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Advances in Medicinal Chemistry of Antifungals
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Advances in Medicinal Chemistry of Antifungals

A special issue of Molecules (ISSN 1420-3049).

Deadline for manuscript submissions: closed (30 October 2013) | Viewed by 96891

Special Issue Editor

Dr. Malgorzata Kostecka

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Guest Editor
Faculty of Food Science and Biotechnology, University of Life Science, ul. Akademicka 15, 20-950 Lublin, Poland
Interests: dietary patterns; complementary feeding; nutrition of infants, children, and adolescents; relationship between nutrition and healthy development of children or quality of life; nutrition knowledge
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

The past decade witnessed numerous advancements in research efforts aiming to synthesize new compounds with antibacterial, antiviral, antifungal, anti-tuberculosis and anti-malaria properties. Those efforts are undertaken to engineer modern fungicides, pesticides and drugs with a broad spectrum of activity and low toxicity for which resistance had not developed. The search for new antifungal drugs is spurred by the dramatic increase in the incidence of fungal infections, growing primary and secondary resistance to popular drugs and the emergence of strains with decreased sensitivity. Molds are the serious problem in modern agriculture. Fusarium infections have been long studied in grain. Recent years witnessed a significant increase in the number of mold contaminations in farm crops and a growing content of mycotoxins, toxic fungal metabolites, in grain. Newest research findings have demonstrated that food and feed contamination may cause serious diseases affecting humans and animals. Fungicides are applied to limit the harmful effects of mycotoxins. The prolonged use of standard combinations of crop protection agents is not always effective.

This special issue is aimed at presenting promising experimental data on structure- lipophilicity- biological activity relationships (SAR). Molecules can be structurally modified with various substituents to produce derivatives whose fungicidal activity is superior to popular fungicides or drugs. New synthesis of compounds with high biological activity should be chance on braving microorganisms.

Dr. Małgorzata Kostecka
Guest Editor

Keywords

  • antifungal agents
  • synthesis
  • molds
  • hydrazides

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Published Papers (9 papers)

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Research

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14 pages, 494 KiB  
Article
Design and Synthesis of N1,N5-bis[4-(5-Alkyl-1,2,4-oxadiazol-3-yl)phenyl]glutaramides as Potential Antifungal Prodrugs
by Nageswara Rao Kode, Jean Jacques Vanden Eynde, Annie Mayence, Guangdi Wang and Tien L. Huang
Molecules 2013, 18(9), 11250-11263; https://doi.org/10.3390/molecules180911250 - 12 Sep 2013
Cited by 11 | Viewed by 6495
Abstract
A facile three step synthesis of a group of N1,N5-bis[4-(5-alkyl-1,2,4-oxadiazol-3-yl)phenyl]glutaramides, N1,N5-bis[4-(1,2,4-oxadiazol-3-yl)phenyl]glutaramide and N1,N5-bis[4-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)phenyl]glutaramide is described. These products are designed to function as masked bis-amidine prodrugs of a promising N1,N5-bis[4-(N'-(carbamimidoyl)phenyl]glutaramide antifungal lead. Full article
(This article belongs to the Special Issue Advances in Medicinal Chemistry of Antifungals)
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22 pages, 719 KiB  
Article
Targeting the Mitochondrial Respiratory Chain of Cryptococcus through Antifungal Chemosensitization: A Model for Control of Non-Fermentative Pathogens
by Jong H. Kim, Ronald P. Haff, Natália C. G. Faria, Maria De L. Martins, Kathleen L. Chan and Bruce C. Campbell
Molecules 2013, 18(8), 8873-8894; https://doi.org/10.3390/molecules18088873 - 25 Jul 2013
Cited by 19 | Viewed by 7763
Abstract
Enhanced control of species of Cryptococcus, non-fermentative yeast pathogens, was achieved by chemosensitization through co-application of certain compounds with a conventional antimicrobial drug. The species of Cryptococcus tested showed higher sensitivity to mitochondrial respiratory chain (MRC) inhibition compared to species of Candida [...] Read more.
Enhanced control of species of Cryptococcus, non-fermentative yeast pathogens, was achieved by chemosensitization through co-application of certain compounds with a conventional antimicrobial drug. The species of Cryptococcus tested showed higher sensitivity to mitochondrial respiratory chain (MRC) inhibition compared to species of Candida. This higher sensitivity results from the inability of Cryptococcus to generate cellular energy through fermentation. To heighten disruption of cellular MRC, octyl gallate (OG) or 2,3-dihydroxybenzaldehyde (2,3-DHBA), phenolic compounds inhibiting mitochondrial functions, were selected as chemosensitizers to pyraclostrobin (PCS; an inhibitor of complex III of MRC). The cryptococci were more susceptible to the chemosensitization (i.e., PCS + OG or 2,3-DHBA) than the Candida with all Cryptococcus strains tested being sensitive to this chemosensitization. Alternatively, only few of the Candida strains showed sensitivity. OG possessed higher chemosensitizing potency than 2,3-DHBA, where the concentration of OG required with the drug to achieve chemosensitizing synergism was much lower than that required of 2,3-DHBA. Bioassays with gene deletion mutants of the model yeast Saccharomyces cerevisiae showed that OG or 2,3-DHBA affect different cellular targets. These assays revealed mitochondrial superoxide dismutase or glutathione homeostasis plays a relatively greater role in fungal tolerance to 2,3-DHBA or OG, respectively. These findings show that application of chemosensitizing compounds that augment MRC debilitation is a promising strategy to antifungal control against yeast pathogens. Full article
(This article belongs to the Special Issue Advances in Medicinal Chemistry of Antifungals)
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16 pages, 236 KiB  
Article
Antifungal Activity of Thymus vulgaris L. Essential Oil and Its Constituent Phytochemicals against Rhizopus oryzae: Interaction with Ergosterol
by Kelly Samara De Lira Mota, Fillipe De Oliveira Pereira, Wylly Araújo De Oliveira, Igara Oliveira Lima and Edeltrudes De Oliveira Lima
Molecules 2012, 17(12), 14418-14433; https://doi.org/10.3390/molecules171214418 - 5 Dec 2012
Cited by 154 | Viewed by 11500
Abstract
Mucormycoses are emerging infections that have high rates of morbidity and mortality. They show high resistance to antifungal agents, and there is a limited therapeutic arsenal currently available, therefore, there is a great need to give priority to testing therapeutic agents for the [...] Read more.
Mucormycoses are emerging infections that have high rates of morbidity and mortality. They show high resistance to antifungal agents, and there is a limited therapeutic arsenal currently available, therefore, there is a great need to give priority to testing therapeutic agents for the treatment of mucormycosis. Along this line, the use of essential oils and phytoconstituents has been emphasized as a new therapeutic approach. The objective of this work was to investigate the antifungal activity of the essential oil (EO) of Thymus vulgaris, and its constituents thymol and p-cymene against Rhizopus oryzae, through microbiological screening, determination of minimal inhibitory concentration (MICs) and minimal fungicidal concentration (MFCs), effects on mycelial growth and germination of sporangiospores and interaction with ergosterol. The MIC of EO and thymol varied 128–512 µg/mL, but the MFC of EO and thymol varied 512–1024 µg/mL and 128–1024 µg/mL, respectively. The results also showed that EO and thymol significantly inhibited mycelial development and germination of sporangiospores. Investigation of the mechanism of antifungal action showed that EO and thymol interact with ergosterol. These data indicate that EO of T. vulgaris and thymol possess strong antifungal activity, which can be related to their interaction with ergosterol, supporting the possible use of these products in the treatment of mucormycosis. Full article
(This article belongs to the Special Issue Advances in Medicinal Chemistry of Antifungals)
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15 pages, 303 KiB  
Article
Antifungal Activity of Homoaconitate and Homoisocitrate Analogs
by Maria J. Milewska, Marta Prokop, Iwona Gabriel, Marek Wojciechowski and Sławomir Milewski
Molecules 2012, 17(12), 14022-14036; https://doi.org/10.3390/molecules171214022 - 27 Nov 2012
Cited by 10 | Viewed by 6385
Abstract
Thirteen structural analogs of two initial intermediates of the L-a-aminoadipate pathway of L-lysine biosynthesis in fungi have been designed and synthesized, including fluoro- and epoxy-derivatives of homoaconitate and homoisocitrate. Some of the obtained compounds exhibited at milimolar range moderate enzyme inhibitory properties against [...] Read more.
Thirteen structural analogs of two initial intermediates of the L-a-aminoadipate pathway of L-lysine biosynthesis in fungi have been designed and synthesized, including fluoro- and epoxy-derivatives of homoaconitate and homoisocitrate. Some of the obtained compounds exhibited at milimolar range moderate enzyme inhibitory properties against homoaconitase and/or homoisocitrate dehydrogenase of Candida albicans. The structural basis for homoisocitrate dehydrogenase inhibition was revealed by molecular modeling of the enzyme-inhibitor complex. On the other hand, the trimethyl ester forms of some of the novel compounds exhibited antifungal effects. The highest antifungal activity was found for trimethyl trans-homoaconitate, which inhibited growth of some human pathogenic yeasts with minimal inhibitory concentration (MIC) values of 16–32 mg/mL. Full article
(This article belongs to the Special Issue Advances in Medicinal Chemistry of Antifungals)
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20 pages, 263 KiB  
Article
Investigation of the Biological Properties of (Hetero)Aromatic Thiosemicarbazones
by Maciej Serda, Anna Mrozek-Wilczkiewicz, Josef Jampilek, Matus Pesko, Katarina Kralova, Marcela Vejsova, Robert Musiol, Alicja Ratuszna and Jaroslaw Polanski
Molecules 2012, 17(11), 13483-13502; https://doi.org/10.3390/molecules171113483 - 14 Nov 2012
Cited by 28 | Viewed by 6886
Abstract
Two series of thiosemicarbazone-based iron chelators (twenty-seven compounds) were designed and synthesized using a microwave-assisted approach. Quinoline and halogenated phenyl were selected as parent scaffolds on the basis of a similarity search. The lipophilicity of the synthesized compounds was measured using HPLC and [...] Read more.
Two series of thiosemicarbazone-based iron chelators (twenty-seven compounds) were designed and synthesized using a microwave-assisted approach. Quinoline and halogenated phenyl were selected as parent scaffolds on the basis of a similarity search. The lipophilicity of the synthesized compounds was measured using HPLC and then calculated. Primary in vitro screening of the synthesized compounds was performed against eight pathogenic fungal strains. Only a few compounds showed moderate activity against fungi, and (E)-2-(quinolin-2-ylvinyl)-N,N-dimethylhydrazine-carbothioamide appeared to be more effective than fluconazole against most of the fungal strains tested. Antiproliferative activity was measured using a human colon cancer cell line (HCT-116). Several of the tested compounds showed submicromolar antiproliferative activity. Compounds were also tested for their activity related to the inhibition of photosynthetic electron transport (PET) in spinach (Spinacia oleracea L.) chloroplasts. The structure-activity relationships are discussed for all of the compounds. Full article
(This article belongs to the Special Issue Advances in Medicinal Chemistry of Antifungals)
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17 pages, 252 KiB  
Article
Antifungal Activity of Salicylanilides and Their Esters with 4-(Trifluoromethyl)benzoic Acid
by Martin Krátký and Jarmila Vinšová
Molecules 2012, 17(8), 9426-9442; https://doi.org/10.3390/molecules17089426 - 7 Aug 2012
Cited by 40 | Viewed by 8868
Abstract
Searching for novel antimicrobial agents still represents a current topic in medicinal chemistry. In this study, the synthesis and analytical data of eighteen salicylanilide esters with 4-(trifluoromethyl)benzoic acid are presented. They were assayed in vitro as potential antimycotic agents against eight fungal strains, [...] Read more.
Searching for novel antimicrobial agents still represents a current topic in medicinal chemistry. In this study, the synthesis and analytical data of eighteen salicylanilide esters with 4-(trifluoromethyl)benzoic acid are presented. They were assayed in vitro as potential antimycotic agents against eight fungal strains, along with their parent salicylanilides. The antifungal activity of the presented derivatives was not uniform and moulds showed a higher susceptibility with minimum inhibitory concentrations (MIC) ³ 0.49 µmol/L than yeasts (MIC ³ 1.95 µmol/L). However, it was not possible to evaluate a range of 4-(trifluoromethyl)benzoates due to their low solubility. In general, the most active salicylanilide was N-(4-bromophenyl)-4-chloro-2-hydroxybenzamide and among esters, the corresponding 2-(4-bromophenylcarbamoyl)-5-chlorophenyl 4-(trifluoromethyl) benzoate exhibited the lowest MIC of 0.49 µmol/L. However, the esterification of salicylanilides by 4-(trifluoromethyl)benzoic acid did not result unequivocally in a higher antifungal potency. Full article
(This article belongs to the Special Issue Advances in Medicinal Chemistry of Antifungals)
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14 pages, 250 KiB  
Article
Synthesis of a New Group of Aliphatic Hydrazide Derivatives and the Correlations between Their Molecular Structure and Biological Activity
by Małgorzata Kostecka
Molecules 2012, 17(3), 3560-3573; https://doi.org/10.3390/molecules17033560 - 22 Mar 2012
Cited by 8 | Viewed by 5862
Abstract
In view of the growing demand for new compounds showing biological activity against pathogenic microorganisms, such as pathogenic and phytopathogenic fungi, the objective of this study was to synthesize a new group of aliphatic and aromatic derivatives of hydrazide. In consequence of the [...] Read more.
In view of the growing demand for new compounds showing biological activity against pathogenic microorganisms, such as pathogenic and phytopathogenic fungi, the objective of this study was to synthesize a new group of aliphatic and aromatic derivatives of hydrazide. In consequence of the reactions observed during synthesis, the resulting compounds retained their linear structure. Their structure and lipophilicity, measured by high-performance liquid chromatography (HPLC), were analyzed. Correlations were determined between the compounds’ molecular parameters and biological activity against Fusarium solani and Fusarium oxysporum fungi. The investigated compounds were also examined for their antifungal activity against Aspergillus fumigatus. The obtained results indicate that compounds with fluorine-containing substituents penetrate the cell structure more effectively and are characterized by higher antifungal potential than analogues with different substituents. Full article
(This article belongs to the Special Issue Advances in Medicinal Chemistry of Antifungals)
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Review

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32 pages, 663 KiB  
Review
Early State Research on Antifungal Natural Products
by Melyssa Negri, Tânia P. Salci, Cristiane S. Shinobu-Mesquita, Isis R. G. Capoci, Terezinha I. E. Svidzinski and Erika Seki Kioshima
Molecules 2014, 19(3), 2925-2956; https://doi.org/10.3390/molecules19032925 - 7 Mar 2014
Cited by 89 | Viewed by 15365
Abstract
Nosocomial infections caused by fungi have increased greatly in recent years, mainly due to the rising number of immunocompromised patients. However, the available antifungal therapeutic arsenal is limited, and the development of new drugs has been slow. Therefore, the search for alternative drugs [...] Read more.
Nosocomial infections caused by fungi have increased greatly in recent years, mainly due to the rising number of immunocompromised patients. However, the available antifungal therapeutic arsenal is limited, and the development of new drugs has been slow. Therefore, the search for alternative drugs with low resistance rates and fewer side effects remains a major challenge. Plants produce a variety of medicinal components that can inhibit pathogen growth. Studies of plant species have been conducted to evaluate the characteristics of natural drug products, including their sustainability, affordability, and antimicrobial activity. A considerable number of studies of medicinal plants and alternative compounds, such as secondary metabolites, phenolic compounds, essential oils and extracts, have been performed. Thus, this review discusses the history of the antifungal arsenal, surveys natural products with potential antifungal activity, discusses strategies to develop derivatives of natural products, and presents perspectives on the development of novel antifungal drug candidates. Full article
(This article belongs to the Special Issue Advances in Medicinal Chemistry of Antifungals)
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35 pages, 381 KiB  
Review
Invasive Fungal Infections in the ICU: How to Approach, How to Treat
by Elisabeth Paramythiotou, Frantzeska Frantzeskaki, Aikaterini Flevari, Apostolos Armaganidis and George Dimopoulos
Molecules 2014, 19(1), 1085-1119; https://doi.org/10.3390/molecules19011085 - 17 Jan 2014
Cited by 120 | Viewed by 26763
Abstract
Invasive fungal infections are a growing problem in critically ill patients and are associated with increased morbidity and mortality. Most of them are due to Candida species, especially Candida albicans. Invasive candidiasis includes candidaemia, disseminated candidiasis with deep organ involvement and chronic disseminated [...] Read more.
Invasive fungal infections are a growing problem in critically ill patients and are associated with increased morbidity and mortality. Most of them are due to Candida species, especially Candida albicans. Invasive candidiasis includes candidaemia, disseminated candidiasis with deep organ involvement and chronic disseminated candidiasis. During the last decades rare pathogenic fungi, such as Aspergillus species, Zygomycetes, Fusarium species and Scedosporium have also emerged. Timely diagnosis and proper treatment are of paramount importance for a favorable outcome. Besides blood cultures, several laboratory tests have been developed in the hope of facilitating an earlier detection of infection. The antifungal armamentarium has also been expanded allowing a treatment choice tailored to individual patients’ needs. The physician can choose among the old class of polyenes, the older and newer azoles and the echinocandins. Factors related to patient’s clinical situation and present co-morbidities, local epidemiology data and purpose of treatment (prophylactic, pre-emptive, empiric or definitive) should be taken into account for the appropriate choice of antifungal agent. Full article
(This article belongs to the Special Issue Advances in Medicinal Chemistry of Antifungals)
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