Esters of 3,4-dihydroxybenzoic acid, highly effective inhibitors of the sn-glycerol-3-phosphate oxidase of Trypanosoma brucei brucei

Rw, Grady; Ej, Bienen; Ab, Clarkson

doi:10.1016/0166-6851(86)90079-4

Cited by 35 publications

(33 citation statements)

References 13 publications

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“…The n-alkyl 3,4-dihydroxybenzoates were synthesized as previously described (8). The N-n-alkyl-3,4-dihydroxybenzamides were synthesized via condensation of the appropriate amines with succinimido 3,4-dihydroxybenzoate or 3,4-dihydroxybenzoyl chloride.…”

Section: Materuils and Methodsmentioning

confidence: 99%

“…In combination with glycerol, which blocks a glycerol-producing pathway by mass action, salicylhydroxamic acid (SHAM) is trypanocidal (4), although the concentrations required for a cure are toxic to the host (9). In a search for alternatives to SHAM, we designed, synthesized, and tested compounds against TAO activity as measured in a crude mitochondrial preparation of T. brucei brucei (5,7,8). The most active compounds were p-n-alkyloxybenzhydroxamic acids and n-alkyl 3,4-dihydroxybenzoates, the latter being the more active.…”

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confidence: 99%

“…T. brucei brucei Lab 110 was the same strain as previously used. Growth of the parasites in rats, harvesting by ion-exchange chromatography, and preparation of assay material by Carborundum grinding and differential centrifugation were carried out under the same conditions as previously described (7,8).Inhibitor synthesis. The n-alkyl 3,4-dihydroxybenzoates were synthesized as previously described (8).…”

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confidence: 99%

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N-n-alkyl-3,4-dihydroxybenzamides as inhibitors of the trypanosome alternative oxidase: activity in vitro and in vivo

Grady

Bienen

Dieck

et al. 1993

Antimicrob Agents Chemother

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On the basis of our previous demonstration of the high inhibitory activity of a series of p-n-alkyloxybenzhydroxamic acids and n-alkyl esters of 3,4-dihydroxybenzoic acid against the trypanosome alternative oxidase in a cell-free mitochondrial preparation of Tiypanosoma brucei brucei, we synthesized a series of N-n-alkyl-3,4-dihydroxybenzamides for evaluation as inhibitors of this enzyme. This class of compounds was selected with the expectation of their having similar inhibitory activity to but greater solubility than the esters and hydroxamic acids noted above and greater resistance to serum hydrolases in vivo. We predicted that such properties would allow an inhibitor of the trypanosome alternative oxidase to be coadministered with glycerol as a means of providing treatment for infections by African trypanosomes. As expected, such benzamides were both more soluble and more stable, some being more active against the target enzyme than the corresponding ester. One, N-n-butyl-3,4-dihydroxybenzamide, was selected for evaluation in vivo against T. brucei brucei.When combined with glycerol, this benzamide was found to be curative. A regimen wherein 450 mg of N-n-butyl-3,4-dihydroxybenzamide per kg and 15 g of glycerol per kg were given hourly in three divided doses cured 17 of 19 mice with established T. brucei brucei infections. This combination is more active in vivo than any other designed to block simultaneously both the unique respiratory electron transport system and the anaerobic glycolytic pathways of these pathogenic protozoa.The Trypanosoma brucei complex, the causative agent of human and animal trypanosomiasis in Africa, has several unusual biochemical pathways, including a mitochondrial terminal oxidase known as the trypanosome alternative oxidase (TAO) (1). This enzyme is the sole terminal oxidase functioning in the life cycle stages found in the mammalian host and, by the following criteria, is similar to the alternative oxidase found in some plants. Both are ubiquinoloxygen oxidoreductases (1). With a monoclonal antibody against the plant enzyme, Western blots (immunoblots) of Trypanosoma brucei brucei show a single band of the same size (35 kDa) as the plant alternative oxidase (3). Furthermore, the two enzymes are sensitive to the same range of specific inhibitors (2).Since the TAO is an enzyme with no homolog in the mammalian host, it has been the target of a rational approach to the design of drugs for the treatment of African trypanosomiasis. Early work showed that the TAO is sensitive to substituted hydroxamic acids (6). In combination with glycerol, which blocks a glycerol-producing pathway by mass action, salicylhydroxamic acid (SHAM) is trypanocidal (4), although the concentrations required for a cure are toxic to the host (9). In a search for alternatives to SHAM, we designed, synthesized, and tested compounds against TAO activity as measured in a crude mitochondrial preparation of T. brucei brucei (5,7,8). The most active compounds were p-n-alkyloxybenzhydroxamic acids and n-alkyl 3,4-dihy...

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Section: Materuils and Methodsmentioning

confidence: 99%

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confidence: 99%

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confidence: 99%

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N-n-alkyl-3,4-dihydroxybenzamides as inhibitors of the trypanosome alternative oxidase: activity in vitro and in vivo

Grady

Bienen

Dieck

et al. 1993

Antimicrob Agents Chemother

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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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“…44 In this paper, we propose a series of potential antimicrobial compounds: phenolic acids, esters, and amides that we postulate should act through the disruption of redox homeostasis in microbial metabolism and cell components, including the cell membrane. 45,46 Our hypothesis is that small structural modifications may have differential impacts on both efficacy and human health hazards. Exploiting these differences between human and microbial biochemical processes or cell structures could improve antimicrobial potency without adverse human health outcomes.…”

Section: ■ Introductionmentioning

confidence: 99%

Design and Testing of Safer, More Effective Preservatives for Consumer Products

Buckley

Hart‐Cooper

Kim

et al. 2017

ACS Sustainable Chem. Eng.

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Preservatives deter microbial growth, providing crucial functions of safety and durability in composite materials, formulated products, and food packaging. Concern for human health and the environmental impact of some preservatives has led to regulatory restrictions and public pressure to remove individual classes of compounds, such as parabens and chromated copper arsenate, from consumer products. Bans do not address the need for safe, effective alternative preservatives, which are critical for both product performance (including lifespan and therefore life cycle metrics) and consumer safety. In this work, we studied both the safety and efficacy of a series of phenolic preservatives and compared them to common preservatives found in personal care products and building materials. We quantified antimicrobial activity against Aspergillus brasiliensis (mold) and Pseudomonas aeruginosa (Gram negative bacteria), and we conducted a hazard assessment, complemented by computational modeling, to evaluate the human and environmental health impacts of these chemicals. We found that octyl gallate demonstrates better antimicrobial activity and comparable or lower hazards, compared to current-use preservatives. Therefore, octyl gallate may serve as a viable small-molecule preservative, particularly in conjunction with low concentrations of other preservatives that act through complementary mechanisms.

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Esters of 3,4-dihydroxybenzoic acid, highly effective inhibitors of the sn-glycerol-3-phosphate oxidase of Trypanosoma brucei brucei

Cited by 35 publications

References 13 publications

N-n-alkyl-3,4-dihydroxybenzamides as inhibitors of the trypanosome alternative oxidase: activity in vitro and in vivo

N-n-alkyl-3,4-dihydroxybenzamides as inhibitors of the trypanosome alternative oxidase: activity in vitro and in vivo

Parasite Mitochondria as a Target for Chemotherapy.

Design and Testing of Safer, More Effective Preservatives for Consumer Products

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