakajima T., Honda Y., Kitao O., Nakai H., Vreven T., Montgomery J. A., Vreven T. J., Peralta J. E., Ogliaro F., Bearpark M., Heyd J. J., Brothers E., Kudin N., Staroverov V. N., Kobayashi R., Normand J., Raghavachari K., Rendell A., Burant J. C., Iyengar S. S., Tomasi J., Cossi M., Rega N., Millam J. M., Klene M., Knox J. E., Cross J. B., Bakken V., Adamo C., Jaramillo J., Gomperts R., Stratmann R. E., Yazyev O., Austin A. J., Cammi R., Pomelli C. J., Ochterski W., Martin L. R., Morokuma K., Zakrzewski V. G., Voth G. A., Salvador P., Dannenberg J. J., Dapprich S., Daniels A. D., Farkas O., Foresman J. B., Ortiz J. V., Cioslowski J., Fox D. J., Gaussian Inc., Wallingford, CT, 2009.
[26] Guedes I. A., Magalhães C. S., Dardenne L. E., Biophys. Rev., 2014, 6, 75.
[27] Trott O., Olson A. J., Journal of Computational Chemistry, 2010, 31, 455.
[28] Biovia, Dassault Systemes, Discovery Studio Client, Software, Dassault Systemes San Diego, 2021.
[29] Gabor N. S., Ferenczy G. G., Chem. Rev., 1995, 829.
[30] Atlam F. M., Awad M. K., El-Bastawissy E. A., Journal of Molecular Structure, 2014, 1075, 311.
[31] Dukhovich F. S., Darkhovskii M. B., J. Mol. Recognit., 2003, 4, 191.
[32] Mondragónchez J. A., Biopolymers, 2011, 95, 641.
[33] Panicker C. Y., Varghese H. T., Nayak P. S., Narayana B., Sarojini B. K., Spectrochimica Acta Part A:Molecular and Biomolecular Spectroscopy, 2015, 148, 18.
[34] Piris M., Matxain J., Lopez X., Ugalde J., The Journal of Chemical Physics, 2012, 136, 174116.
[35] Shankar R., Senthilkumar K., Kolandaivel P., International Journal of Quantum Chemistry, 2009, 109, 764.
[36] Chandrakumar K. R. S., Ghanty T. K., Ghosh S. K., The Journal of Physical Chemistry A, 2004, 108, 6661.
[37] Pearson R. G., J. Am. Chem. Soc., 2018, 107, 6801.
[38] Mary C. P., Violet V. S., Shankar R., Journal of Molecular Graphics and Modelling, 2018, 79, 1.
[39] Vijayakumar S., Kolandaivel P., Journal of Molecular Structure THEOCHEM, 2006, 770, 23.
[40] Li X. B., Wang H. Y., Lv R., Wu W. D., Luo J. S., Tang Y. J., J. Phys. Chem. A, 2009, 24, 10335.
[41] Kaya S., Kaya C., Computational and Theoretical Chemistry, 2015, 1060, 66.
[42] Zhan C. G., Nichols J. A., Dixon D. A., The Journal of Physical Chemistry A, 2003, 107, 4184.
[43] Mahasenan K. V., Molina R., Bouley R., Batuecas M. T., Fisher J. F., Hermoso J. A., Chang M., Mobashery S., Journal of the American Chemical Society, 2017, 139, 2102.
[44] Bocheńska O., Rąpała-Kozik M., Wolak N., Braś G., Kozik A., Dubin A., Aoki W., Ueda M., Mak P., Peptides, 2013, 48, 49.
[45] Sheppard D. C., Yeaman M. R., Welch W. H., Phan Q. T., Fu Y., Ibrahim A. S., Filler S. G., Zhang M., Waring A. J., Edwards J. E., J. Biol. Chem., 2004, 16, 30480.
[46] Borelli C., Ruge E., Schaller M., Monod M., Korting H. C., Huber R., Maskos K., Proteins, 2007, 15, 738.
[47] Nirwan S., Chahal V., Kakkar R., Journal of Biomolecular Structure and Dynamics, 2021, 40, 11229.
[48] Shen Y, Liu J., Estiu G., Isin B., Ahn, Y. Y., Lee D. S., Barabási A. L., Kapatral V., Wiest O., Oltvai Z. N., Proceedings of the National Academy of Sciences of the United States of America, 2010, 107, 1082.
[49] Brad M. S., Jill R. F., James P. E., Tetrahedron Letters, 2009, 50, 2490.
[50] Nwahara N., Achadu O., Nyokong T., Journal of Photochemistry and Photobiology A:Chemistry, 2018, 359, 131.
[51] Pasa S., Journal of Molecular Structure, 2019, 1195, 198.
[52] Omidi S., Kakanejadifard A., Azarbani F., Journal of Molecular Liquids, 2017, 242, 812.
[53] Shi S., Liu H., Chen T., Chen C., Ko B., Front Mater., 2023, 10, 1.
[54] Huang S., Qiu H., Lu S., Zhu F., Xiao Q., Journal of Hazardous Materials, 2015, 285, 18.
[55] Kim S., Hwang S. W., Kim M. K., Shin D. Y., Shin D. H., Kim C. O., Yang S. B., Park J. H., Hwang E., Choi S. H., Ko G., Sim S., Sone C., Choi H. J., Bae S., Hong B. H., ACS Nano, 2012, 6, 8203.
[56] Sen P., Nyokong T., Photodiagnosis and Photodynamic Therapy, 2021, 34, 102300.
[57] Safardoust-Hojaghana H., Amirib O., Hassanpoura M., Panahi-Kalamueia M., Moayedic H., Salavati-Niasar M., Food Chemistry, 2019, 295, 530.
[58] Dervishi E., Ji Z., Htoon H., Sykora M., Doorn S. K., Nanoscale, 2019, 11, 16571.
[59] Achadu O. J., Nyokong T., J. Fluoresc., 2016, 26, 283.
[60] Sen P., Mack J., Nyokong T., Journal of Molecular Structure, 2022, 1250, 131850.
[61] Vestergaard M., Frees D., Ingmer H., Microbiol. Spectr., 2019, 7, 1.
[62] Parthasarathi R., Subramanian V., Royb D.R., Chattarajb P. K., Bioorganic & Medicinal Chemistry, 2004, 12, 5533.
[63] Das A., Banik B. K., J. Indian Chem. Soc., 2021, 98, 100005.
[64] Hushcha V., Ben A., Felczak A., Lisowska K., Kinart Z., Gacki M., Chęcińska L., Scientific Reports, 2024, 14, 29317.
[65] Zhao C., Wang X., Yu L., Wu L., Hao X., Liu Q., Lin L., Huang Z., Ruan Z., Weng S., Liu A., Lin X., Acta Biomater., 2022, 138, 528.
[66] Rajendiran K., Zhao Z., Pei D.S., Fu A., Polymers (Basel), 2019, 14, 1670.
[67] Sheikhi M., Balali E., Lari H., Journal of Physical and Theoretical Chemistry, 2016, 13, 155.
[68] Zheng Y. Z., Deng G., Liang Q., Chen D. F., Guo R., Lai R. C., Scientific Reports, 2017, 7, 7543.
[69] Cai W., Chen Y., Xie L., Zhang H., Hou C., Eur. Food Res. Technol., 2014, 238, 121.
[70] Parr R. G., Pearson R. G., J. Am. Chem. Soc., 1983, 105, 7512.
[71] Pauling L., The Nature of the Chemical Bond, 3rd Ed.; Cornell University Press:Ithaca, New York, 1960.
[72] Pearson R. G., Hard and Soft Acids and Bases, Dowen, Hutchinson and Ross, Stroudsberg, 1973.
[73] Parr R. G., Szentpaly L. V., Liu S., J. Am. Chem. Soc., 1999, 121, 1922.