Rational design of N-alkyl derivatives of 2-amino-2-deoxy-d-glucitol-6P as antifungal agents

Melcer, Anna; Łącka, Izabela; Gabriel, Iwona; Wojciechowski, Marek; Liberek, Beata; Wiśniewski, Andrzej; Milewski, Sławomir

doi:10.1016/j.bmcl.2007.09.072

Cited by 9 publications

(4 citation statements)

References 21 publications

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“…177 Furthermore, the same group synthesized novel N-alkyl and N,N-dialkyl derivatives (114) which displayed improved inhibitory activity against human pathogenic fungi. 189 The MICs for analogs 27B). The same group also reported GlcN6S (117, Figure 28A), its N-acetyl (118) and methyl ester derivatives, ADGS (119) and NAcADGS (120) as inhibitors of GlcN-6-P synthase.…”

Section: Antifungals Targeting the Cell Wallmentioning

confidence: 78%

“…Further study revealed that these more lipophilic derivatives can easily cross the cell membrane, behaved as “pro-drugs”, and were converted into ADGP after internalization . Furthermore, the same group synthesized novel N -alkyl and N , N -dialkyl derivatives ( 114 ) which displayed improved inhibitory activity against human pathogenic fungi . The MICs for analogs 115 and 116 against C. albicans , C. glabrata , and C. tropicalis are in the range of 0.16–0.625 mg/mL.…”

Section: Antifungals Targeting the Cell Wallmentioning

confidence: 99%

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Recent Progress in the Discovery of Antifungal Agents Targeting the Cell Wall

2020

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Due to the limit of available treatments and the emergence of drug resistance in the clinic, invasive fungal infections are an intractable problem with high morbidity and mortality. The cell wall, as a fungi-specific structure, is an appealing target for the discovery and development of novel and low-toxic antifungal agents. In an attempt to accelerate the discovery of novel cell wall targeted drugs, this Perspective will provide a comprehensive review of the progress made to date on the development of fungal cell wall inhibitors. Specifically, this review will focus on the targets, discovery process, chemical structures, antifungal activities, and structure–activity relationships. Although two types of cell wall antifungal agents are clinically available or in clinical trials, it is still a long way for the other cell wall targeted inhibitors to be translated into clinical applications. Future efforts should be focused on the identification of inhibitors against novel conserved cell wall targets.

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Section: Antifungals Targeting the Cell Wallmentioning

confidence: 78%

Section: Antifungals Targeting the Cell Wallmentioning

confidence: 99%

Recent Progress in the Discovery of Antifungal Agents Targeting the Cell Wall

2020

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“…studied N- alkyl and N,N -dialkyl derivatives of ADGP , which exhibited higher antifungal activity than the parent compound, due to the better uptake by fungal cells. The most potent inhibitor 48 ( Scheme 11B ) was prepared by subsequent exhaustive reductive amination with acetaldehyde 69 .…”

Section: Analogues Of Transition State Intermediates At the Isom Acti...mentioning

confidence: 99%

Inhibitors of glucosamine-6-phosphate synthase as potential antimicrobials or antidiabetics – synthesis and properties

Stefaniak

Nowak

Wojciechowski

et al. 2022

Journal of Enzyme Inhibition and Medicinal Chemistry

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Glucosamine-6-phosphate synthase (GlcN-6-P synthase) is known as a promising target for antimicrobial agents and antidiabetics. Several compounds of natural or synthetic origin have been identified as inhibitors of this enzyme. This set comprises highly selective l -glutamine, amino sugar phosphate or transition state intermediate cis -enolamine analogues. Relatively low antimicrobial activity of these inhibitors, poorly penetrating microbial cell membranes, has been improved using the pro-drug approach. On the other hand, a number of heterocyclic and polycyclic compounds demonstrating antimicrobial activity have been presented as putative inhibitors of the enzyme, based on the results of molecular docking to GlcN-6-P synthase matrix. The most active compounds of this group could be considered promising leads for development of novel antimicrobial drugs or antidiabetics, provided their selective toxicity is confirmed.

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“…Other possible antifungal agents are the synthase inhibitors such as pleofungins (inositol phosphorylceramide) 109 , N-alkyl derivatives that inhibit glucosamine-6p synthase 65 , elastase inhibitor from A. flavus (AFLEI) in combination with other existent licensed agents 74 , the GMP synthase inhibitors in C. albicans and A. fumigatus 88 and the inhibition of mRNA polyadenosine polymerase 43,81 by the natural products parnafungins; these inhibitors deserve further investigation for potential clinical use.…”

Section: Synthases and Other Enzymatic Targetsmentioning

confidence: 99%