Designing New Antimicrobials Based on Known Valuable Heterocycles as Building Blocks

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Dear Colleagues,

Heterocycles are essential structural components in various antimicrobial drugs. The significance of heterocycles in drug design resides in their ability to modify the drug candidate’s physicochemical characteristics, biological impact, and pharmacokinetic and toxicological profile. Numerous recent studies have targeted therapeutic agents with heterocycle-based structures. In the last decade, diverse heterocyclic compounds have been synthesized to develop new antimicrobials capable of treating bacterial, viral, fungal, or parasitic infections. The physicochemical properties imparted by a heterocycle are associated with the biological activity of the drug (the spectrum of activity and potency) and its pharmacokinetic, pharmacologic, and toxicological profiles. Highlighting the relationships between heterocycles in the molecular structure of antimicrobial drugs and their biological properties can serve as the basis for many other rational design studies for discovering new antimicrobials (antibiotics, antivirals, antifungals, and antiparasitics). Incorporating valuable heterocycles into the molecular structure of antimicrobials represents a promising avenue for advancing drug development. It offers opportunities to enhance drug efficacy, safety, and diversity, which is crucial in the ongoing battle with infections, parasitosis, and resistance to antimicrobials. As a result of drug resistance in bacteria, fungi, HIV, tuberculosis, malaria, and tropical diseases, antibiotics and other antimicrobial drugs become ineffective, and infections become difficult or impossible to treat, increasing the risk of disease, severe illness, disability, and death.

This Topic focuses on the rational design of novel antimicrobials by leveraging the structural diversity and pharmacological potential of known valuable heterocycles as fundamental building blocks. Continued research is essential to translate all promising findings into effective treatments that benefit global public health. The proposed Topic aims to identify the latest trends in discovering new antimicrobials based on valuable heterocycles as building blocks and will welcome both research papers and reviews.

Prof. Dr. Aura Rusu
Prof. Dr. Gabriel Hancu
Dr. Vladimír Garaj
Topic Editors

Keywords

Participating Journals

Journal Name	Impact Factor	CiteScore	Launched Year	First Decision (median)	APC
Antibiotics antibiotics	4.6	8.7	2012	15 Days	CHF 2900
International Journal of Molecular Sciences ijms	4.9	9.0	2000	20.5 Days	CHF 2900
Molecules molecules	4.6	8.6	1996	16.1 Days	CHF 2700
Pharmaceutics pharmaceutics	5.5	10.0	2009	14.9 Days	CHF 2900
Scientia Pharmaceutica scipharm	2.5	4.6	1930	38.1 Days	CHF 1000
Biophysica biophysica	1.4	2.3	2021	22.9 Days	CHF 1200

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Published Papers (3 papers)

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All Antibiotics IJMS Molecules Pharmaceutics Sci. Pharm. Biophysica

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Open AccessArticle

New Derivatives of Chalcones, Chromenes, and Stilbenoids, Complexed with Methyl-β-Cyclodextrin with Antioxidant Properties and Antibacterial Synergism with Antibiotics

by Igor D. Zlotnikov, Sergey S. Krylov, Natalya G. Belogurova, Alexander N. Blinnikov, Victor E. Kalugin and Elena V. Kudryashova

Biophysica 2024, 4(4), 667-694; https://doi.org/10.3390/biophysica4040044 - 13 Dec 2024

Cited by 1 | Viewed by 1171

Abstract

Cyclodextrins (CDs) are natural cyclic oligosaccharides with the ability to form inclusion complexes with various organic substances. In this paper, we investigate the potential of CD complex formation to enhance the antibacterial activity and antioxidant properties of poorly soluble bioactive agents, such as [...] Read more.

Cyclodextrins (CDs) are natural cyclic oligosaccharides with the ability to form inclusion complexes with various organic substances. In this paper, we investigate the potential of CD complex formation to enhance the antibacterial activity and antioxidant properties of poorly soluble bioactive agents, such as chalcones, chromenes, stilbenoids and xanthylium derivatives, serving as potential adjuvants, in comparison with standard antiseptics. The interaction of these bioactive agents with the hydrophobic pocket of methyl-β-cyclodextrin (MCD) was confirmed using spectroscopic methods such as UV-vis, FTIR, ¹H and ¹³C NMR, mass-spectrometry. CD-based delivery system allows for combining multiple active agents, improving solubility, antibacterial efficacy by enhancing penetration into target bacterial cells (E. coli selectivity demonstrated via confocal microscopy). Novel compounds of chalcones and stilbenoids derivatives additionally enhance efficacy by inhibiting bacterial efflux pumps, increasing membrane permeability, and inhibiting bacterial enzymes, and showed a synergy when used in combination with metronidazole. The intricate relationship between the structural characteristics and functional properties of chalcones and stilbenoids in terms of their antibacterial and antioxidative capabilities is revealed. The substituents within aromatic rings significantly influence this activity, where position of electron-donating methoxy groups playing a crucial role. Among chalcones, stilbenoids, ana xanthyliums, the compounds caring a benzodioxol ring, analogous to natural bioactive compounds like apiol, dillapiol, and myristicin, emerge as prominent antibacterial activity. To explore the possibility to create theranostic formulations, we used fluorescent markers to visualize target cells, antiseptics to provide antibacterial activity, and bioactive agents as chalcones acting as adjuvants. Additionally, new antioxidant compounds were found such as Xanthylium derivative (R351) and chromene derivative: 1-methyl-3-(2-amino-3-cyano-7-methoxychromene-4-yl)-pyridinium methanesulfate: the pronounced antioxidant properties of these substances are observed comparable to quercetin in the efficiency. Rhodamine 6G, gentian violet, and Congo Red exhibit good antioxidant properties, although their activity is an order of magnitude lower than that of quercetin. However, they have remarkable potential due to their multifaceted nature, including the ability to visualize target cells. The most effective theranostic formulation is the combination of the antibiotic (metronidazole) + dye/fluorophore (methylene blue/rhodamine 6G) for visualization of target cells + adjuvant (chalcones or xanthylium derivatives) for antiinflammation effect. This synergistic combination, results in a promising theranostic formulation for treating bacterial infections, with enhanced efficiency, selectivity and minimizing side effects. Full article

(This article belongs to the Topic Designing New Antimicrobials Based on Known Valuable Heterocycles as Building Blocks)

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Open AccessReview

Unlocking the Potential of Pyrrole: Recent Advances in New Pyrrole-Containing Compounds with Antibacterial Potential

by Aura Rusu, Octavia-Laura Oancea, Corneliu Tanase and Livia Uncu

Int. J. Mol. Sci. 2024, 25(23), 12873; https://doi.org/10.3390/ijms252312873 - 29 Nov 2024

Cited by 4 | Viewed by 4614

Abstract

Nitrogen heterocycles are valuable structural elements in the molecules of antibacterial drugs approved and used to treat bacterial infections. Pyrrole is a five-atom heterocycle found in many natural compounds with biological activity, including antibacterial activity. Numerous compounds are being develop based on the [...] Read more.

Nitrogen heterocycles are valuable structural elements in the molecules of antibacterial drugs approved and used to treat bacterial infections. Pyrrole is a five-atom heterocycle found in many natural compounds with biological activity, including antibacterial activity. Numerous compounds are being develop based on the pyrrole heterocycle as new potential antibacterial drugs. Due to the phenomenon of antibacterial resistance, there is a continuous need to create new effective antibacterials. In the scientific literature, we have identified the most relevant studies that aim to develop new compounds, such as pyrrole derivatives, that are proven to have antibacterial activity. Nature is an endless reservoir of inspiration for designing new compounds based on the structure of pyrrole heterocycles such as calcimycin, lynamycins, marinopyrroles, nargenicines, phallusialides, and others. However, many other synthetic compounds based on the pyrrole heterocycle have been developed and can be optimized in the future. The identified compounds were classified according to the type of chemical structure. The chemical structure–activity relationships, mechanisms of action, and antibacterial effectiveness of the most valuable compounds were highlighted. This review highlights scientific progress in designing new pyrrole-containing compounds and provides examples of lead compounds that can be successfully optimized further. Full article

(This article belongs to the Topic Designing New Antimicrobials Based on Known Valuable Heterocycles as Building Blocks)

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15 pages, 1918 KiB  

Open AccessArticle

Imidazoquinoline Derivatives as Potential Inhibitors of InhA Enzyme and Mycobacterium tuberculosis

by Pascal Hoffmann, Joëlle Azéma-Despeyroux, Fernanda Goncalves, Alessandro Stamilla, Nathalie Saffon-Merceron, Frédéric Rodriguez, Giulia Degiacomi, Maria Rosalia Pasca and Christian Lherbet

Molecules 2024, 29(13), 3076; https://doi.org/10.3390/molecules29133076 - 27 Jun 2024

Cited by 2 | Viewed by 1499

Abstract

Tuberculosis is a serious public health problem worldwide. The search for new antibiotics has become a priority, especially with the emergence of resistant strains. A new family of imidazoquinoline derivatives, structurally analogous to triazolophthalazines, which had previously shown good antituberculosis activity, were designed [...] Read more.

Tuberculosis is a serious public health problem worldwide. The search for new antibiotics has become a priority, especially with the emergence of resistant strains. A new family of imidazoquinoline derivatives, structurally analogous to triazolophthalazines, which had previously shown good antituberculosis activity, were designed to inhibit InhA, an essential enzyme for Mycobacterium tuberculosis survival. Over twenty molecules were synthesized and the results showed modest inhibitory efficacy against the protein. Docking experiments were carried out to show how these molecules could interact with the protein’s substrate binding site. Disappointingly, unlike triazolophthlazines, these imidazoquinoline derivatives showed an absence of inhibition on mycobacterial growth. Full article

(This article belongs to the Topic Designing New Antimicrobials Based on Known Valuable Heterocycles as Building Blocks)

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