Acetohydroxamate: Bacterial Urease Inhibitor with Therapeutic Potential in Hyperammonaemic States

Fishbein, William N.; Carbone, Paul P.; Hochstein, H D

doi:10.1038/208046a0

Cited by 50 publications

(27 citation statements)

References 15 publications

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“…It is a stable synthetic lead molecule, weakly acidic and, highly soluble in water, which structurally resemble with urea molecule. It is a very potent urease inhibitor with Ki value of 5µm at 25 o C [75]. AHA cause rapid and essentially complete inhibition of urease and other metalloenzymes.…”

Section: Hydroxamic Acidmentioning

confidence: 99%

Chemistry and Mechanism of Urease Inhibition

Amtul¹,

Atta-ur-Rahman²,

Siddiqui³

et al. 2002

CMC

339

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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Section: Hydroxamic Acidmentioning

confidence: 99%

Chemistry and Mechanism of Urease Inhibition

Amtul¹,

Atta-ur-Rahman²,

Siddiqui³

et al. 2002

CMC

339

182

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“…The unsubstituted aliphatic hydroxamic acids (such as acetohydroxamic acid) are well established as effective inhibitors of plant and bacterial urease in vitro (Fishbein et al, 1965;Kobashi and Hase, 1967) and have been shown to effectively inhibit ureolytic activity and/or to lower blood ammonia levels in mice, rats, sheep, cows, dogs and men (Brent and Adepoju, 1967;Streeter et al, 1969).…”

Section: Introductionmentioning

confidence: 97%

An improved bioprocess for synthesis of acetohydroxamic acid using DTT (dithiothreitol) treated resting cells of Bacillus sp. APB-6

Pandey¹,

Singh²,

Chand³

2011

Bioresource Technology

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“…16 Recently, our research group has reported some vanadium complexes with urease inhibitory activities. 17,18 Considering that acetohydroxamic acid (HAHA) is an effective urease inhibitor, 19,20 and can coordinate to metal ions, 21,22 in the present paper, a new oxovanadium(V) complex (Scheme 1, left) with AHA as co-ligand, derived from N 0 -(3-bromo-2-hydroxybenzylidene)-4-methoxybenzohydrazide (H 2 L, Scheme 1, right) was prepared and investigated from its coordination and biological aspects. The molecular structure of H 2 L is shown in Figure 1.…”

Section: Introductionmentioning

confidence: 99%