On the Diversity of Oxidative Bioactivation Reactions on Nitrogen- Containing Xenobiotics

Kalgutkar, Amit S.; Dalvie, Deepak; O’Donnell, John P.; Taylor, Timothy J.; Sahakian, Diana C.

doi:10.2174/1389200023337360

Cited by 97 publications

(60 citation statements)

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“…In most cases hepatic metabolism results in the loss of biological activity , and such metabolic reactions are therefore regarded as detoxification pathways. However, it has become increasingly clear that the biotransformation of some xenobiotics results in the formation of reactive intermediates and/or metabolites [7,8]. In fact, the formation of reactive metabolites represents a frequent underlying mechanism that gives rise to hepatotoxicity.…”

Section: Role Of Reactive Metabolites In Adrsmentioning

confidence: 99%

A Comprehensive Listing of Bioactivation Pathways of Organic Functional Groups

Kalgutkar¹,

Gardner²,

Obach³

et al. 2005

CDM

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584

507

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The occurrence of idiosyncratic adverse drug reactions during late clinical trials or after a drug has been released can lead to a severe restriction in its use and even in its withdrawal. Metabolic activation of relatively inert functional groups to reactive electrophilic intermediates is considered to be an obligatory event in the etiology of many drug-induced adverse reactions. Therefore, a thorough examination of the biochemical reactivity of functional groups/structural motifs in all new drug candidates is essential from a safety standpoint. A major theme attempted in this review is the comprehensive cataloging of all of the known bioactivation pathways of functional groups or structural motifs commonly utilized in drug design efforts. Potential strategies in the detection of reactive intermediates in biochemical systems are also discussed. The intention of this review is not to "black list" functional groups or to immediately discard compounds based on their potential to form reactive metabolites, but rather to serve as a resource describing the structural diversity of these functionalities as well as experimental approaches that could be taken to evaluate whether a "structural alert" in a new drug candidate undergoes bioactivation to reactive metabolites.

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Section: Role Of Reactive Metabolites In Adrsmentioning

confidence: 99%

A Comprehensive Listing of Bioactivation Pathways of Organic Functional Groups

Kalgutkar¹,

Gardner²,

Obach³

et al. 2005

CDM

Self Cite

584

507

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“…Upon oxidative dehydrogenation, catalyzed by P450 enzymes, ortho-quinone imines can be formed from these metabolites ( Fig. 1) (Kalgutkar et al, 2002;Aynur et al, 2009). Quinones and quinone imines are well known reactive metabolites, which very often undergo adduct formation with cellular compounds such as GSH, proteins, or DNA (Bolton et al, 2000).…”

Section: Introductionmentioning

confidence: 99%

Electrochemistry-Mass Spectrometry Unveils the Formation of Reactive Triclocarban Metabolites

Baumann¹,

Lohmann²,

Rose³

et al. 2010

Drug Metab Dispos

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ABSTRACT:Triclocarban (3,4,4-trichlorocarbanilide, TCC) is a widely used antibacterial agent in personal care products and is frequently detected as an environmental pollutant in waste waters and surface waters. In this study, we report novel reactive metabolites potentially formed during biotransformation of TCC. The oxidative metabolism of TCC has been predicted using an electrochemical cell coupled online to liquid chromatography and electrospray ionization mass spectrometry. The electrochemical oxidation unveils the fact that hydroxylated metabolites of TCC may form reactive quinone imines. Moreover, a so-far unknown dechlorinated and hydroxylated TCC metabolite has been identified. The results were confirmed by in vitro studies with human and rat liver microsomes. The reactivity of the newly discovered quinone imines was demonstrated by their covalent binding to glutathione and macromolecules, using ␤-lactoglobulin A as a model protein. The results regarding the capability of the electrochemical cell to mimic the oxidative metabolism of TCC are discussed. Moreover, the occurrence of reactive metabolites is compared with findings from earlier in vivo studies and their relevance in vivo is argued.

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“…Such an observation can be explained using the well known metabolic pathway for tertiary amines which involves formation of iminium ions and aldehydes. 31 Our previous results (table 1) had shown that a highly basic tertiary amine side chain gave the most potent antiplasmodial activity. Thus a functional group considered essential for activity was also involved in bioactivation.…”

Section: Bioactivation Studies On Previously Synthesized Analoguesmentioning

confidence: 90%

Antimalarial benzoheterocyclic 4-aminoquinolines: Structure–activity relationship, in vivo evaluation, mechanistic and bioactivation studies

Ongarora

Strydom

Wicht

et al. 2015

Bioorganic & Medicinal Chemistry

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A novel class of benzoheterocyclic analogues of amodiaquine designed to avoid toxic reactive metabolite formation was synthesized and evaluated for antiplasmodial activity against K1 (multidrug resistant) and NF54 (sensitive) strains of the malaria parasite Plasmodium falciparum. Structure-activity relationship studies led to the identification of highly promising analogs, the most potent of which had IC50s in the nanomolar range against both strains. The compounds further demonstrated good in vitro microsomal metabolic stability while those subjected to in vivo pharmacokinetic studies had desirable pharmacokinetic profiles. In vivo antimalarial efficacy in Plasmodium berghei infected mice was evaluated for four compounds, all of which showed good activity following oral administration. In particular, compound 19 completely cured treated mice at a low multiple dose of 4×10 mg/kg. Mechanistic and bioactivation studies suggest hemozoin formation inhibition and a low likelihood of forming quinone-imine reactive metabolites, respectively. KEYWORDS: amodiaquine, benzoxazole, antiplasmodial activity, antimalarial activity, malaria, reactive metabolite, 4-aminoquinolines; bioactivation; structure-activity relationship; β-hematin; quinone imine. INTRODUCTIONMalaria remains a leading cause of morbidity and mortality globally. In 2012, there were an estimated 207 million cases of malaria and 627 000 deaths worldwide, with 90% of all malaria deaths occurring in sub-Saharan Africa. 1 One of the biggest challenges facing malaria chemotherapy is the rapid emergence of resistance to existing antimalarial drugs. 2 This challenge underscores the need for the continued search for new antimalarials.Chloroquine (1) (structure shown in Figure 1), was undoubtedly one of the most successful antimalarials ever owing to its good efficacy and low cost which made it affordable especially in the developing countries with high malaria endemicity. 3 Chloroquine was replaced as first line therapy by the sulfonamide antimalarials and, later on, artemisinin combination therapy (ACT), following the development of widespread resistance against the drug by Plasmodium falciparum. 4An aromatic side chain analogue of chloroquine, amodiaquine (2), however, retains activity against chloroquine-resistant Plasmodium strains. 5 Besides, it is an established fact that resistance against these 4-aminoquinolines is not a result of target modification but is caused by impaired accumulation of the drug at the target. 6,7 Consequently, amodiaquine is an attractive lead compound in the search for new antimalarials. Despite the desirable antimalarial efficacy of amodiaquine, chronic use especially during prophylaxis has been found to precipitate severe hepatotoxicity, myelotoxicity and agranulocytosis. 8,9 This toxicity has been attributed to the bioactivation of amodiaquine to reactive quinone imine (3) and aldehyde quinone imine (4) metabolites (figure 1) which covalently bind to cellular macromolecules causing drug-induced toxicity and cell damage di...

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On the Diversity of Oxidative Bioactivation Reactions on Nitrogen- Containing Xenobiotics

Cited by 97 publications

References 0 publications

A Comprehensive Listing of Bioactivation Pathways of Organic Functional Groups

A Comprehensive Listing of Bioactivation Pathways of Organic Functional Groups

Electrochemistry-Mass Spectrometry Unveils the Formation of Reactive Triclocarban Metabolites

Antimalarial benzoheterocyclic 4-aminoquinolines: Structure–activity relationship, in vivo evaluation, mechanistic and bioactivation studies

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