Identification of Thiazoyl Guanidine Derivatives as Novel Antifungal Agents Inhibiting Ergosterol Biosynthesis for Treatment of Invasive Fungal Infections

Kato, Issei; Ukai, Yuuta; Kondo, Noriyasu; Nozu, Kohei; Kimura, C.; Hashimoto, Kumi; Mizusawa, Eri; Maki, Hideki; Naito, Akira; Kikuchi, Makoto

doi:10.1021/acs.jmedchem.1c00883

Cited by 15 publications

(6 citation statements)

References 29 publications

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“…On the other hand, Kato et al prepared thiazoyl guanidine derivatives that inhibit fungal ergosterol biosynthesis [61]. Their hit compound N-(2 -(4-(methylsulfonyl)phenyl)-[4,4 -bithiazol]-2-yl)-tetrahydropyrimidin-2(1H)-imine (compound 6h in original paper) is structurally related to the antifungal abafungin and showed potent in vitro antifungal activity against Aspergillus fumigatus (MIC = 4.7 µM) with a favorable pharmacokinetic profile.…”

Section: New Compounds As Potential Antifungals (In Preclinical Stages)mentioning

confidence: 99%

“…Fungal ergosterol biosynthesis [59] Biphenylethylaminoacetamides Fungal cell wall integrity [60] Thiazoyl guanidine derivatives Fungal ergosterol biosynthesis [61] Carboline HDAC inhibitors Fungal histone deacetylase [62] Fungal ergosterol biosynthesis [59] Biphenylethylaminoacetamides scaffold required for dual activity for the first time, which shall serve as a template for future synthetic efforts. Among their prepared inhibitors, they identified 2-((1-(4-fluorophenyl)-3-oxo-3-phenylpropyl)thio)benzoate (compound 10 in original paper) as the most promising dual inhibitor, since it significantly decreased IL-1β release (IC50 = 2.3 ± 0.8 µM) without affecting mammalian cell viability (viability = 101.5 ± 1.4%) and exerted potent in vitro antifungal activity against Candida albicans (MIC = 6.4 ± 2.6 µM).…”

Section: Phloeodictine Analoguesmentioning

confidence: 99%

“…Fungal ergosterol biosynthesis [59] Biphenylethylaminoacetamides Fungal cell wall integrity [60] Thiazoyl guanidine derivatives Fungal ergosterol biosynthesis [61] Carboline HDAC inhibitors Fungal histone deacetylase [62] Fungal histone deacetylase [62] Acyl hydrazides Aside from the mentioned small molecules with intracellular targets, membrane-interacting antifungal antimicrobial peptides (AMPs) are another example of a promising class of antifungals. AMPs generally consist of 12 to 54 amino acids with a net positive charge at physiological pH [68].…”

Section: Phloeodictine Analoguesmentioning

confidence: 99%

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Advances in Antifungal Drug Development: An Up-To-Date Mini Review

Bouz

Doležal

2021

Pharmaceuticals

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The utility of clinically available antifungals is limited by their narrow spectrum of activity, high toxicity, and emerging resistance. Antifungal drug discovery has always been a challenging area, since fungi and their human host are eukaryotes, making it difficult to identify unique targets for antifungals. Novel antifungals in clinical development include first-in-class agents, new structures for an established target, and formulation modifications to marketed antifungals, in addition to repurposed agents. Membrane interacting peptides and aromatherapy are gaining increased attention in the field. Immunotherapy is another promising treatment option, with antifungal antibodies advancing into clinical trials. Novel targets for antifungal therapy are also being discovered, allowing the design of new promising agents that may overcome the resistance issue. In this mini review, we will summarize the current status of antifungal drug pipelines in clinical stages, and the most recent advancements in preclinical antifungal drug development, with special focus on their chemistry.

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Section: New Compounds As Potential Antifungals (In Preclinical Stages)mentioning

confidence: 99%

Section: Phloeodictine Analoguesmentioning

confidence: 99%

“…Fungal ergosterol biosynthesis [59] Biphenylethylaminoacetamides Fungal cell wall integrity [60] Thiazoyl guanidine derivatives Fungal ergosterol biosynthesis [61] Carboline HDAC inhibitors Fungal histone deacetylase [62] Fungal histone deacetylase [62] Acyl hydrazides Aside from the mentioned small molecules with intracellular targets, membrane-interacting antifungal antimicrobial peptides (AMPs) are another example of a promising class of antifungals. AMPs generally consist of 12 to 54 amino acids with a net positive charge at physiological pH [68].…”

Section: Phloeodictine Analoguesmentioning

confidence: 99%

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Advances in Antifungal Drug Development: An Up-To-Date Mini Review

Bouz

Doležal

2021

Pharmaceuticals

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“…Furthermore, in 2021, Kato et al published their research in to thiazoyl guanidine derivatives as antifungal agents, [ 73 ]. The group initiated their investigations from the previously described thiazole abafungin ( 20 ), Figure 11 .…”

Section: Introductionmentioning

confidence: 99%

Guanidine-Containing Antifungal Agents against Human-Relevant Fungal Pathogens (2004–2022)—A Review

Baugh

2022

JoF

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The guanidine moiety is typically a highly basic group, and can be found in a wide variety of drugs, such as zanamivir (Relenza) and metformin (Fortamet), as well as in biologically active compounds for numerous disease areas, including central nervous system (CNS) diseases and chemotherapeutics. This review will focus on antifungal agents which contain at least one guanidine group, for the treatment of human-related fungal pathogens, described in the literature between 2004 and 2022. These compounds include small molecules, steroids, polymers, metal complexes, sesquiterpenes, natural products, and polypeptides. It shall be made clear that a diverse range of guanidine-containing derivatives have been published in the literature and have antifungal activity, including efficacy in in vivo experiments.

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“…Examples of pharmaceutically active drugs containing guanidine groups include antimicrobial drugs, , cytotoxic, antifungal, , and antiviral drugs, etc. Guanidine-based drugs have also shown considerable promise in inhibiting the activity of proteins implicated in (i) neurodegenerative diseases like Alzheimer’s (β-secretase inhibitors), (ii) viral diseases (HIV-1 proteases, avian flu neuraminidases), and (iii) angiogenesis in tumors (acid ceramidase) .…”

Section: Introductionmentioning

confidence: 99%

pH Regulates Ligand Binding to an Enzyme Active Site by Modulating Intermediate Populations

et al. 2022

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Understanding the mechanism of ligands binding to their protein targets and the influence of various factors governing the binding thermodynamics is essential for rational drug design. The solution pH is one of the critical factors that can influence ligand binding to a protein cavity, especially in enzymes whose function is sensitive to the pH. Using computer simulations, we studied the pH effect on the binding of a guanidinium ion (Gdm+) to the active site of hen egg-white lysozyme (HEWL). HEWL serves as a model system for enzymes with two acidic residues in the active site and ligands with Gdm+ moieties, which can bind to the active sites of such enzymes and are present in several approved drugs treating various disorders. The computed free energy surface (FES) shows that Gdm+ binds to the HEWL active site using two dominant binding pathways populating multiple intermediates. We show that the residues close to the active site that can anchor the ligand could play a critical role in ligand binding. Using a Markov state model, we quantified the lifetimes and kinetic pathways connecting the different states in the FES. The protonation and deprotonation of the acidic residues in the active site in response to the pH change strongly influence the Gdm+ binding. There is a sharp jump in the ligand-binding rate constant when the pH approaches the largest pK a of the acidic residue present in the active site. The simulations reveal that, at most, three Gdm+ can bind at the active site, with the Gdm+ bound in the cavity of the active site acting as a scaffold for the other two Gdm+ ions binding. These results can aid in providing greater insights into designing novel molecules containing Gdm+ moieties that can have high binding affinities to inhibit the function of enzymes with acidic residues in their active site.

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Identification of Thiazoyl Guanidine Derivatives as Novel Antifungal Agents Inhibiting Ergosterol Biosynthesis for Treatment of Invasive Fungal Infections

Cited by 15 publications

References 29 publications

Advances in Antifungal Drug Development: An Up-To-Date Mini Review

Advances in Antifungal Drug Development: An Up-To-Date Mini Review

Guanidine-Containing Antifungal Agents against Human-Relevant Fungal Pathogens (2004–2022)—A Review

pH Regulates Ligand Binding to an Enzyme Active Site by Modulating Intermediate Populations

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