Design, synthesis and biological evaluation of novel diazaspiro[4.5]decan-1-one derivatives as potential chitin synthase inhibitors and antifungal agents

Li, Bing; Wang, Kaiyuan; Zhang, Rui; Li, Baihui; Shen, Yangli; Ji, Qinggang

doi:10.1016/j.ejmech.2019.111669

Cited by 14 publications

(6 citation statements)

References 26 publications

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“…On the basis of this study, the same group further synthesized novel diazaspiro[4.5]decan-1-one derivatives as Chs inhibitors. 110 These derivatives displayed moderate Chs inhibition with IC 50 values ranging from 120 to 290 μM, which was less potent than polyoxins B (IC 50 = 80 μM). Derivative 63 displayed the best antifungal activity against C. albicans ATCC 90023 (MIC = 0.04 mM), which was superior to FLC (0.104 mM) and polyoxin B (0.129 mM).…”

Section: Antifungals Targeting the Cell Wallmentioning

confidence: 95%

“…The natural products polyoxin B ( 56 , Figure ) and nikkomycin Z ( 57 , Figure ) are peptidyl nucleoside antibiotics which display good Chs inhibitory activity due to their structural similarity to UDP-GlcNAc . Polyoxin B displayed a moderate inhibitory activity against Chs of S. cerevisiae and C. tropicalis with IC 50 values of 180 μM and 90 μM, respectively. , The MIC values of polyoxin B against C. albicans , A. fumigatus , and C. neofonmans are 2 μg/mL, 2 μg/mL, and 4 μg/mL, respectively, which are comparable to that of FLC .…”

Section: Antifungals Targeting the Cell Wallmentioning

confidence: 99%

“…Derivative 62 displayed moderate Chs inhibition with an IC 50 value of 100 μM. On the basis of this study, the same group further synthesized novel diazaspiro[4.5]decan-1-one derivatives as Chs inhibitors . These derivatives displayed moderate Chs inhibition with IC 50 values ranging from 120 to 290 μM, which was less potent than polyoxins B (IC 50 = 80 μM).…”

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: 95%

Section: Antifungals Targeting the Cell Wallmentioning

confidence: 99%

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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“…have become a major global health problem for both immunocompetent and immunocompromised patients. It is estimated that invasive fungal infections result in over 1.5 million deaths per year, which is higher than patients dying globally from breast cancer or malaria [ 162 ]. The fungal cell wall, including chitin synthesis, presents an interesting target for antifungal drug development, simply because humans do not have a cell wall [ 1 ].…”

Section: Chitin Biosynthesis As a Target For Antifungal Drugsmentioning

confidence: 99%

Chitin Biosynthesis in Aspergillus Species

Brauer

Pessoni

Freitas

et al. 2023

JoF

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The fungal cell wall (FCW) is a dynamic structure responsible for the maintenance of cellular homeostasis, and is essential for modulating the interaction of the fungus with its environment. It is composed of proteins, lipids, pigments and polysaccharides, including chitin. Chitin synthesis is catalyzed by chitin synthases (CS), and up to eight CS-encoding genes can be found in Aspergillus species. This review discusses in detail the chitin synthesis and regulation in Aspergillus species, and how manipulation of chitin synthesis pathways can modulate fungal growth, enzyme production, virulence and susceptibility to antifungal agents. More specifically, the metabolic steps involved in chitin biosynthesis are described with an emphasis on how the initiation of chitin biosynthesis remains unknown. A description of the classification, localization and transport of CS was also made. Chitin biosynthesis is shown to underlie a complex regulatory network, with extensive cross-talks existing between the different signaling pathways. Furthermore, pathways and recently identified regulators of chitin biosynthesis during the caspofungin paradoxical effect (CPE) are described. The effect of a chitin on the mammalian immune system is also discussed. Lastly, interference with chitin biosynthesis may also be beneficial for biotechnological applications. Even after more than 30 years of research, chitin biosynthesis remains a topic of current interest in mycology.

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“…The drug combination studies between the 3-(pyrazol-3-yl)imino-2oxoindoline derivatives 8b, 9a, 9c, and 10a with antibiotics related to different groups (levofloxacin, ciprofloxacin, ofloxacin, amikacin, cefepime, ceftazidime, gentamicin) against multidrug-resistant P. aeruginosa clinical isolate were performed using 96-well plates using the two-dimensional broth microdilution checkboard assay. [96] The experiment was duplicated, and the plates were incubated for 24 h at (the concentration at which 50% enzyme inhibition occurred) were measured using GraphPad Prism software.…”

Section: Drug Combination Assaymentioning

confidence: 99%

Design, synthesis, molecular modeling, and antimicrobial potential of novel 3‐[(1H‐pyrazol‐3‐yl)imino]indolin‐2‐one derivatives as DNA gyrase inhibitors

Ammar

Salem

Abu-Elghait

2021

Archiv der Pharmazie

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A series of 3-[(1H-pyrazol-3-yl)imino]indolin-2-one derivatives were designed using the molecular hybridization method, characterized using different spectroscopic techniques, and evaluated for their in vitro antimicrobial activity. Most of the target compounds demonstrated good to moderate antimicrobial activity compared with ciprofloxacin and fluconazole. Four compounds (8b, 9a, 9c, and 10a) showed encouraging results, with minimal inhibitory concentration (MIC) values (53.45-258.32 µM) comparable to those of norfloxacin (100.31-200.63 µM) and ciprofloxacin (48.33-96.68 µM). Noticeably, the four derivatives revealed excellent bactericidal and fungicidal activities, except for the bacteriostatic potential of compounds 8b and 9a against Escherichia coli and Staphylococcus aureus, respectively. The time-killing kinetic study against S. aureus confirmed the efficacy of these derivatives. Furthermore, two of the four promising derivatives, 9a and 10a, could prevent the formation of biofilms of S. aureus without affecting the bacterial growth at low concentrations. A combination study with seven commercial antibiotics against the multidrug-resistant bacterium P. aeruginosa showed a notable reduction in the antibiotic MIC values, represented mainly through a synergistic or additive effect. The enzymatic assay implied that the most active derivatives had inhibition potency against DNA gyrase comparable to that of ciprofloxacin. Molecular docking and density functional theory calculations were performed to explore the binding mode and study the reactivity of the promising compounds.3-(pyrazol-3-yl)imino-2-oxoindoline derivatives, antibiofilm, antimicrobial activity, DFT calculations, DNA gyrase, drug combination, molecular docking, time-killing kinetics | INTRODUCTIONIn recent years, infectious diseases caused by bacterial pathogens have become a main public health problem due to the high occurrence of drug resistance. [1] Additionally, infections caused by multidrug-resistant bacteria are a major health concern worldwide. [2] Particularly important are infections caused by the Gram-positive bacteria Staphylococcus aureus and species of the genus Enterococcus due to the increasing incidence of infections caused by these microorganisms in hospitals and communities and their ability to

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Design, synthesis and biological evaluation of novel diazaspiro[4.5]decan-1-one derivatives as potential chitin synthase inhibitors and antifungal agents

Cited by 14 publications

References 26 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

Chitin Biosynthesis in Aspergillus Species

Design, synthesis, molecular modeling, and antimicrobial potential of novel 3‐[(1H‐pyrazol‐3‐yl)imino]indolin‐2‐one derivatives as DNA gyrase inhibitors

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