Synthesis and antibacterial activity of 8-nitro-7-(aryl/alkyl) and tetracyclic fluoroquinolones encompassing thiophene, furan, and related congeners
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Ala’a A. Al-Akhras
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Mustafa M. El-Abadelah
Abstract
This work outlines the synthesis of six novel 8-nitro-7-(aryl/hetaryl)fluoroquinolones and five (aryl/hetaryl)tetracyclic fluoroquinolones; 4-oxo-4,11-dihydro-1H-pyrido[2,3-a]carbazole-3-carboxylic acids (10b, 11b) and 4-oxo-4,10-dihydro-1H-thieno/furo[4,5]pyrrolo[3,2-h]quinoline-3-carboxylic acids (3b–5b). The tetracyclic fluoroquinolone compounds were synthesized using a Suzuki–Miyaura cross-coupling acylation reaction of ethyl 7-chloro-1-cyclopropyl-6-fluoro-8-nitro-4-oxo-1,4-dihydroquinoline-3-carboxylate, followed by a microwave-assisted phosphite-mediated Cadogan reaction. The antibacterial activity of the compounds was evaluated against a range of Gram-negative bacteria, including Salmonella typhimurium, Pseudomonas aeruginosa, Escherichia coli, Acinetobacter baumannii, and Klebsiella aerogenes, as well as Gram-positive bacteria, including Listeria monocytogenes, Enterococcus faecalis, Streptococcus agalactiae, Staphylococcus aureus, and Staphylococcus epidermidis. The results demonstrated significant antibacterial activity against most of the tested strains. The lowest minimum inhibitory concentration (MIC) values observed were 7.7 μg/mL for compound 4b against S. agalactiae and compound 9b against S. aureus. These values are comparable to Streptomycin, which exhibited an MIC greater than 3.8 μg/mL for all tested pathogens.
Acknowledgments
We thank the Deanship of Scientific Research at the University of Jordan, Amman, Jordan, for financial support.
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Research ethics: Not applicable.
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Informed consent: Not applicable.
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Author contributions: All authors have accepted responsibility for the entire content of this manuscript and approved its submission.
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Use of Large Language Models, AI and Machine Learning Tools: None declared.
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Conflict of interest: The author states no conflict of interest.
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Research funding: This study was funded by the University of Jordan, Amman, Jordan. Grant Number 2485/2022.
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Data availability: Not applicable.
References
1. Linder, JA, Huang, ES, Steinman, MA, Gonzales, R, Stafford, RS. Fluoroquinolone prescribing in the United States: 1995 to 2002. Am J Med 2005;118:259–68. https://doi.org/10.1016/j.amjmed.2004.09.015.Search in Google Scholar PubMed
2. Bhatt, S, Chatterjee, S. Fluoroquinolone antibiotics: occurrence, mode of action, resistance, environmental detection, and remediation – a comprehensive review. Environ Pollut 2022;315:120440. https://doi.org/10.1016/j.envpol.2022.120440.Search in Google Scholar PubMed
3. Hryhoriv, H, Mariutsa, I, Kovalenko, SM, Sidorenko, L, Perekhoda, L, Filimonova, N, et al.. Structural modification of ciprofloxacin and norfloxacin for searching new antibiotics to combat drug-resistant bacteria. ScienceRise Pharm Sci 2021;5:4–11. https://doi.org/10.15587/2519-4852.2021.242997.Search in Google Scholar
4. Jiang, D. 4-Quinolone derivatives and their activities against gram-negative pathogens. J Heterocyclic Chem 2018;55:2003–18. https://doi.org/10.1002/jhet.3244.Search in Google Scholar
5. Millanao, AR, Mora, AY, Villagra, NA, Bucarey, SA, Hidalgo, AA. Biological effects of quinolones: a family of broad-spectrum antimicrobial agents. Molecules 2021;26. https://doi.org/10.3390/molecules26237153.Search in Google Scholar PubMed PubMed Central
6. Jia, Y, Zhao, L. The antibacterial activity of fluoroquinolone derivatives: an update (2018–2021). Eur J Med Chem 2021;224:113741. https://doi.org/10.1016/j.ejmech.2021.113741.Search in Google Scholar PubMed
7. Kaur, M, Kumar, R. A minireview on the scope of Cadogan cyclization reactions leading to diverse azaheterocycles. Asian J Org Chem 2022;11:e202200092. https://doi.org/10.1002/ajoc.202200092.Search in Google Scholar
8. Peytou, V, Condom, R, Patino, N, Guedj, R, Aubertin, AM, Gelus, N, et al.. Synthesis and antiviral activity of ethidium−arginine conjugates directed against the TAR RNA of HIV-1. J Med Chem 1999;42:4042–53. https://doi.org/10.1021/jm980728e.Search in Google Scholar PubMed
9. Sahoo, MK, Rana, J, Subaramanian, M, Balaraman, E. Room-temperature direct arylation of anilides under external oxidant-free conditions using CO2-derived dimethyl carbonate (DMC) as a ‘green’ solvent. ChemistrySelect 2017;2:7565–9. https://doi.org/10.1002/slct.201701108.Search in Google Scholar
10. Bhatthula, B, Kanchani, J, Arava, V, Subha, MCS. Total synthesis of carbazole alkaloids. Tetrahedron 2019;75:874–87. https://doi.org/10.1016/j.tet.2019.01.003.Search in Google Scholar
11. Stockmann, V, Fiksdahl, A. Preparation of new pyrido[3,4-b]thienopyrroles and pyrido[4,3-e]thienopyridazines. Tetrahedron 2008;64:7626–32. https://doi.org/10.1016/j.tet.2008.05.062.Search in Google Scholar
12. Al-Trawneh, SA, Zahra, JA, Kamal, MR, El-Abadelah, MM, Zani, F, Incerti, M, et al.. Synthesis and biological evaluation of tetracyclic fluoroquinolones as antibacterial and anticancer agents. Bioorg Med Chem 2010;18:5873–84. https://doi.org/10.1016/j.bmc.2010.06.098.Search in Google Scholar PubMed
13. Al-Akhras, AA, Zahra, JA, El-Abadelah, MM, Abu-Niaaj, LF, Khanfar, MA. 8-Amino-7-(aryl/hetaryl)fluoroquinolones. An emerging set of synthetic antibacterial agents. Zeitschrift fur Naturforschung C 2023;78:157–68. https://doi.org/10.1515/znc-2022-0143.Search in Google Scholar PubMed
14. Al-Trawneh, SA, El-Abadelah, MM, Al-Abadleh, MM, Zani, F, Incerti, M, Vicini, P. A new efficient route to 7-aryl-6-fluoro-8-nitroquinolones as potent antibacterial agents. Eur J Med Chem 2014;86:364–7. https://doi.org/10.1016/j.ejmech.2014.08.065.Search in Google Scholar PubMed
15. Al-Trawneh, SA, El-Abadelah, MM, Zahra, JA, Al-Taweel, SA, Zani, F, Incerti, M, et al.. Synthesis and biological evaluation of tetracyclic thienopyridones as antibacterial and antitumor agents. Bioorg Med Chem 2011;19:2541–8. https://doi.org/10.1016/j.bmc.2011.03.018.Search in Google Scholar PubMed
16. Osadnik, A, Lützen, A. Synthesis of symmetrically functionalized oligo(het)arylenes containing phenylene, thiophene, benzthiophene, furan, benzofuran, pyridine, and/or pyrimidine groups. Synthesis 2014;46:2976–82. https://doi.org/10.1055/s-0034-1378894.Search in Google Scholar
17. Al-Soud, YA, Marchais-Oberwinkler, S, Frotscher, M, Hartmann, RW. Synthesis and biological evaluation of phenyl substituted 1H-1,2,4-triazoles as non-steroidal inhibitors of 17β-hydroxysteroid dehydrogenase type 2. Arch Pharmazie 2012;345:610–21. https://doi.org/10.1002/ardp.201200025.Search in Google Scholar PubMed
18. Pudlo, M, Csányi, D, Moreau, F, Hajós, G, Riedl, Z, Sapi, J. First Suzuki–Miyaura type cross-coupling of ortho-azidobromobenzene with arylboronic acids and its application to the synthesis of fused aromatic indole-heterocycles. Tetrahedron 2007;63:10320–9. https://doi.org/10.1016/j.tet.2007.07.068.Search in Google Scholar
19. Sanchez, JP, Domagala, JM, Hagen, SE, Heifetz, CL, Hutt, MP, Nichols, JB, et al.. Quinolone antibacterial agents. Synthesis and structure-activity relationships of 8-substituted quinoline-3-carboxylic acids and 1, 8-naphthyridine-3-carboxylic acids. J Med Chem 1988;31:983–91. https://doi.org/10.1021/jm00400a016.Search in Google Scholar PubMed
20. Grohe, K, Heitzer, H. Cycloaracylierung von Enaminen, I. Synthese von 4-Chinolon-3-carbonsäuren. Liebigs Ann Chem 1987;1987:29–37. https://doi.org/10.1002/jlac.198719870106.Search in Google Scholar
21. Pulla, R, Venkaiah, C. An improved process for the preparation of quinolone derivatives, eg ciprofloxacin. PCT Int Appl WO 085; 2001:692 p.Search in Google Scholar
22. Kadu, BS. Suzuki–Miyaura cross coupling reaction: recent advancements in catalysis and organic synthesis. Catal Sci Technol 2021;11:1186–221. https://doi.org/10.1039/d0cy02059a.Search in Google Scholar
23. D’Alterio, MC, Casals-Cruañas, È, Tzouras, NV, Talarico, G, Nolan, SP, Poater, A. Mechanistic aspects of the palladium-catalyzed Suzuki–Miyaura cross-coupling reaction. Chemistry 2021;27:13481–93. https://doi.org/10.1002/chem.202185461.Search in Google Scholar
24. Beletskaya, IP, Alonso, F, Tyurin, V. The Suzuki–Miyaura reaction after the nobel prize. Coord Chem Rev 2019;385:137–73. https://doi.org/10.1016/j.ccr.2019.01.012.Search in Google Scholar
25. Kabri, Y, Crozet, MD, Terme, T, Vanelle, P. Efficient access to 2,6,8-trisubstituted 4-aminoquinazolines through microwave-assisted one-pot chemoselective tris-Suzuki–Miyaura or SNAr/bis-Suzuki–Miyaura reactions in water. Eur J Org Chem 2015;2015:3806–17. https://doi.org/10.1002/ejoc.201500162.Search in Google Scholar
26. Oster, A, Klein, T, Werth, R, Kruchten, P, Bey, E, Negri, M, et al.. Novel estrone mimetics with high 17beta-HSD1 inhibitory activity. Bioorg Med Chem 2010;18:3494–505. https://doi.org/10.1016/j.bmc.2010.03.065.Search in Google Scholar PubMed
27. Mohamed, MF, Hamed, MI, Panitch, A, Seleem, MN. Targeting methicillin-resistant Staphylococcus aureus with short salt-resistant synthetic peptides. Antimicrob Agents Chemother 2014;58:4113–22. https://doi.org/10.1128/aac.02578-14.Search in Google Scholar PubMed PubMed Central
28. Doi, Y, Murray, GL, Peleg, AY. Acinetobacter baumannii: evolution of antimicrobial resistance-treatment options. Semin Respir Crit Care Med 2015;36:85–98. https://doi.org/10.1055/s-0034-1398388.Search in Google Scholar PubMed PubMed Central
29. Breidenstein, EB, de la Fuente-Núñez, C, Hancock, RE. Pseudomonas aeruginosa: all roads lead to resistance. Trends Microbiol 2011;19:419–26. https://doi.org/10.1016/j.tim.2011.04.005.Search in Google Scholar PubMed
Supplementary Material
This article contains supplementary material (https://doi.org/10.1515/znc-2025-0091).
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