Fluorosugars as inhibitors of bacterial enzymes

Delbrouck, Julien A.; Chêne, Loïc P.; Vincent, Stéphane

doi:10.1016/b978-0-12-812733-9.00006-4

Cited by 5 publications

(11 citation statements)

References 104 publications

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“…Carbohydrate fluorination, in which fluorine is used to replace a hydroxyl group, has been widely used for studying glycan-protein interactions 186 and developing carbohydrate-based drugs. 186 , 187 Earlier studies demonstrated that C-3-fluorinated N -acetylneuraminic acid worked as a competitive inhibitor for bacterial and viral sialidases. 188 In addition, C-3-fluorinated sialosides were reported to inhibit C. perfringens bacterial sialidase 189 and the activities of both hemagglutinins and neuraminidases of the influenza virus.…”

Section: Discussionmentioning

confidence: 99%

Sialidase Inhibitors with Different Mechanisms

et al. 2022

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Sialidases, or neuraminidases, are enzymes that catalyze the hydrolysis of sialic acid (Sia)-containing molecules, mostly removal of the terminal Sia (desialylation). By desialylation, sialidase can modulate the functionality of the target compound and is thus often involved in biological pathways. Inhibition of sialidases with inhibitors is an important approach for understanding sialidase function and the underlying mechanisms and could serve as a therapeutic approach as well. Transition-state analogues, such as anti-influenza drugs oseltamivir and zanamivir, are major sialidase inhibitors. In addition, difluoro-sialic acids were developed as mechanism-based sialidase inhibitors. Further, fluorinated quinone methide-based suicide substrates were reported. Sialidase product analogue inhibitors were also explored. Finally, natural products have shown competitive inhibiton against viral, bacterial, and human sialidases. This Perspective describes sialidase inhibitors with different mechanisms and their activities and future potential, which include transition-state analogue inhibitors, mechanism-based inhibitors, suicide substrate inhibitors, product analogue inhibitors, and natural product inhibitors.

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Section: Discussionmentioning

confidence: 99%

Sialidase Inhibitors with Different Mechanisms

et al. 2022

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“…This reaction synthesizes coumarins through cyclisation of the lactone group without the presence of solvents in processes carried out with microwaves 178 or the Reformatsky reaction, which generates the condensation of aldehydes (or ketones) with α-halo esters in the presence of metallic zinc, forming β-hydroxy esters that are dehydrated in subsequent steps to produce an unsaturated ester. 179,180 On the other hand, the Wittig reaction synthesizes an alkene from the reaction of an aldehyde or ketone with the ilium generated from a phosphonium salt. 181 Claisen also developed a decarboxylative condensation reaction, where, starting from an ester and a strong base used as a catalyst, a single carbon-carbon bond is produced.…”

Section: Synthesis Of Coumarinsmentioning

confidence: 99%

Background on the control of the cattle tick R. (B.) microplus and the use of coumarin substances as an alternative

Molano¹,

Torres²,

Monrroy³

2020

PPIJ

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“…31−34 The addition of an electronegative fluorine atom as a good leaving group at C-2 of sialic acids was shown to allow the formation of a covalent bond between the sialic acid and the sialidase. Adding another fluorine at C-3 of sialic acid was shown to destabilize the oxocarbenium-like transition state 35,36 and slow down the cleavage of the glycosyl−enzyme covalent bond, thus trapping the intermediate. 31−33,37−39 Indeed, the designed difluoro-compounds were demonstrated to form glycosyl− enzyme intermediates with several parasite trans-sialidases, some bacterial sialidases, and human cytosolic sialidase hNEU2 by nuclear magnetic resonance (NMR) spectroscopy, mass spectrometry (MS), and/or X-ray crystal structures.…”

Section: ■ Introductionmentioning

confidence: 98%

“…In addition to inhibitors designed based on sialidase transition-state analogue 2-deoxy-2,3-didehydro- N -acetylneuraminic acid (Neu5Ac2en or DANA) ,− or sialidase product analogue, , difluorosialic acids were developed as a new class of mechanism-based sialidase inhibitors. − The addition of an electronegative fluorine atom as a good leaving group at C-2 of sialic acids was shown to allow the formation of a covalent bond between the sialic acid and the sialidase. Adding another fluorine at C-3 of sialic acid was shown to destabilize the oxocarbenium-like transition state , and slow down the cleavage of the glycosyl–enzyme covalent bond, thus trapping the intermediate. − ,− Indeed, the designed difluoro-compounds were demonstrated to form glycosyl–enzyme intermediates with several parasite trans -sialidases, some bacterial sialidases, and human cytosolic sialidase hNEU2 by nuclear magnetic resonance (NMR) spectroscopy, mass spectrometry (MS), and/or X-ray crystal structures. − ,, Influenza A virus neuraminidases were shown to follow the same mechanism involving the formation of a glycosyl–enzyme intermediate . 2(e),3(e)-Difluorosialic acid with a C4-guanidinium group was proven to have superior in vitro anti-influenza A virus efficacy compared to its C4-ammonium or its 2(e),3(a)-difluorosialic acid counterpart with an inhibition efficacy comparable to that of Zanamivir …”

Section: Introductionmentioning

confidence: 99%

9-Azido-9-deoxy-2,3-difluorosialic Acid as a Subnanomolar Inhibitor against Bacterial Sialidases

Santra

et al. 2019

J. Org. Chem.

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A library of 2(e),3(a/e)-difluorosialic acids and their C-5 and/or C-9 derivatives were chemoenzymatically synthesized. Pasteurella multocida sialic acid aldolase (PmAldolase), but not its Escherichia coli homolog (EcAldolase), was found to catalyze the formation of C5-azido analog of 3-fluoro(equatorial)-sialic acid. In comparison, both PmAldolase and EcAldolase could catalyze the synthesis of 3-fluoro (axial or equatorial)-sialic acids and their C-9 analogs although PmAldolase was generally more efficient. The chemoenzymatically synthesized 3-fluoro (axial or equatorial)-sialic acid analogs were purified and chemically derivatized to form desired difluorosialic acids and derivatives. Inhibition studies against several bacterial sialidases and a recombinant human cytosolic sialidase hNEU2 indicated that sialidase inhibition was affected by the C-3 fluorine stereochemistry and derivatization at C-5 and/or C-9 of the inhibitor. Opposite to that observed for influenza A virus sialidases and hNEU2, compounds with an axial fluorine at C-3 were better inhibitors (up to 100-fold) against bacterial sialidases compared to their 3Fequatorial counterparts. While C-5-modified compounds were less efficient anti-bacterial sialidase inhibitors, 9-N 3 -modified 2,3-difluoro-Neu5Ac showed increased inhibitory activity against bacterial sialidases. 9-Azido-9-deoxy-2-equatorial-3-axial-difluoro-N-acetylneuraminic acid (2e3aDFNeu5Ac9N 3 ) was identified as an effective inhibitor with a long effective duration selectively against pathogenic bacterial sialidases from Clostridium perfringens (CpNanI) and V. cholerae.

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Fluorosugars as inhibitors of bacterial enzymes

Cited by 5 publications

References 104 publications

Sialidase Inhibitors with Different Mechanisms

Sialidase Inhibitors with Different Mechanisms

Background on the control of the cattle tick R. (B.) microplus and the use of coumarin substances as an alternative

9-Azido-9-deoxy-2,3-difluorosialic Acid as a Subnanomolar Inhibitor against Bacterial Sialidases

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