p-alkyloxybenzhydroxamic acids, effective inhibitors of the trypanosome glycerol-3-phosphate oxidase

Rw, Grady; Ej, Bienen; Ab, Clarkson

doi:10.1016/0166-6851(86)90005-8

Cited by 34 publications

(26 citation statements)

References 23 publications

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“…As a result, several hydroxamic acid derivatives were prepared and screened for enzyme inhibition and in vitro trypanocidal activity of which p ‐ n ‐tetradecyloxybenzhydroxamic acid ( 57 ) was found to be the most potent. Compound 57 displayed over 70‐fold better inhibitory potency against the enzyme ( K i = 0.43 µM) and 400 times greater trypanocidal activity when compared with SHAM . Recent efforts have led to the discovery of even more potent compounds with potencies several thousands of times more potent than SHAM …”

Section: Validation Of Tao As Drug Target In African Trypanosomesmentioning

confidence: 99%

Alternative oxidase inhibitors: Mitochondrion‐targeting as a strategy for new drugs against pathogenic parasites and fungi

Ebiloma

Balogun

Cueto-Díaz

et al. 2019

Medicinal Research Reviews

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The alternative oxidase (AOX) is a ubiquitous terminal oxidase of plants and many fungi, catalyzing the four‐electron reduction of oxygen to water alongside the cytochrome‐based electron transfer chain. Unlike the classical electron transfer chain, however, the activity of AOX does not generate adenosine triphosphate but has functions such as thermogenesis and stress response. As it lacks a mammalian counterpart, it has been investigated intensely in pathogenic fungi. However, it is in African trypanosomes, which lack cytochrome‐based respiration in their infective stages, that trypanosome alternative oxidase (TAO) plays the central and essential role in their energy metabolism. TAO was validated as a drug target decades ago and among the first inhibitors to be identified was salicylhydroxamic acid (SHAM), which produced the expected trypanocidal effects, especially when potentiated by coadministration with glycerol to inhibit anaerobic energy metabolism as well. However, the efficacy of this combination was too low to be of practical clinical use. The antibiotic ascofuranone (AF) proved a much stronger TAO inhibitor and was able to cure Trypanosoma vivax infections in mice without glycerol and at much lower doses, providing an important proof of concept milestone. Systematic efforts to improve the SHAM and AF scaffolds, aided with the elucidation of the TAO crystal structure, provided detailed structure‐activity relationship information and reinvigorated the drug discovery effort. Recently, the coupling of mitochondrion‐targeting lipophilic cations to TAO inhibitors has dramatically improved drug targeting and trypanocidal activity while retaining target protein potency. These developments appear to have finally signposted the way to preclinical development of TAO inhibitors.

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Section: Validation Of Tao As Drug Target In African Trypanosomesmentioning

confidence: 99%

Alternative oxidase inhibitors: Mitochondrion‐targeting as a strategy for new drugs against pathogenic parasites and fungi

Ebiloma

Balogun

Cueto-Díaz

et al. 2019

Medicinal Research Reviews

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“…Concerning about the electron transport inhibitors, many studies have been performed for TAO. [64][65][66] Inhibitors of plant AOX, SHAM and n-propyl gallate, have a benzene ring, as ubiquinone, and these agents inhibit TAO. Therefore, structure-function relationship was studied in detail among p-alkyloxybenzhydroxaminc acid, which is a structural analogue of SHAM, and various derivatives of 3,4-dihydroxybenzoic acid.…”

Section: Ii-1-3 Inhibitors Targeting Taomentioning

confidence: 99%

Parasite Mitochondria as a Target for Chemotherapy.

Kita

Miyadera

Saruta

et al. 2001

JOURNAL OF HEALTH SCIENCE

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The survival of parasites is dependent on that of the host. It is considered that parasites originated from nonparasitic ancestors and adapted to the environment in the host during the evolutional process, and developed hostand organ-specificities. Regarding energy metabolism, which is an essential factor for the survival, parasites adapt to the environment under a low oxygen tension in the host using metabolic systems which are very different from that of the host mammals. In such systems, parasite mitochondria play diverse roles. Especially, marked changes in the morphology and components of the mitochondria in the life cycle are very interesting in biological aspects such as developmental control and environmental adaptation. Such unique properties of parasite mitochondria could be promising targets for chemotherapy.

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“…This was done beand this would not be possible if this group had already been eliminated, the first mole of H / produced must cause, although some of the respiratory inhibitors frequently used in studies with trypanosomes are active therefore represent the ionization of the acidic N-2 hydrogen. Hammett analyses of the effects of various at micromolar concentrations (11), and would be well suited to the above assay, many are not very potent para substituents in the N-1 and N-2 positions of the benzenesulfonyl moieties on the first-order rate con-and must be employed at concentrations close to 1 mM to inhibit O 2 utilization by 100%. SHAM is one such stants gave linear plots (7).…”

mentioning

confidence: 99%

Spectrophotometric Assay for Processes Involving Changes in Hydrogen Ion Concentration in Aqueous Solution

Penketh

Shyam

Patton

et al. 1996

Analytical Biochemistry

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p-alkyloxybenzhydroxamic acids, effective inhibitors of the trypanosome glycerol-3-phosphate oxidase

Cited by 34 publications

References 23 publications

Alternative oxidase inhibitors: Mitochondrion‐targeting as a strategy for new drugs against pathogenic parasites and fungi

Alternative oxidase inhibitors: Mitochondrion‐targeting as a strategy for new drugs against pathogenic parasites and fungi

Parasite Mitochondria as a Target for Chemotherapy.

Spectrophotometric Assay for Processes Involving Changes in Hydrogen Ion Concentration in Aqueous Solution

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