Design and synthesis of thiazolylhydrazone derivatives as inhibitors of chitinolytic N-acetyl-β-d-hexosaminidase

Yang, Huibin; Liu, Tian; Qi, Huitang; Huang, Zhisong; Hao, Zesheng; Ying, Junwu; Yang, Qing; Qian, Xuhong

doi:10.1016/j.bmc.2018.09.014

Cited by 19 publications

(17 citation statements)

References 33 publications

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“…As shown in Figure 5, the trend lines drawn for different concentrations intersect in quadrant two, which suggests that compounds 10k, 10u, and 10v are competitive inhibitors of Of Hex1, similar to previously reported inhibitors. 13,14,17,18,21,22 Moreover, the K i values of 10k, 10u, and 10v are 4.30, 3.72, and 4.56 μM, respectively. Although the target compounds in this work are less active than Q2, their chemical structures are simpler, and their synthetic route is less complex.…”

Section: ■ Results and Discussionmentioning

confidence: 99%

“…To elucidate the mechanism of Of Hex1 inhibition by compounds 10k , 10u , and 10v (three representative compounds with sulfonamide bonds at para -, meta- , or ortho- position in the terminal phenyl group), the Dixon plots of these inhibitors were analyzed. As shown in Figure , the trend lines drawn for different concentrations intersect in quadrant two, which suggests that compounds 10k , 10u , and 10v are competitive inhibitors of Of Hex1, similar to previously reported inhibitors. ,,,,, Moreover, the K i values of 10k , 10u , and 10v are 4.30, 3.72, and 4.56 μM, respectively. Although the target compounds in this work are less active than Q2 , their chemical structures are simpler, and their synthetic route is less complex.…”

Section: Resultsmentioning

confidence: 99%

“…So far, two types of Of Hex1 inhibitors have been reported (Figure ). The first type is the glycosyl-based inhibitors with K i values in the micromolar to nanomolar range, such as TMG-chitotriomycin, allosamidin, PUGNAc, NMAGT, and glycosylated naphthalimide ( 1 ). − The second type is nonglycosyl–based inhibitors with K i values in the micromolar range, such as Q1 , Q2 , and their analogs, − natural products phlegmacin B 1 and berberine, and compounds 2 and 3 (obtained from virtual screening). The application of glycosyl-based inhibitors is limited by their nonpesticide-like properties, including low clogP, metabolic instability, and membrane permeability, , as well as by their complicated structures and synthesis processes.…”

Section: Introductionmentioning

confidence: 99%

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Discovery of Biphenyl–Sulfonamides as Novel β-N-Acetyl-d-Hexosaminidase Inhibitors via Structure-Based Virtual Screening

Chen

Liu

et al. 2021

J. Agric. Food Chem.

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Novel insecticidal targets are always in demand due to the development of resistance. OfHex1, a β-N-acetyl-d-hexosaminidase identified in Ostrinia furnacalis (Asian corn borer), is involved in insect chitin catabolism and has proven an ideal target for insecticide development. In this study, structure-based virtual screening, structure simplification, and biological evaluation are used to show that compounds with a biphenyl–sulfonamide skeleton have great potential as OfHex1 inhibitors. Specifically, compounds 10k, 10u, and 10v have K i values of 4.30, 3.72, and 4.56 μM, respectively, and thus, they are more potent than some reported nonglycosyl–based inhibitors such as phlegmacin B1 (K i = 26 μM), berberine (K i = 12 μM), 2 (K i = 11.2 μM), and 3 (K i = 28.9 μM). Furthermore, inhibitory kinetic assessments reveal that the target compounds are competitive inhibitors with respect substrate, and based on toxicity predictions, most of them have potent drug properties. The obtained results indicate that the biphenyl–sulfonamide skeleton characterized by simple chemical structure, synthetic tractability, potent activity, and low toxicity has potential for further development in pest management targeting OfHex1.

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Section: ■ Results and Discussionmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Discovery of Biphenyl–Sulfonamides as Novel β-N-Acetyl-d-Hexosaminidase Inhibitors via Structure-Based Virtual Screening

Chen

Liu

et al. 2021

J. Agric. Food Chem.

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“…Some HEXs inhibitors have been uncovered via structure-based virtual screening [ 7 , 38 , 52 , 53 , 54 ] but they are all based on the crystal structure information of OfHex1. This is because the OfHex1 of O. furnacalis is the only insect-derived HEX with crystal structure information.…”

Section: Discussionmentioning

confidence: 99%

The Role of Chitooligosaccharidolytic β-N-Acetylglucosamindase in the Molting and Wing Development of the Silkworm Bombyx mori

Zhang

Luan

et al. 2022

IJMS

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The insect glycoside hydrolase family 20 β-N-acetylhexosaminidases (HEXs) are key enzymes involved in chitin degradation. In this study, nine HEX genes in Bombyx mori were identified by genome-wide analysis. Bioinformatic analysis based on the transcriptome database indicated that each gene had a distinct expression pattern. qRT-PCR was performed to detect the expression pattern of the chitooligosaccharidolytic β-N-acetylglucosaminidase (BmChiNAG). BmChiNAG was highly expressed in chitin-rich tissues, such as the epidermis. In the wing disc and epidermis, BmChiNAG has the highest expression level during the wandering stage. CRISPR/Cas9-mediated BmChiNAG deletion was used to study the function. In the BmChiNAG-knockout line, 39.2% of female heterozygotes had small and curly wings. The ultrastructure of a cross-section showed that the lack of BmChiNAG affected the stratification of the wing membrane and the formation of the correct wing vein structure. The molting process of the homozygotes was severely hindered during the larva to pupa transition. Epidermal sections showed that the endocuticle of the pupa was not degraded in the mutant. These results indicate that BmChiNAG is involved in chitin catabolism and plays an important role in the molting and wing development of the silkworm, which highlights the potential of BmChiNAG as a pest control target.

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“…Hexosaminidases (Hexs) are widely distributed exoglycosidases involved in the hydrolysis of N -acetyl- d -hexosamine residues from the nonreducing end of glycoconjugates. − These enzymes play an important role in chitin degradation, , pathogen invasion, N-linked glycan modification, cell proliferation, egg–sperm recognition, and human autoimmune diseases. , Remarkably, insect hexosaminidase (such as OfHex1) participates in the catabolism of insect old chitinous cuticles during its metamorphosis processes and is considered to be a promising ecofriendly pesticide target. − Human hexosaminidase (HsHex) is responsible for catalyzing degradation GM2 ganglioside in neuronal lysosomes . The deficiency of HsHex can cause the storage of GM2 ganglioside, which leads to Tay-Sachs or Sandhoff disease. , Therefore, inhibitors of these Hexs are particularly useful in the studies of pathogenic mechanisms and the regulation of related bioprocesses .…”

mentioning

confidence: 99%

Novel Glycosylated Naphthalimide-Based Activatable Fluorescent Probe: A Tool for the Assessment of Hexosaminidase Activity and Intracellular Hexosaminidase Imaging

Dong

Shen

et al. 2019

ACS Sens.

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The development of effective detection methods for hexosaminidase is of great importance for the rapid screening of potential inhibitors in vitro and for the early diagnosis of related diseases ex vivo. In this study, the activatable fluorescent probes that are based on naphthalimide decorated with ethylene glycol units were synthesized using N-acetyl-β-d-glucosaminide as a hexosaminidase-responsive group. When exposed to this enzyme, the glucoside-linked naphthalimide moiety of 1c can be cleaved quickly with significant changes in both color (from colorless to yellow) and fluorescence (from blue to green). Probe 1c shows better water-solubility and fluorescence properties than common substrate 4-methylumbelliferyl N-acetyl-β-d-glucosaminide. Furthermore, the response mechanism of 1c to hexosaminidase was evaluated using HPLC analysis and TD-DFT calculations. Molecular docking was performed to investigate the interaction mode. In addition, 1c has successfully achieved the straightforward rapid discovery of effective hexosaminidase inhibitors. Fluorescence imaging experiments indicate that 1c has good cell safety and can be employed as a useful tool for detecting intracellular hexosaminidase activity.

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Design and synthesis of thiazolylhydrazone derivatives as inhibitors of chitinolytic N-acetyl-β-d-hexosaminidase

Cited by 19 publications

References 33 publications

Discovery of Biphenyl–Sulfonamides as Novel β-N-Acetyl-d-Hexosaminidase Inhibitors via Structure-Based Virtual Screening

Discovery of Biphenyl–Sulfonamides as Novel β-N-Acetyl-d-Hexosaminidase Inhibitors via Structure-Based Virtual Screening

The Role of Chitooligosaccharidolytic β-N-Acetylglucosamindase in the Molting and Wing Development of the Silkworm Bombyx mori

Novel Glycosylated Naphthalimide-Based Activatable Fluorescent Probe: A Tool for the Assessment of Hexosaminidase Activity and Intracellular Hexosaminidase Imaging

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