Inhibition of trypanosome alternative oxidase without its N-terminal mitochondrial targeting signal (ΔMTS-TAO) by cationic and non-cationic 4-hydroxybenzoate and 4-alkoxybenzaldehyde derivatives active against T. brucei and T. congolense

Ebiloma, Godwin U.; Ayuga, Teresa Díaz; Balogun, E.O.; Abad-Gil, Lucía; Donachie, Anne M.; Kaiser, Marcel; Herraiz, Tomás; Inaoka, Daniel Ken; Shiba, T.; Harada, Shigeharu; Kita, Kiyoshi; Koning, Harry P. de; Dardonville, Christophe

doi:10.1016/j.ejmech.2018.02.075

Cited by 27 publications

(115 citation statements)

References 47 publications

(64 reference statements)

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“…The same result was observed in T. brucei . In contrast, 2,4‐dihydroxybenzoic acid ( 80 ) or other 2‐substituted‐4‐hydroxybenzoic acids ( 78 and 81‐83 ) are greater than 10 times more potent inhibitors against rTAO, indicating that the ortho substituent at C2 (eg, OH, F, and Me) is essential for potent inhibition by 4‐hydroxybenzoic acid derivatives (Figure ) …”

Section: Progress In Chemical Scaffolds and Aox Inhibitor Developmentsupporting

confidence: 63%

“…The methyl and ethyl hydroxybenzoates ( 98 , 100‐102 , 106 , 108 ‐ 109 , and 116‐129 ) display comparable SAR to that of hydroxybenzoic acids ( 77‐97 ), suggesting a similar mode of binding to TAO, with the carboxylate group in close proximity to the di‐iron catalytic center (Figures and ) . Esters of 2,5‐dihydroxybenzoic acid ( 106 and 107 ) have no inhibitory effect even though the orientation of the hydroxyl groups better mimics that of ubiquinol .…”

Section: Progress In Chemical Scaffolds and Aox Inhibitor Developmentmentioning

confidence: 99%

“…However, until recently only the full‐length protein had been produced and studied by the various authors, despite difficulties associated with its stability, solubility, and yield, and although it is clearly desirable to conduct inhibitor studies with the physiologically relevant form of the protein. When a ΔMTS‐rTAO, lacking the first 75 nucleotides, was produced, it was found to have relatively higher activity, solubility, and stability compared with the full‐length enzyme …”

Section: Aox In Human and Veterinary Parasitesmentioning

confidence: 99%

“…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%

“…After a further series of screening and optimization, 1.4% (wt/vol) of n ‐octyl‐β‐ d ‐glucopyranoside (OG) was described to be better at maintaining the protein's activity and improving the yield, which increased to 5‐9 mg/10 L culture (Table ). The OG was replaced with 0.042% (wt/vol) n ‐dodecyl‐β‐ d ‐maltopyranoside during the elution step of the purification …”

Section: Validation Of Tao As Drug Target In African Trypanosomesmentioning

confidence: 99%

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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: Progress In Chemical Scaffolds and Aox Inhibitor Developmentsupporting

confidence: 63%

Section: Progress In Chemical Scaffolds and Aox Inhibitor Developmentmentioning

confidence: 99%

Section: Aox In Human and Veterinary Parasitesmentioning

confidence: 99%

Section: Validation Of Tao As Drug Target In African Trypanosomesmentioning

confidence: 99%

Section: Validation Of Tao As Drug Target In African Trypanosomesmentioning

confidence: 99%

See 3 more Smart Citations

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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Synthesis and testing of novel alternative oxidase (AOX) inhibitors with antifungal activity against Moniliophthora perniciosa (Stahel), the causal agent of witches' broom disease of cocoa, and other phytopathogens

Barsottini

Pires

Vieira

et al. 2018

Pest Management Science

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BACKGROUND: Moniliophthora perniciosa (Stahel) Aime & Phillips-Mora is the causal agent of witches' broom disease (WBD) of cocoa (Theobroma cacao L.) and a threat to the chocolate industry. The membrane-bound enzyme alternative oxidase (AOX) is critical for M. perniciosa virulence and resistance to fungicides, which has also been observed in other phytopathogens. Notably AOX is an escape mechanism from strobilurins and other respiration inhibitors, making AOX a promising target for controlling WBD and other fungal diseases. RESULTS:We present the first study aimed at developing novel fungal AOX inhibitors. N-Phenylbenzamide (NPD) derivatives were screened in the model yeast Pichia pastoris through oxygen consumption and growth measurements. The most promising AOX inhibitor (NPD 7j-41) was further characterized and displayed better activity than the classical AOX inhibitor SHAM in vitro against filamentous fugal phytopathogens, such as M. perniciosa, Sclerotinia sclerotiorum and Venturia pirina. We demonstrate that 7j-41 inhibits M. perniciosa spore germination and prevents WBD symptom appearance in infected plants. Finally, a structural model of P. pastoris AOX was created and used in ligand structure-activity relationships analyses. CONCLUSION: We present novel fungal AOX inhibitors with antifungal activity against relevant phytopathogens. We envisage the development of novel antifungal agents to secure food production.

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Synthesis and in vitro evaluation of triphenylphosphonium derivatives of acetylsalicylic and salicylic acids: structure-dependent interactions with cancer cells, bacteria, and mitochondria

et al. 2021

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Inhibition of trypanosome alternative oxidase without its N-terminal mitochondrial targeting signal (ΔMTS-TAO) by cationic and non-cationic 4-hydroxybenzoate and 4-alkoxybenzaldehyde derivatives active against T. brucei and T. congolense

Abstract: Inhibition of trypanosome alternative oxidase without its N-terminal mitochondrial targeting signal (ΔMTS-TAO) by cationic and non-cationic 4-hydroxybenzoate and 4-alkoxybenzaldehyde derivatives active against T.

Cited by 27 publications

References 47 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

Synthesis and testing of novel alternative oxidase (AOX) inhibitors with antifungal activity against Moniliophthora perniciosa (Stahel), the causal agent of witches' broom disease of cocoa, and other phytopathogens

Synthesis and in vitro evaluation of triphenylphosphonium derivatives of acetylsalicylic and salicylic acids: structure-dependent interactions with cancer cells, bacteria, and mitochondria

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