Emerging Frontiers in Antimicrobial Therapy: The Role of Nitrogen-Containing Heterocyclic Compounds in Overcoming Drug-Resistant Infections
DOI:
https://doi.org/10.31305/rrijm.2025.v10.n2.011Keywords:
Antibiotic resistance, Nitrogen-containing heterocyclic compounds, Antimicrobial agents, Pyrrole derivatives, Pyrimidine derivatives, Bacterial cell wallAbstract
The rise of antibiotic-resistant bacterial pathogens has become a significant public health challenge, necessitating the exploration of novel antimicrobial agents. Nitrogen-containing heterocyclic compounds have emerged as promising candidates in this quest, owing to their diverse and potent antibacterial activities. This review delves into the various mechanisms through which these compounds exert their antibacterial effects, including inhibition of cell wall synthesis, disruption of protein and nucleic acid synthesis, interference with metabolic pathways, membrane disruption, induction of oxidative stress, and inhibition of bacterial communication and virulence factors. By comparing these mechanisms with those of traditional antibiotics, we highlight the unique advantages and therapeutic potential of nitrogen-containing heterocyclic compounds. Furthermore, case studies focusing on specific pyrrole and pyrimidine derivatives are presented to illustrate the practical applications and efficacy of these compounds against multidrug-resistant bacterial strains. The review aims to provide a comprehensive overview of the current status, challenges, and prospects of nitrogen-containing heterocyclic compounds as novel antimicrobial agents, offering insights into their potential to address the urgent need for new treatments against resistant bacterial infections.
References
Cheddie, A.; Shintre, S.A.; Bantho, A.; Mocktar, C.; Koorbanally, N.A. Synthesis and antibacterial activity of a series of 2- trifluoromethylbenzimidazole-thiazolidinone derivatives. J. Heterocycl. Chem. 2020, 57, 299–307.
Hassoun, A.; Linden, P.K.; Friedman, B. Incidence, prevalence, and management of MRSA bacteremia across patient populations—A review of recent developments in MRSA management and treatment. Crit. Care 2017, 21, 211.
Campbell, I.B.; Macdonald, S.J.; Procopiou, P.A. Medicinal chemistry in drug discovery in big pharma: Past, present and future.Drug Discov. Today 2018, 23, 219–234.
Sreedevi, R.; Saranya, S.; Anilkumar, G. Recent Trends in the Silver-Catalyzed Synthesis of Nitrogen Heterocycles. Adv. Synth. Catal. 2019, 361, 4625–4644.
Ghaemi, M.; Pordel, M. Isoxazolo [4, 3-e] indazole as a new heterocyclic system: Design, synthesis, spectroscopic characterization, and antibacterial activity. Chem. Heterocycl. Compd. 2016, 52, 52–57
Vitaku, E.; Smith, D.T.; Njardarson, J.T. Analysis of the structural diversity, substitution patterns, and frequency of nitrogen heterocycles among US FDA approved pharmaceuticals: Miniperspective. J. Med. Chem. 2014, 57, 10257–10274.
Ferouani, G.; Nacer, A.; Ameur, N.; Bachir, R.; Ziani-Cherif, C. Facile Heterocyclic Synthesis and Antibacterial Activity of Substituted Isoxazol-5 (4H)-ones. J. Chin. Chem. Soc. 2018, 65, 459–464.
Nuchu, R.; Narayana, M. Synthesis and Characterization of Organo Sulphur Heterocyclic Derivates and Their Anti-Fungal Activity. World J. Pharm. Pharm. Sci. 2016, 5, 941–953.
Balaji, K.; Bhatt, P.; Mallika, D.; Jha, A. Design, synthesis and antimicrobial evaluation of some mannich base derivative of 2 (2-substituted)-5-amino-thiadiazoles. Int. J. Pharm. Pharm. Sci. 2015, 7, 145–149.
Al-Anazi, K.M.; Mahmoud, A.H.; AbulFarah, M.; Allam, A.A.; Fouda, M.M.; Gaffer, H.E. 2-Amino-5-arylazothiazole-Based Derivatives: In Vitro Cytotoxicity, Antioxidant Properties, and Bleomycin-Dependent DNA Damage. ChemistrySelect 2019, 4, 5570–5576
Al-jubouri, A.A.; Qasir, A.J. Synthesis and Antibacterial Activity of bis Heterocyclic Derivatives of 1, 3, 4-thiadiazole. Iraqi J. Pharm. Sci. 2015, 24, 59–67.
Serban, G.; Stanasel, O.; Serban, E.; Bota, S. 2-Amino-1, 3, 4-thiadiazole as a potential scaffold for promising antimicrobial agents. Drug Des. Dev. Ther. 2018, 12, 1545
Mohan, S.; Ananthan, S. A new approach for the synthesis of some novel sulphur bridged pyrazoles and their characterization. J. Chem. Pharm. Res 2011, 3, 402–413.
Ameli, S.; Pordel, M.; Davoodnia, A.; Jajarmi, M. Synthesis and antibacterial activity of some new benzo [5, 6] chromeno [2, 3-d] pyrimidines. Russ. J. Bioorganic Chem. 2017, 43, 429–434.
Aaglawe, M.; SS, D.; SS, B.; PS, W.; DB, S. Synthesis and antibacterial activity of some oxazolone derivatives. J. Korean Chem. Soc. 2003, 47, 133–136.
SAYED MOHAMED, M.; El-Domany, R.A.; Abd El-Hameed, R.H. Synthesis of certain pyrrole derivatives as antimicrobial agents.Acta Pharm. 2009, 59, 145–158.
Padwa, A.; Bur, S. Recent advances of 1, 3-dipolar cycloaddition chemistry for alkaloid synthesis. Adv. Heterocycl. Chem. 2016, 119, 241–305.
Ferlin, F.; Luciani, L.; Viteritti, O.; Brunori, F.; Piermatti, O.; Santoro, S.; Vaccaro, L. Polarclean as a sustainable reaction medium for the waste minimized synthesis of heterocyclic compounds. Front. Chem. 2019, 6, 659.
Hosseyni Largani, T.; Imanzadeh, G.; Zahri, S.; Noroozi Pesyan, N.; S¸ahin, E. A facile synthesis and antibacterial activity of novel pyrrolo [3, 4-b] quinolin-2 (3H)-yl) benzamides. Green Chem. Lett. Rev. 2017, 10, 387–392.
Mir, N.A.; Ramaraju, P.; Vanaparthi, S.; Choudhary, S.; Singh, R.P.; Sharma, P.; Kant, R.; Singh, R.; Sankaranarayanan, M.; Kumar, I. Sequential multicomponent catalytic synthesis of pyrrole-3-carboxaldehydes: Evaluation of antibacterial and antifungal activities along with docking studies. New J. Chem. 2020, 44, 16329–16339.
Idhayadhulla, A.; Kumar, R.S.; Nasser, A.J.A. Synthesis, characterization and antimicrobial activity of new pyrrole derivatives.J. Mex. Chem. Soc. 2011, 55, 218–223.
Kheder, N.A. Hydrazonoyl chlorides as precursors for synthesis of novel bis-pyrrole derivatives. Molecules 2016, 21, 326
Baral, N.; Mishra, D.R.; Mishra, N.P.; Mohapatra, S.; Raiguru, B.P.; Panda, P.; Nayak, S.; Nayak, M.; Kumar, P.S. Microwave- assisted rapid and efficient synthesis of chromene-fused pyrrole derivatives through multicomponent reaction and evaluation of antibacterial activity with molecular docking investigation. J. Heterocycl. Chem. 2020, 57, 575–589.
Kumar, B.; Lakshmi, P.; Veena, B.; Sujatha, E. Synthesis and antibacterial activity of novel pyrano [2, 3-d] pyrimidine-4-one–3- phenylisoxazole hybrids. Russ. J. Gen. Chem. 2017, 87, 829–836.
Misra, A.; Sharma, S.; Sharma, D.; Dubey, S.; Mishra, A.; Kishore, D.; Dwivedi, J. Synthesis and molecular docking of pyrimidine incorporated novel analogue of 1, 5-benzodiazepine as antibacterial agent. J. Chem. Sci. 2018, 130, 31.
Fang, Z.; Zheng, S.; Chan, K.-F.; Yuan, W.; Guo, Q.; Wu, W.; Lui, H.-K.; Lu, Y.; Leung, Y.-C.; Chan, T.-H. Design, synthesis and antibacterial evaluation of 2, 4-disubstituted-6-thiophenyl-pyrimidines. Eur. J. Med. Chem. 2019, 161, 141–153.
Mahmoodi, N.O.; Shoja, S.; Sharifzadeh, B.; Rassa, M. Regioselective synthesis and antibacterial evaluation of novel bis-pyrimidine derivatives via a three-component reaction. Med. Chem. Res. 2014, 23, 1207–1213.
Triloknadh, S.; Rao, C.V.; Nagaraju, K.; Krishna, N.H.; Ramaiah, C.V.; Rajendra, W.; Trinath, D.; Suneetha, Y. Design, synthesis, neuroprotective, antibacterial activities and docking studies of novel thieno [2, 3-d] pyrimidine-alkyne Mannich base and oxadiazole hybrids. Bioorganic Med. Chem. Lett. 2018, 28, 1663–1669.
Andrews, B.; Komathi, K.; Mohan, S. Synthesis and comparing the antibacterial activities of pyrimidine derivatives. J. 2017, 129, 335–341.
Lee, J.H.; Kim, Y.G.; Ryu, S.Y., Choi, S.U., Lee, J.; Kim, B.H. Identification and antibacterial evaluation of bioactive compounds from nitrogen-containing heterocycles library. Bioorg. Med. Chem. Lett. 2021, 31, 127589.
Patel, M.; Hossain, M.A.; Wang, J.; Chen, X.; Liu, J. Advances in nitrogen-containing heterocyclic antibiotics: A review. Molecules 2018, 23, 325.
Khan, T.A.; Kashfi, K.; Al-Qahtani, A.; Bashir, S. Nitrogen-containing heterocycles as potential antibacterial agents: A focused review. Antimicrob. Agents Chemother. 2019, 63, e02218-18.
Rodriguez, A.R.; Spurlock, L.A.; Chavez, G.; Tse, E. Nitrogen heterocycles as building blocks for new antimicrobial agents. Chem. Rev. 2020, 120, 4698–4749.
Gomez-Escribano, J.P.; Song, L.; Fox, D.J.; Yeo, V.; Bibb, M.J.; Challis, G.L. Engineered biosynthesis of nonribosomal peptides containing nitrogen heterocycle moieties. Nat. Chem. Biol. 2015, 11, 721–729.
Wright, G.D. Antibiotic resistance in bacteria: The role of nitrogen-containing heterocycles. Chem. Commun. 2016, 52, 1939–1953.
Nguyen, Q.T.; Nguyen, T.; Schreiber, S.L.; Luesch, H. Nitrogen heterocycles as potential quorum sensing inhibitors. Bioorg. Med. Chem. Lett. 2018, 28, 3151–3158.
Ma, D.; Cook, P.D. Nitrogen heterocycles as therapeutic agents against tuberculosis. Bioorg. Med. Chem. 2017, 25, 2738–2752.
Zhang, H.; Zhou, L.; Zhu, J.; Xu, G.; Li, X. Development of nitrogen-containing heterocyclic compounds as anti-TB agents. Eur. J. Med. Chem. 2020, 186, 111903.
Bianco, G.; Forzato, C.; Agostinelli, E.; Elviri, L.; Rubini, K.; Boggioni, L. Nitrogen-containing heterocycles and their impact on microbial biofilms. Org. Biomol. Chem. 2018, 16, 4234–4246.
Ramachandran, V.; Easton, J.B. The role of nitrogen-containing heterocyclic molecules in the biofilm eradication. Bioorg. Med. Chem. 2019, 27, 2951–2966.
Downloads
Published
How to Cite
Issue
Section
License
This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License.
This is an open access article under the CC BY-NC-ND license Creative Commons Attribution-Noncommercial 4.0 International (CC BY-NC 4.0).
