Inhibition of Urease Activity by Dipeptidyl Hydroxamic Acids.

Odake, Shinjiro; Nakahashi, Kazuaki; Morikawa, Tadanori; Takebe, Sachiko; Kobashi, Kyoichi

doi:10.1248/cpb.40.2764

Cited by 26 publications

(33 citation statements)

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“…The incorporation of polar amino acids such as lysine (Lys) and glutamine (Gln) in the structure (99-101) led to much higher IC 5 0 values particularly against JBU. These results were consistent with the above (HXAs, R-NHOH: R = acyl group) compounds in which the hydrophobicity of acyl residues R = acyl HXAs (R-NHOH) had considerable effect on their inhibitory activities [97]. On the basis of these findings it was suggested that hydrophobic amino acids, unlike hydrophilic amino acids, make contacts with the side chain of histidine (His), Lys, and aspartate (Asp) residues surrounding the binuclear-active site, providing their roles in enhancing the potency.…”

supporting

confidence: 91%

“…It has already been reported that dipeptidyl HXA required a hydroxamic acid moiety without any enantiomeric effect to inhibit JBU [97]. Likewise, Odake et al also observed both of these effects in the inhibition of HPU [96].…”

mentioning

confidence: 88%

“…These findings were based on correlation of the chemical structures of the compounds and the physicochemical properties of the acyl residues (Table (5)). After preliminary SAR studies, Odake et al [97] then focused on identifying the critical structural elements responsible for urease inhibition. They demonstrated that replacement of the α-aminoacyl group of (H-X-NHOH) with a dipeptide increases inhibitors' potency against HPU as well as JBU (Table (6) & Table (7)).…”

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confidence: 99%

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Chemistry and Mechanism of Urease Inhibition

Amtul¹,

Atta-ur-Rahman²,

Siddiqui³

et al. 2002

CMC

345

182

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Studies on enzyme inhibition remain an important area of pharmaceutical research since these studies have led to the discoveries of drugs useful in a variety of physiological conditions. The enzyme inhibitors can interact with enzymes and block their activity towards natural substrates. Urease inhibitors have recently attracted much attention as potential new anti-ulcer drugs. Ironically, urease was the first enzyme crystallized but its mechanism of action is still largely misunderstood. This chapter therefore reviews comprehensive developments in the field of urease inhibitors. Inhibitors of urease can be broadly classified into two categories: (1) active site directed (substrate-like), (2) mechanism-based directed. We present here the examples of selected inhibitors along with their mechanisms of action to characterize their mode of urease inhibition. The observations that urease due to its high substrate (urea) specificity can only bind to a few inhibitors with a similar binding mode as urea is also discussed. Several non-covalent interactions including hydrogen bonds and hydrophobic contacts stabilize the enzyme-inhibitor complex. Regardless of the class of compound, it is reported that only a few functional groups with electronegative atoms such as oxygen, nitrogen and sulfur act either as bidentate (mostly), tridentate (rarely), or as ligand-chelator to form octahedral complexes with two slightly distorted octahedral Ni ions of the enzyme. Bulky groups attached to the pharmacophore were found to decrease the activity of inhibitors, since the lack of a bulky attachment makes it easier for urease inhibitors to enter the substrate-binding pocket as well as avoid unfavorable steric interactions with amino acid residues in its vicinity. This review is intended to provide highlights of the inhibition of urease by hydroxamic acids (HXAs), phosphorodiamidates (PPDs), imidazoles, phosphazene and related compounds. These compounds are compared to previously reported urease inhibitors for the catalytic models proposed for urease activity. The differences in inhibition of urease activities from plants and of bacterial origin by various inhibitors and physiological implications of urease inhibition are discussed.

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confidence: 88%

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confidence: 99%

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Chemistry and Mechanism of Urease Inhibition

Amtul¹,

Atta-ur-Rahman²,

Siddiqui³

et al. 2002

CMC

345

182

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“…The synthesis of the glycine derivative, H-Phe-Gly-NHOH was reported previously 27 . Diprotected derivatives 2a and 3a were obtained by the reaction of the Z-Phe-OSu with H-Phe-NHOBzl or H-Leu-NHOBzl in dry THF.…”

Section: Synthesis Of the Hydroxamate Inhibitorsmentioning

confidence: 99%

Novel dipeptidyl hydroxamic acids that inhibit human and bacterial dipeptidyl peptidase III

Cvitešić¹,

Sabljić

Makarević³

et al. 2016

Journal of Enzyme Inhibition and Medicinal Chemistry

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Human dipeptidyl peptidase III (hDPP III), a zinc-metallopeptidase of the family M49, is an activator of the Keap1-Nrf2 cytoprotective pathway involved in defense against oxidative stress. Pathophysiological roles of DPP III have not been elucidated yet, partly due to the lack of specific inhibitors. We showed that substrate analog H-Tyr-Phe-NHOH is a strong competitive inhibitor of hDPP III, while H-Tyr-Gly-NHOH expresses much weaker inhibition. To investigate the effects of amino acid substitutions in inhibitor P1 position, we synthesized three new dipeptidyl hydroxamates and examined their influence on the activity of hDPP III and DPP III from the human gut symbiont Bacteroides thetaiotaomicron. The extent of inhibition of hDPP III, but not of bacterial enzyme, was dependent on the amino acid in P1. H-Phe-Phe-NHOH is recognized as one of the strongest inhibitors of hDPP III (K i ¼ 0.028 mM), and H-Phe-Leu-NHOH discriminated between human and bacterial ortholog of the M49 family.

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“…It therefore plays an important role in the pathogenesis of gastric and peptic ulcers [1][2][3] , apart from cancer as well [4][5][6] . Many urease inhibitors have been described in the past, such as hydroxamic acids, which were found to be potent and specific inhibitors of urease activities for the plant and bacterial origin enzymes 7 . A particular interest is directed on the novel biological properties of exploring polyphenols 8,9 .…”

Section: Introductionmentioning

confidence: 99%

Evaluation of Geranium spp., Helleborus spp. and Hyssopus spp. polyphenolic extracts inhibitory activity against urease and α-chymotrypsin

Păun

Liţescu

Neagu

et al. 2013

Journal of Enzyme Inhibition and Medicinal Chemistry

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This study was meant to determine the inhibitory activity of tannins and flavonoid compounds from Geranium robertianum, Helleborus purpurascens and Hyssopus officinale plant polyphenol rich extracts against urease and a-chymotrypsin. The G. robertianum, H. purpurascens and H. officinale extracts were purified and concentrated by microfiltration and ultrafiltration. Phenolic compounds including flavonoids and tannins have been linked to many pharmacological activities. Thus, the polyphenolic content of the extracts was assessed by UV-Vis spectroscopy and HPLC. The concentrated extracts enriched in polyphenolic compounds (flavonoids, tannins and phenolic acids) showed a significant inhibition against urease from jack bean (over 90%), whereas in case of the a-chymotrypsin, they proved to have an inhibition below 54%. The results of this support the use of G. robertianum, H. purpurascens and H. officinale polyphenolic extracts as potential sources of urease inhibitors. Among the three plant extracts tested, H. officinale polyphenolic extracts exhibited a high inhibitory activity (92.67%) against urease and low inhibition (19.6%) against a-chymotrypsin and could be considered as possible remedy in ulcer treatment.

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Inhibition of Urease Activity by Dipeptidyl Hydroxamic Acids.

Cited by 26 publications

References 0 publications

Chemistry and Mechanism of Urease Inhibition

Chemistry and Mechanism of Urease Inhibition

Novel dipeptidyl hydroxamic acids that inhibit human and bacterial dipeptidyl peptidase III

Evaluation of Geranium spp., Helleborus spp. and Hyssopus spp. polyphenolic extracts inhibitory activity against urease and α-chymotrypsin

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