Synthesis and biological activity of novel ester derivatives of N3-(4-metoxyfumaroyl)-(S)-2,3-diaminopropanoic acid containing amide and keto function as inhibitors of glucosamine-6-phosphate synthase

Pawlak, Dorota A.; Schielmann, Marta; Wojciechowski, Marek; Andruszkiewicz, Ryszard

doi:10.1016/j.bmcl.2016.06.016

Cited by 13 publications

(8 citation statements)

References 13 publications

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“…For the GAT domain in C. albicans , the crystal structure has not been reported. But all amino acids forming the glutamine binding site are completely conserved in both E. coli and C. albicans enzymes; therefore, the available structure of the prokaryotic GlcN-6-P synthase (PDB code 1GMS) was always used as the receptor model. , The crystal structure of ISOM domain of GlcN-6-P synthase in C. albicans was reported by Rypniewski and co-workers in 2007 (PDB code 2POC, Figure B–D) …”

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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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: 99%

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

2020

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“…albicans suggests that the use of more lipophilic formulations of conjugates while slightly scarifying the biocompatibility toward mammalian cells might be a better strategy for more efficient nanoparticle internalization by fungal cells. Similar strategies were very recently adopted for the development of lipophilic FMDP prodrugs that have already proven the applicability of the high lipophilicity concept. , …”

Section: Results and Discussionmentioning

confidence: 99%

“…Similar strategies were very recently adopted for the development of lipophilic FMDP prodrugs that have already proven the applicability of the high lipophilicity concept. 40,41 The current results obtained for the GlcN-6-P synthase targeting by the nanomedical approach further complicate the antifungal therapy expectations. The results were in conflict with the previously reported nontoxic in vitro activity of FMDP−peptide conjugates against human cell lines.…”

Section: Langmuirmentioning

confidence: 99%

Emerging Anticancer Activity of Candidal Glucoseamine-6-Phosphate Synthase Inhibitors upon Nanoparticle-Mediated Delivery

Kertmen

Przysiecka²,

Coy³

et al. 2019

Langmuir

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Numerous glutamine analogues have been reported as irreversible inhibitors of the glucosamine-6-phosphate (GlcN-6-P) synthase in pathogenic Candida albicans in the last 3.5 decades. Among the reported inhibitors, the most effective N 3-(4-methoxyfumaroyl)-l-2,3-diaminopropanoic acid (FMDP) has been extensively studied in order to develop its more active analogues. Several peptide–FMDP conjugates were tested to deliver FMDP to its subcellularly located GlcN-6-P synthase target. However, the rapid development of fungal resistance to FMDP–peptides required development of different therapeutic approaches to tackle antifungal resistance. In the current state of the global antifungal resistance, subcellular delivery of FMDP via free diffusion or endocytosis has become crucial. In this study, we report on in vitro nanomedical applications of FMDP and one of its ketoacid analogues, N 3-trans-4-oxo-4-phenyl-2-butenoyl-l-2,3-diaminopropanoic acid (BADP). FMDP and BADP covalently attached to polyethylene glycol-coated iron oxide/silica core–shell nanoparticles are tested against intrinsically multidrug-resistant C. albicans. Three different human cancer cell lines potentially overexpressing the GlcN-6-P synthase enzyme are tested to demonstrate the immediate inhibitory effects of nanoparticle conjugates against mammalian cells. It is shown that nanoparticle-mediated delivery transforms FMDP and BADP into strong anticancer agents by inhibiting the growth of the tested cancer cells, whereas their anti-Candidal activity is decreased. This study discusses the emerging inhibitory effect of the FMDP/BADP–nanoparticle conjugates based on their cellular internalization efficiency and biocompatibility.

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“…As shown in Figure 1, currently the development of antifungal compounds based on GlcN-6-P synthase has been carried out. Derivatives of N 3 -(4-methoxyfumaroyl)-(S)-2,3diaminopropanoic acid (FMDP) which have great antifungal activities targeted GlcN-6-P synthase have been synthesized, including compounds 4, 5, 11, 12, and 13 (mentioned in this review is FMDP derivatives 1, 2, 3, 4, and 5), with MIC of 4, 32, 0.25, 0.5, and 0.5 µg/ml, respectively (Pawlak et al, 2015(Pawlak et al, , 2016. These findings indicated the significance of exploiting GlcN-6-P synthase inhibitors for antifungal treatment, and we believe that there will be more new effective antifungal drugs produced based on this target.…”

Section: Glucosamine-6-phosphate Synthasementioning

confidence: 99%

Potential Antifungal Targets Based on Glucose Metabolism Pathways of Candida albicans

et al. 2020

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In recent years, fungal infections have become a serious health problem. Candida albicans are considered as the fourth most common isolates associated with approximately 40% mortality in bloodstream infections among hospitalized patients. Due to various limitations of classical antifungals used currently, such as limited kinds of drugs, inevitable toxicities, and high price, there is an urgent need to explore new antifungal agents based on novel targets. Generally, nutrient metabolism is involved with fungal virulence, and glucose is one of the important nutrients in C. albicans. C. albicans can obtain and metabolize glucose through a variety of pathways; in theory, many enzymes in these pathways can be potential targets for developing new antifungal agents, and several studies have confirmed that compounds which interfere with alpha-glucosidase, acid trehalase, trehalose-6-phosphate synthase, class II fructose bisphosphate aldolases, and glucosamine-6-phosphate synthase in these pathways do have antifungal activities. In this review, the glucose metabolism pathways in C. albicans, the potential antifungal targets based on these pathways, and some compounds which have antifungal activities by inhibiting several enzymes in these pathways are summarized. We believe that our review will be helpful to the exploration of new antifungal drugs with novel antifungal targets.

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Synthesis and biological activity of novel ester derivatives of N3-(4-metoxyfumaroyl)-(S)-2,3-diaminopropanoic acid containing amide and keto function as inhibitors of glucosamine-6-phosphate synthase

Cited by 13 publications

References 13 publications

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

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

Emerging Anticancer Activity of Candidal Glucoseamine-6-Phosphate Synthase Inhibitors upon Nanoparticle-Mediated Delivery

Potential Antifungal Targets Based on Glucose Metabolism Pathways of Candida albicans

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