Design and Synthesis of Coumarin-based Amphoteric Antimicrobials with Biofilm Interference and Immunoregulation Effects

Overview

Journal RSC Med Chem

Publisher Royal Society of Chemistry

Date 2025 Jan 13

PMID 39802671

Authors

Qun Tang

Haiyang Zhang

Kasemsiri Chandarajoti

Zirui Jiao

Lianhua Nie

Sai Lv

Jiakun Zuo

Wen Zhou

Xiangan Han

Affiliations

Soon will be listed here.

Abstract

Bacterial infections pose a threat to human and animal health, and the formation of biofilm exacerbates the microbial threat. New antimicrobial agents to address this challenge are much needed. In this study, several new amphoteric compounds derived from the natural product coumarin were designed and synthesized by mimicking the structure and function of antimicrobial peptides. Strong inhibitory effect of 8b was observed on 29213 and five isolated clinically positive strains, with an MIC value of 1-4 μg mL, accompanied by the potential advantages of rapid sterilization and no drug resistance. The activity of 8b was supported by good antibacterial and anti-inflammatory effects in a mouse wound infection model. More importantly, good immunomodulatory effects, inhibition of biofilm formation, and biofilm clearance were detected in the treatment using 8b, which makes it a potential candidate antibacterial for controlling infections forming biofilm.

References

Maiti S, Park N, Han J, Jeon H, Lee J, Bhuniya S . Gemcitabine-coumarin-biotin conjugates: a target specific theranostic anticancer prodrug. J Am Chem Soc. 2013; 135(11):4567-72. DOI: 10.1021/ja401350x. View

Trykowska Konc J, Hejchman E, Kruszewska H, Wolska I, Maciejewska D . Synthesis and pharmacological activity of O-aminoalkyl derivatives of 7-hydroxycoumarin. Eur J Med Chem. 2011; 46(6):2252-63. DOI: 10.1016/j.ejmech.2011.03.006. View

Emam S, Sonousi A, Osman E, Hwang D, Kim G, Hassan R . Design and synthesis of methoxyphenyl- and coumarin-based chalcone derivatives as anti-inflammatory agents by inhibition of NO production and down-regulation of NF-κB in LPS-induced RAW264.7 macrophage cells. Bioorg Chem. 2021; 107:104630. DOI: 10.1016/j.bioorg.2021.104630. View

Li S, Tan Y, Zhang L, Zhou C . Comprehensive Insights into Medicinal Research on Imidazole-Based Supramolecular Complexes. Pharmaceutics. 2023; 15(5). PMC: 10222694. DOI: 10.3390/pharmaceutics15051348. View

Kumar A, Alam A, Rani M, Ehtesham N, Hasnain S . Biofilms: Survival and defense strategy for pathogens. Int J Med Microbiol. 2017; 307(8):481-489. DOI: 10.1016/j.ijmm.2017.09.016. View

OConnell K, Hodgkinson J, Sore H, Welch M, Salmond G, Spring D . Combating multidrug-resistant bacteria: current strategies for the discovery of novel antibacterials. Angew Chem Int Ed Engl. 2013; 52(41):10706-33. DOI: 10.1002/anie.201209979. View

Teng P, Shao H, Huang B, Xie J, Cui S, Wang K . Small Molecular Mimetics of Antimicrobial Peptides as a Promising Therapy To Combat Bacterial Resistance. J Med Chem. 2023; 66(4):2211-2234. DOI: 10.1021/acs.jmedchem.2c00757. View

Yap C, Ramle A, Lim S, Rames A, Tay S, Chin S . Synthesis and Staphylococcus aureus biofilm inhibitory activity of indolenine-substituted pyrazole and pyrimido[1,2-b]indazole derivatives. Bioorg Med Chem. 2023; 95:117485. DOI: 10.1016/j.bmc.2023.117485. View

Chen N, Jiang C . Antimicrobial peptides: Structure, mechanism, and modification. Eur J Med Chem. 2023; 255:115377. DOI: 10.1016/j.ejmech.2023.115377. View

10.

Li W, Sun Y, Yan X, Yang S, Kim E, Kang H . Coumarins and lignans from Zanthoxylum schinifolium and their anticancer activities. J Agric Food Chem. 2013; 61(45):10730-40. DOI: 10.1021/jf403479c. View

11.

Gebreyohannes G, Nyerere A, Bii C, Sbhatu D . Challenges of intervention, treatment, and antibiotic resistance of biofilm-forming microorganisms. Heliyon. 2019; 5(8):e02192. PMC: 6709409. DOI: 10.1016/j.heliyon.2019.e02192. View

12.

Yang R, Xue Z, Li X, Xu T, Zhong Y, Hu S . Novel natural osthole-inspired amphiphiles as membrane targeting antibacterials against methicillin-resistant Staphylococcus aureus (MRSA). Eur J Med Chem. 2024; 271:116449. DOI: 10.1016/j.ejmech.2024.116449. View

13.

Chaudhary S, Ali Z, Tehseen M, Haney E, Pantoja-Angles A, Alshehri S . Efficient in planta production of amidated antimicrobial peptides that are active against drug-resistant ESKAPE pathogens. Nat Commun. 2023; 14(1):1464. PMC: 10020429. DOI: 10.1038/s41467-023-37003-z. View

14.

Smith W, Wucher B, Nadell C, Foster K . Bacterial defences: mechanisms, evolution and antimicrobial resistance. Nat Rev Microbiol. 2023; 21(8):519-534. DOI: 10.1038/s41579-023-00877-3. View

15.

Puttaraju K, Shivashankar K, Chandra , Mahendra M, Rasal V, Venkata Vivek P . Microwave assisted synthesis of dihydrobenzo[4,5]imidazo[1,2-a]pyrimidin-4-ones; synthesis, in vitro antimicrobial and anticancer activities of novel coumarin substituted dihydrobenzo[4,5]imidazo[1,2-a]pyrimidin-4-ones. Eur J Med Chem. 2013; 69:316-22. DOI: 10.1016/j.ejmech.2013.07.015. View

16.

Zhu Y, Hao W, Wang X, Ouyang J, Deng X, Yu H . Antimicrobial peptides, conventional antibiotics, and their synergistic utility for the treatment of drug-resistant infections. Med Res Rev. 2022; 42(4):1377-1422. DOI: 10.1002/med.21879. View

17.

Lin S, Koh J, Aung T, Sin W, Lim F, Wang L . Semisynthetic Flavone-Derived Antimicrobials with Therapeutic Potential against Methicillin-Resistant Staphylococcus aureus (MRSA). J Med Chem. 2017; 60(14):6152-6165. DOI: 10.1021/acs.jmedchem.7b00380. View

18.

Silva A, Guimaraes M, Rabelo J, Belen L, Perecin C, Farias J . Recent advances in the design of antimicrobial peptide conjugates. J Mater Chem B. 2022; 10(19):3587-3600. DOI: 10.1039/d1tb02757c. View

19.

Fu J, Liu T, Feng X, Zhou Y, Chen M, Wang W . A Perfect Pair: Stabilized Black Phosphorous Nanosheets Engineering with Antimicrobial Peptides for Robust Multidrug Resistant Bacteria Eradication. Adv Healthc Mater. 2022; 11(10):e2101846. DOI: 10.1002/adhm.202101846. View

20.

Symeonidis T, Fylaktakidou K, Hadjipavlou-Litina D, Litinas K . Synthesis and anti-inflammatory evaluation of novel angularly or linearly fused coumarins. Eur J Med Chem. 2009; 44(12):5012-7. DOI: 10.1016/j.ejmech.2009.09.004. View