Design, Synthesis, and Biological Evaluation of Schiff Base and Azo Derivatives of Cefixime: Antibacterial, Antifungal, Antioxidant, ADMET, and Docking Studies

Aqeel Sami; Mohammed Rifaat Ahmad

doi:10.18596/jotcsa.1739097

Design, Synthesis, and Biological Evaluation of Schiff Base and Azo Derivatives of Cefixime: Antibacterial, Antifungal, Antioxidant, ADMET, and Docking Studies

Abstract

The development of new antibiotics is imperative due to the increasing resistance of bacteria to existing drugs. This study aimed to synthesize Schiff bases and azo derivatives of cefixime, a third-generation cephalosporin, and to evaluate their antimicrobial and antioxidant activities. The antibacterial activity of the synthesized compounds was assessed against Candida albicans and various Gram-positive and Gram-negative pathogens. Several derivatives exhibited potent antibacterial and antifungal activities, with compounds C6 and C9 demonstrating superior efficacy compared to standard antibiotics. Furthermore, molecular docking simulations revealed favorable interactions between these derivatives and beta-lactamase enzymes as well as penicillin-binding proteins, providing insights into their mechanism of action. Despite some limitations in bioavailability, the ADMET analysis clarified their pharmacokinetic profiles and confirmed their potential for systemic administration. These findings highlight the potential of cefixime-derived azo compounds and Schiff bases as novel strategies to overcome antibiotic resistance. Notably, compounds C9 and C6 differentiated themselves through enhanced antibacterial and antioxidant properties, making them promising candidates for further research, including preclinical and clinical evaluations following comprehensive pharmacological and therapeutic assessments.

Keywords

Thanks

We would like to thank the Head of the Chemistry Department / College of Science / University of Baghdad and the staff of the service laboratory, especially Hajjah Munira. I would also like to thank everyone who helped me or facilitated my work.

References

1. Aslam B, Khurshid M, Arshad MI, Muzammil S, Rasool M, Yasmeen N, et al. Antibiotic resistance: One health one world outlook. Front Cell Infect Microbiol [Internet]. 2021 Nov 25;11:771510. Available from: .
2. Piergiacomo F, Brusetti L, Pagani L. Understanding the interplay between antimicrobial resistance, microplastics and xenobiotic contaminants: A leap towards one health? Int J Environ Res Public Health [Internet]. 2022 Dec 20;20(1):42. Available from: .
3. Santra H, Bhadury P. Prevalence of antimicrobial resistance in fecal coliforms in wastewater settings: Challenges and way forward from the perspective of global south. In Springer, Singapore; 2024. p. 3–32. Available from: .
4. Bharadwaj A, Rastogi A, Pandey S, Gupta S, Sohal JS. Multidrug‐resistant bacteria: Their mechanism of action and prophylaxis. Kaushik S, editor. Biomed Res Int [Internet]. 2022 Jan 5;2022(1):5419874. Available from: .
5. Terreni M, Taccani M, Pregnolato M. New antibiotics for multidrug-resistant bacterial strains: Latest research developments and future perspectives. Molecules [Internet]. 2021 May 2;26(9):2671. Available from: .
6. Brüssow H. The antibiotic resistance crisis and the development of new antibiotics. Microb Biotechnol [Internet]. 2024 Jul 5;17(7):e14510. Available from: .
7. Abbas AT, Salih HA, Hassan BA. Review of Beta lactams. Ann Rom Soc Cell Biol [Internet]. 2022;26(1):1863–81. Available from: .
8. Gupta R, Gupta N, Bindal S. Bacterial cell wall biosynthesis and inhibitors. In: Fundamentals of Bacterial Physiology and Metabolism [Internet]. Singapore: Springer Singapore; 2021. p. 81–98. Available from: .

9. Torrens G, Cava F. Mechanisms conferring bacterial cell wall variability and adaptivity. Biochem Soc Trans [Internet]. 2024 Oct 30;52(5):1981–93. Available from: .
10. Aliashkevich A, Cava F. LD‐transpeptidases: The great unknown among the peptidoglycan cross‐linkers. FEBS J [Internet]. 2022 Aug 22;289(16):4718–30. Available from: .
11. Vacariu CM, Tanner ME. Recent advances in the synthesis and biological applications of peptidoglycan fragments. Chem – A Eur J [Internet]. 2022 Aug 16;28(43):e202200788. Available from: .
12. Orsini Delgado ML, Gamelas Magalhaes J, Morra R, Cultrone A. Muropeptides and muropeptide transporters impact on host immune response. Gut Microbes [Internet]. 2024 Dec 31;16(1). Available from: .
13. Dabhi M, Patel R, Shah V, Soni R, Saraf M, Rawal R, et al. Penicillin-binding proteins: The master builders and breakers of bacterial cell walls and its interaction with β-lactam antibiotics. J Proteins Proteomics [Internet]. 2024 Apr 6;15(2):215–32. Available from: .
14. Liu X, den Blaauwen T. NlpI-Prc proteolytic complex mediates peptidoglycan synthesis and degradation via regulation of hydrolases and synthases in Escherichia coli. Int J Mol Sci [Internet]. 2023 Nov 15;24(22):16355. Available from: .
15. Arumugham VB, Gujarathi R, Cascella M. Third-Generation Cephalosporins. StatPearls [Internet]. 2023 Jun 4; Available from: .
16. Zaragoza G, Pérez-Vázquez M, Villar-Gómara L, González-Prieto A, Oteo-Iglesias J, Alós JI. Community emergence of cefixime-resistant Escherichia coli belonging to ST12 with chromosomal AmpC hyperproduction. Antibiotics [Internet]. 2024 Feb 27;13(3):218. Available from: .
17. Mora-Ochomogo M, Lohans CT. β-Lactam antibiotic targets and resistance mechanisms: from covalent inhibitors to substrates. RSC Med Chem [Internet]. 2021 Oct 20;12(10):1623–39. Available from: .
18. Bush K, Bradford PA. β-Lactams and β-Lactamase inhibitors: An overview. Cold Spring Harb Perspect Med [Internet]. 2016 Aug 1;6(8):a025247. Available from: .
19. Baquero F, Cantón R, Pérez-Cobas AE, Coque TM, Levin B, Rodríguez-Beltrán J. Antechodynamics and antechokinetics: Dynamics and kinetics of antibiotic resistance biomolecules. Biomolecules [Internet]. 2025 Jun 5;15(6):823. Available from: .
20. Karvouniaris M, Almyroudi MP, Abdul-Aziz MH, Blot S, Paramythiotou E, Tsigou E, et al. Novel antimicrobial agents for gram-negative pathogens. Antibiotics [Internet]. 2023 Apr 16;12(4):761. Available from: .
21. Gajic I, Tomic N, Lukovic B, Jovicevic M, Kekic D, Petrovic M, et al. A comprehensive overview of antibacterial agents for combating multidrug-resistant bacteria: The current landscape, development, future opportunities, and challenges. Antibiotics [Internet]. 2025 Feb 21;14(3):221. Available from: .
22. Cook MA, Wright GD. The past, present, and future of antibiotics. Sci Transl Med [Internet]. 2022 Aug 10;14(657). Available from: .
23. Bhattacharjee R, Negi A, Bhattacharya B, Dey T, Mitra P, Preetam S, et al. Nanotheranostics to target antibiotic-resistant bacteria: Strategies and applications. OpenNano [Internet]. 2023 May 1;11:100138. Available from: .
24. Hamad AA, Omer RA, Kaka KN, Abdulkareem EI, Rashid RF. Biological activities of metal complexes with schiff base. Rev Inorg Chem [Internet]. 2025 Sep 25;45(3):543–52. Available from: .
25. Al-Mosawy M. Review of the biological effects of schiff bases and their derivatives, including their synthesis. Med Sci J Adv Res [Internet]. 2023 Jul 31;4(2):67–85. Available from: .
26. Alsantali RI, Raja QA, Alzahrani AYA, Sadiq A, Naeem N, Mughal EU, et al. Miscellaneous azo dyes: A comprehensive review on recent advancements in biological and industrial applications. Dye Pigment [Internet]. 2022 Mar 1;199:110050. Available from: .
27. Banaszak-Leonard E, Fayeulle A, Franche A, Sagadevan S, Billamboz M. Antimicrobial azo molecules: A review. J Iran Chem Soc [Internet]. 2021 Nov 22;18(11):2829–51. Available from: .
28. Tuna Subasi N. Overview of schiff bases. In: Akitsu T, editor. Schiff Base in Organic, Inorganic and Physical Chemistry [Internet]. IntechOpen; 2023. p. 15–36. Available from: .
29. Jorge J, Del Pino Santos KF, Timóteo F, Piva Vasconcelos RR, Ignacio Ayala Cáceres O, Juliane Arantes Granja I, et al. Recent advances on the antimicrobial activities of schiff bases and their metal complexes: An updated overview. Curr Med Chem [Internet]. 2024 May 24;31(17):2330–44. Available from: .
30. Razali NA, Jamain Z. Synthesis, chemical identification and biological application of Azo-based molecules containing different terminal group: A review. J Mol Struct [Internet]. 2023 Jul 15;1284:135329. Available from: .
31. Prasad Mishra D, Kumar Sahu P, Acharya B, Prasad Mishra S, Bhati S. A review of the synthesis and application of azo dyes and metal complexes for emerging antimicrobial therapies. Results Chem [Internet]. 2024 Aug 1;10:101712. Available from: .
32. Trivedi HD, Patel BY, Patel PK, Sagar SR. Synthesis, molecular modeling, ADMET and fastness studies of some quinoline encompassing pyrimidine azo dye derivatives as potent antimicrobial agents. Chem Data Collect [Internet]. 2022 Oct 1;41:100923. Available from: .
33. Mustapha B, Saleh AA, El‐Seifat R, Bufarwa S, Hasan H, Moustafa D. Exploring the antituberculosis, anti‐inflammatory, and antimicrobial activities and computational potential of quinoline‐8‐ol azo dye complexes. Appl Organomet Chem [Internet]. 2025 Aug 20;39(8):e70310. Available from: .
34. Al-Hiyari BA, Shakya AK, Naik RR, Bardaweel S. Microwave-assisted synthesis of schiff bases of isoniazid and evaluation of their anti-proliferative and antibacterial activities. Molbank [Internet]. 2021 Feb 4;2021(1):M1189. Available from: .
35. Benkhaya S, M’rabet S, El Harfi A. Classifications, properties, recent synthesis and applications of azo dyes. Heliyon [Internet]. 2020 Jan 1;6(1):e03271. Available from: .
36. Daina A, Michielin O, Zoete V. SwissADME: A free web tool to evaluate pharmacokinetics, drug-likeness and medicinal chemistry friendliness of small molecules. Sci Rep [Internet]. 2017 Mar 3;7(1):42717. Available from: .
37. Banerjee P, Kemmler E, Dunkel M, Preissner R. ProTox 3.0: A webserver for the prediction of toxicity of chemicals. Nucleic Acids Res [Internet]. 2024 Jul 5;52(W1):W513–20. Available from: .
38. Lim D, Strynadka NCJ. Structural basis for the β lactam resistance of PBP2a from methicillin-resistant Staphylococcus aureus. Nat Struct Biol [Internet]. 2002 Oct 21;9(11):870–6. Available from: .
39. Contreras-Martel C, Dahout-Gonzalez C, Martins ADS, Kotnik M, Dessen A. PBP active site flexibility as the key mechanism for β-Lactam resistance in pneumococci. J Mol Biol [Internet]. 2009 Apr 10;387(4):899–909. Available from: .
40. Chesnel L, Pernot L, Lemaire D, Champelovier D, Croizé J, Dideberg O, et al. The structural modifications induced by the M339F substitution in PBP2x from Streptococcus pneumoniae further decreases the susceptibility to β-Lactams of resistant strains. J Biol Chem [Internet]. 2003 Nov 7;278(45):44448–56. Available from: .
41. Ibuka AS, Ishii Y, Galleni M, Ishiguro M, Yamaguchi K, Frère JM, et al. Crystal structure of extended-spectrum β-Lactamase toho-1: Insights into the molecular mechanism for catalytic reaction and substrate specificity expansion. Biochemistry [Internet]. 2003 Sep 1;42(36):10634–43. Available from: .
42. Bitencourt-Ferreira G, Pintro VO, de Azevedo WF. Docking with AutoDock4. In: Methods in Molecular Biology [Internet]. Humana, New York, NY; 2019. p. 125–48. Available from: .
43. Hossain TJ. Methods for screening and evaluation of antimicrobial activity: A review of protocols, advantages, and limitations. Eur J Microbiol Immunol [Internet]. 2024 May 14;14(2):97–115. Available from: .
44. Maged AS, Ahamed LS. Synthesis and applications of new heterocyclic derivatives from 2-furyl methanethiol Synthesis of new heterocyclic derivatives from 2-furyl methanethiol and study their applications. Eurasian Chem Commun [Internet]. 2021;3:461–76. Available from: .
45. Silverstein RM, Bassler GC. Spectrometric identification of organic compounds. J Chem Educ [Internet]. 1962 Nov 1;39(11):546. Available from: .
46. Zapun A, Contreras-Martel C, Vernet T. Penicillin-binding proteins and β-lactam resistance. FEMS Microbiol Rev [Internet]. 2008 Mar 1;32(2):361–85. Available from: .
47. Agu PC, Afiukwa CA, Orji OU, Ezeh EM, Ofoke IH, Ogbu CO, et al. Molecular docking as a tool for the discovery of molecular targets of nutraceuticals in diseases management. Sci Rep [Internet]. 2023 Aug 17;13(1):13398. Available from: .
48. Latief BH, Al-Azzawi AM. Synthesis and antimicrobial activity screening of new cyclic imides comprising antipyrine and oxazole cycles. Biochem Cell Arch [Internet]. 2019 Oct 1;19(2):4419–24. Available from: .

Details

Primary Language

English

Subjects

Organic Chemical Synthesis, Organic Green Chemistry, Biomolecular Modelling and Design

Journal Section

Research Article

Authors

Aqeel Sami ^*
0000-0001-6471-4975
Iraq

Mohammed Rifaat Ahmad This is me
0000-0002-6960-4932
Iraq

Publication Date

December 1, 2025

Submission Date

July 10, 2025

Acceptance Date

October 3, 2025

Published in Issue

Year 2025 Volume: 12 Number: 4

DOI

https://doi.org/10.18596/jotcsa.1739097

IZ

https://izlik.org/JA56DD79DR

Cite

RIS / Bibtex

APA

Sami, A., & Rifaat Ahmad, M. (2025). Design, Synthesis, and Biological Evaluation of Schiff Base and Azo Derivatives of Cefixime: Antibacterial, Antifungal, Antioxidant, ADMET, and Docking Studies. Journal of the Turkish Chemical Society Section A: Chemistry, 12(4), 269-286. https://doi.org/10.18596/jotcsa.1739097

AMA

1.Sami A, Rifaat Ahmad M. Design, Synthesis, and Biological Evaluation of Schiff Base and Azo Derivatives of Cefixime: Antibacterial, Antifungal, Antioxidant, ADMET, and Docking Studies. JOTCSA. 2025;12(4):269-286. doi:10.18596/jotcsa.1739097

Chicago

Sami, Aqeel, and Mohammed Rifaat Ahmad. 2025. “Design, Synthesis, and Biological Evaluation of Schiff Base and Azo Derivatives of Cefixime: Antibacterial, Antifungal, Antioxidant, ADMET, and Docking Studies”. Journal of the Turkish Chemical Society Section A: Chemistry 12 (4): 269-86. https://doi.org/10.18596/jotcsa.1739097.

EndNote

Sami A, Rifaat Ahmad M (December 1, 2025) Design, Synthesis, and Biological Evaluation of Schiff Base and Azo Derivatives of Cefixime: Antibacterial, Antifungal, Antioxidant, ADMET, and Docking Studies. Journal of the Turkish Chemical Society Section A: Chemistry 12 4 269–286.

IEEE

[1]A. Sami and M. Rifaat Ahmad, “Design, Synthesis, and Biological Evaluation of Schiff Base and Azo Derivatives of Cefixime: Antibacterial, Antifungal, Antioxidant, ADMET, and Docking Studies”, JOTCSA, vol. 12, no. 4, pp. 269–286, Dec. 2025, doi: 10.18596/jotcsa.1739097.

ISNAD

Sami, Aqeel - Rifaat Ahmad, Mohammed. “Design, Synthesis, and Biological Evaluation of Schiff Base and Azo Derivatives of Cefixime: Antibacterial, Antifungal, Antioxidant, ADMET, and Docking Studies”. Journal of the Turkish Chemical Society Section A: Chemistry 12/4 (December 1, 2025): 269-286. https://doi.org/10.18596/jotcsa.1739097.

JAMA

1.Sami A, Rifaat Ahmad M. Design, Synthesis, and Biological Evaluation of Schiff Base and Azo Derivatives of Cefixime: Antibacterial, Antifungal, Antioxidant, ADMET, and Docking Studies. JOTCSA. 2025;12:269–286.

MLA

Sami, Aqeel, and Mohammed Rifaat Ahmad. “Design, Synthesis, and Biological Evaluation of Schiff Base and Azo Derivatives of Cefixime: Antibacterial, Antifungal, Antioxidant, ADMET, and Docking Studies”. Journal of the Turkish Chemical Society Section A: Chemistry, vol. 12, no. 4, Dec. 2025, pp. 269-86, doi:10.18596/jotcsa.1739097.

Vancouver

1.Aqeel Sami, Mohammed Rifaat Ahmad. Design, Synthesis, and Biological Evaluation of Schiff Base and Azo Derivatives of Cefixime: Antibacterial, Antifungal, Antioxidant, ADMET, and Docking Studies. JOTCSA. 2025 Dec. 1;12(4):269-86. doi:10.18596/jotcsa.1739097