A comprehensive overview of the medicinal chemistry of antifungal drugs: perspectives and promise

Howard, Kaitlind C.; Dennis, Emily K.; Watt, David S.; Garneau‐Tsodikova, Sylvie

doi:10.1039/c9cs00556k

Cited by 93 publications

(88 citation statements)

References 259 publications

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“…Such AAGs target bacterial and/or fungal membranes. The identification of non-antibacterial antifungal AAGs targeting fungal membranes demonstrates that the main targets of AAGs can be discriminated [ 121 , 122 , 123 , 124 , 125 , 126 , 127 ]. This selectivity could be found in the difference between monoalkylated and di- or tri-alkylated derivatives of similar lipophilicities.…”

Section: Discussionmentioning

confidence: 99%

“…Recent years saw the expansion of AAGs in the search for new antifungal agents and probes for related mechanistic studies. The corresponding advances were reviewed in 2020 [ 121 ]. AAGs were shown to disrupt fungal cell membranes.…”

Section: Other Biological Activities Of Aagsmentioning

confidence: 99%

“…Their development, through the delineation of structure–activity relationships, led to the novel antifungal agent K20 ( Figure 13 ), which is capable of inhibiting many fungal species such as Fusarium graminearum , the causal agent in wheat Fusarium head blight (FHB) [ 122 , 123 , 124 , 125 , 126 , 127 , 128 ]. Plasma membrane permeabilization is probably the principal antifungal mechanism of action of AAGs, leading to the suggestion that they mechanistically and structurally comprise a novel class of antifungal agents [ 121 , 124 , 127 ].…”

Section: Other Biological Activities Of Aagsmentioning

confidence: 99%

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Amphiphilic Aminoglycosides as Medicinal Agents

Dezanet

Kempf

Mingeot‐Leclercq

et al. 2020

IJMS

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The conjugation of hydrophobic group(s) to the polycationic hydrophilic core of the antibiotic drugs aminoglycosides (AGs), targeting ribosomal RNA, has led to the development of amphiphilic aminoglycosides (AAGs). These drugs exhibit numerous biological effects, including good antibacterial effects against susceptible and multidrug-resistant bacteria due to the targeting of bacterial membranes. In the first part of this review, we summarize our work in identifying and developing broad-spectrum antibacterial AAGs that constitute a new class of antibiotic agents acting on bacterial membranes. The target-shift strongly improves antibiotic activity against bacterial strains that are resistant to the parent AG drugs and to antibiotic drugs of other classes, and renders the emergence of resistant Pseudomonas aeruginosa strains highly difficult. Structure–activity and structure–eukaryotic cytotoxicity relationships, specificity and barriers that need to be crossed in their development as antibacterial agents are delineated, with a focus on their targets in membranes, lipopolysaccharides (LPS) and cardiolipin (CL), and the corresponding mode of action against Gram-negative bacteria. At the end of the first part, we summarize the other recent advances in the field of antibacterial AAGs, mainly published since 2016, with an emphasis on the emerging AAGs which are made of an AG core conjugated to an adjuvant or an antibiotic drug of another class (antibiotic hybrids). In the second part, we briefly illustrate other biological and biochemical effects of AAGs, i.e., their antifungal activity, their use as delivery vehicles of nucleic acids, of short peptide (polyamide) nucleic acids (PNAs) and of drugs, as well as their ability to cleave DNA at abasic sites and to inhibit the functioning of connexin hemichannels. Finally, we discuss some aspects of structure–activity relationships in order to explain and improve the target selectivity of AAGs.

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Section: Discussionmentioning

confidence: 99%

Section: Other Biological Activities Of Aagsmentioning

confidence: 99%

Section: Other Biological Activities Of Aagsmentioning

confidence: 99%

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Amphiphilic Aminoglycosides as Medicinal Agents

Dezanet

Kempf

Mingeot‐Leclercq

et al. 2020

IJMS

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“…This is largely due to the increase in the population of immunocompromised individuals. Several factors contribute to such increase, such as HIV infection, tuberculosis, leukaemia, immunosuppressive therapy, cancer chemotherapy, organ transplantation, or the use of broad-spectrum antibiotics [2]. In these individuals, a common infection can easily become fatal if the disease is prolonged [3].…”

Section: Introductionmentioning

confidence: 99%

Structural and Bioactivity Characterization of Filipin Derivatives from Engineered Streptomyces filipinensis Strains Reveals Clues for Reduced Haemolytic Action

et al. 2020

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The rise in the number of immunocompromised patients has led to an increased incidence of fungal infections, with high rates of morbidity and mortality. Furthermore, misuse of antifungals has boosted the number of resistant strains to these agents; thus, there is urgent need for new drugs against these infections. Here, the in vitro antifungal activity of filipin III metabolic intermediates has been characterized against a battery of opportunistic pathogenic fungi—Candida albicans, Candida glabrata, Candida krusei, Cryptococcus neoformans, Trichosporon cutaneum, Trichosporon asahii, Aspergillus nidulans, Aspergillus niger, and Aspergillus fumigatus—using the Clinical and Laboratory Standards Institute broth microdilution method. Structural characterization of these compounds was undertaken by mass spectrometry (MS) and nuclear magnetic resonance (NMR) following HPLC purification. Complete NMR assignments were obtained for the first time for filipins I and II. In vitro haemolytic assays revealed that the haemolytic action of these compounds relies largely on the presence of a hydroxyl function at C26, since derivatives lacking such moiety show remarkably reduced activity. Two of these derivatives, 1′-hydroxyfilipin I and filipin I, show decreased toxicity towards cholesterol-containing membranes while retaining potent antifungal activity, and could constitute excellent leads for the development of efficient pharmaceuticals, particularly against Cryptococcosis.

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“…Despite this gamut of hurdles, the complexity of fungal cell architecture offers an array of as yet, unexplored targets for drug development. Prior efforts by multiple investigators focused on antifungal agents [6a,11] possessing chemically diverse scaffolds including aminoglycosides, [12] benzimidazoles, [12d,13] azoles, [14] haloperidols, [15] gold(I) complexes, [16] and ebselen/ebsulfur [17] . We now report the development of fluorinated, aryl‐ and heteroaryl‐substituted hydrazones as compounds that meet these challenges and represent a new class of potential agents for the selective treatment of candidiasis [18] .…”

Section: Introductionmentioning

confidence: 99%

Broad‐Spectrum Antifungal Agents: Fluorinated Aryl‐ and Heteroaryl‐Substituted Hydrazones

et al. 2020

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Fluorinated aryl‐ and heteroaryl‐substituted monohydrazones displayed excellent broad‐spectrum activity against various fungal strains, including a panel of clinically relevant Candida auris strains relative to a control antifungal agent, voriconazole (VRC). These monohydrazones displayed less hemolysis of murine red blood cells than that of VRC at the same concentrations, possessed fungicidal activity in a time‐kill study, and exhibited no mammalian cell cytotoxicity. In addition, these monohydrazones prevented the formation of biofilms that otherwise block antibiotic effectiveness and did not trigger the development of resistance when exposed to C. auris AR Bank # 0390 over 15 passages.

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A comprehensive overview of the medicinal chemistry of antifungal drugs: perspectives and promise

Abstract: The emergence of new fungal pathogens makes the development of new antifungal drugs a medical imperative that in recent years motivates the talents of numerous investigators across the world.

Cited by 93 publications

References 259 publications

Amphiphilic Aminoglycosides as Medicinal Agents

Amphiphilic Aminoglycosides as Medicinal Agents

Structural and Bioactivity Characterization of Filipin Derivatives from Engineered Streptomyces filipinensis Strains Reveals Clues for Reduced Haemolytic Action

Broad‐Spectrum Antifungal Agents: Fluorinated Aryl‐ and Heteroaryl‐Substituted Hydrazones

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