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Antifungal Drug Design, Synthesis and Molecular Mechanisms

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Informatics".

Deadline for manuscript submissions: 25 August 2024 | Viewed by 1382

Special Issue Editor


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Guest Editor
National Key Laboratory of Green Pesticide, Key Laboratory of Green Pesticide and Agricultural Bioengineering, Ministry of Education, Center for R&D of Fine Chemicals of Guizhou University, Guiyang 550025, China
Interests: organic synthesis methodology of pesticides and functional molecules; mechanisms of active molecules

Special Issue Information

Dear Colleagues,

Phytopathogenic fungal infections are a major global threat to agricultural production, food security, and human health. More than 8000 species of fungi are known to cause plant diseases, of which they cause 85%, and contribute to huge economic crop losses. The antifungal compounds play a pivotal role in controlling fungal diseases. This Special Issue will from the perspective of molecular science focus on but not be limited to the discovery of natural products with antifungal activity, antifungal compound molecular structures derived from natural products, computer-aided drug design and synthesis of antifungal drugs, the molecular mechanism of action of antifungal drugs, and the development of fungal disease management strategies. We welcome well-prepared manuscripts of original research, review articles, and short communications from different fields, such as chemistry, biology, biochemistry, pharmacology, medicinal chemistry, and computational chemistry. The opportunity to capture all these views together in a Special Issue of the International Journal of Molecular Sciences is exciting. Our goal is to make this topic representative of the current state of knowledge in antifungal drug development.

Dr. Zhibing Wu
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

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Keywords

  • fungal diseases
  • antifungal compounds/agents
  • natural products
  • computer-aided drug design
  • synthetic compounds
  • mechanism of action
  • fungal disease management strategies

Published Papers (2 papers)

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Research

12 pages, 1639 KiB  
Article
Disclosing the Antifungal Mechanisms of the Cyclam Salt H4[H2(4-CF3PhCH2)2Cyclam]Cl4 against Candida albicans and Candida krusei
by Inês Costa, Inês Lopes, Mariana Morais, Renata Silva, Fernando Remião, Rui Medeiros, Luís G. Alves, Eugénia Pinto and Fátima Cerqueira
Int. J. Mol. Sci. 2024, 25(10), 5209; https://doi.org/10.3390/ijms25105209 - 10 May 2024
Viewed by 552
Abstract
Mycoses are one of the major causes of morbidity/mortality among immunocompromised individuals. Considering the importance of these infections, the World Health Organization (WHO) defined a priority list of fungi for health in 2022 that include Candida albicans as belonging to the critical priority [...] Read more.
Mycoses are one of the major causes of morbidity/mortality among immunocompromised individuals. Considering the importance of these infections, the World Health Organization (WHO) defined a priority list of fungi for health in 2022 that include Candida albicans as belonging to the critical priority group and Pichia kudriavzevii (Candida krusei) to the medium priority group. The existence of few available antifungal drugs, their high toxicity, the acquired fungal resistance, and the appearance of new species with a broader spectrum of resistance, points out the need for searching for new antifungals, preferably with new and multiple mechanisms of action. The cyclam salt H4[H2(4-CF3PhCH2)2Cyclam]Cl4 was previously tested against several fungi and revealed an interesting activity, with minimal inhibitory concentration (MIC) values of 8 µg/mL for C. krusei and of 128 µg/mL for C. albicans. The main objective of the present work was to deeply understand the mechanisms involved in its antifungal activity. The effects of the cyclam salt on yeast metabolic viability (resazurin reduction assay), yeast mitochondrial function (JC-1 probe), production of reactive oxygen species (DCFH-DA probe) and on intracellular ATP levels (luciferin/luciferase assay) were evaluated. H4[H2(4-CF3PhCH2)2Cyclam]Cl4 induced a significant decrease in the metabolic activity of both C. albicans and C. krusei, an increase in Reactive Oxygen Species (ROS) production, and an impaired mitochondrial function. The latter was observed by the depolarization of the mitochondrial membrane and decrease in ATP intracellular levels, mechanisms that seems to be involved in the antifungal activity of H4[H2(4-CF3PhCH2)2Cyclam]Cl4. The interference of the cyclam salt with human cells revealed a CC50 value against HEK-293 embryonic kidney cells of 1.1 μg/mL and a HC10 value against human red blood cells of 0.8 μg/mL. Full article
(This article belongs to the Special Issue Antifungal Drug Design, Synthesis and Molecular Mechanisms)
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36 pages, 5181 KiB  
Article
Synthesis, In Silico Study, and In Vitro Antifungal Activity of New 5-(1,3-Diphenyl-1H-Pyrazol-4-yl)-4-Tosyl-4,5-Dihydrooxazoles
by Neively Tlapale-Lara, Julio López, Elizabeth Gómez, Lourdes Villa-Tanaca, Edson Barrera, Carlos H. Escalante, Joaquín Tamariz, Francisco Delgado, Dulce Andrade-Pavón and Omar Gómez-García
Int. J. Mol. Sci. 2024, 25(10), 5091; https://doi.org/10.3390/ijms25105091 - 7 May 2024
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Abstract
The increase in multi-drug resistant Candida strains has caused a sharp rise in life-threatening fungal infections in immunosuppressed patients, including those with SARS-CoV-2. Novel antifungal drugs are needed to combat multi-drug-resistant yeasts. This study aimed to synthesize a new series of 2-oxazolines and [...] Read more.
The increase in multi-drug resistant Candida strains has caused a sharp rise in life-threatening fungal infections in immunosuppressed patients, including those with SARS-CoV-2. Novel antifungal drugs are needed to combat multi-drug-resistant yeasts. This study aimed to synthesize a new series of 2-oxazolines and evaluate the ligands in vitro for the inhibition of six Candida species and in silico for affinity to the CYP51 enzymes (obtained with molecular modeling and protein homology) of the same species. The 5-(1,3-diphenyl-1H-pyrazol-4-yl)-4-tosyl-4,5-dihydrooxazoles 6a-j were synthesized using the Van Leusen reaction between 1,3-diphenyl-4-formylpyrazoles 4a-j and TosMIC 5 in the presence of K2CO3 or KOH without heating, resulting in short reaction times, high compound purity, and high yields. The docking studies revealed good affinity for the active site of the CYP51 enzymes of the Candida species in the following order: 6a-j > 4a-j > fluconazole (the reference drug). The in vitro testing of the compounds against the Candida species showed lower MIC values for 6a-j than 4a-j, and for 4a-j than fluconazole, thus correlating well with the in silico findings. According to growth rescue assays, 6a-j and 4a-j (like fluconazole) inhibit ergosterol synthesis. The in silico toxicity assessment evidenced the safety of compounds 6a-j, which merit further research as possible antifungal drugs. Full article
(This article belongs to the Special Issue Antifungal Drug Design, Synthesis and Molecular Mechanisms)
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