Metabolism and Bioactivation: It’s Time to Expect the Unexpected

Driscoll, James P.; Sadlowski, Corinne M.; Shah, Nina R.; Feula, Antonio

doi:10.1021/acs.jmedchem.0c00026

Cited by 25 publications

(20 citation statements)

References 39 publications

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“…6. Some of the transformations are discussed elsewhere in this review, and others are presented in detail elsewhere [57, [142][143][144][145][146][147].…”

Section: Toxicophoresmentioning

confidence: 99%

A history of the roles of cytochrome P450 enzymes in the toxicity of drugs

Guengerich

2020

Toxicol Res.

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The history of drug metabolism began in the 19th Century and developed slowly. In the mid-20th Century the relationship between drug metabolism and toxicity became appreciated, and the roles of cytochrome P450 (P450) enzymes began to be defined in the 1960s. Today we understand much about the metabolism of drugs and many aspects of safety assessment in the context of a relatively small number of human P450s. P450s affect drug toxicity mainly by either reducing exposure to the parent molecule or, in some cases, by converting the drug into a toxic entity. Some of the factors involved are enzyme induction, enzyme inhibition (both reversible and irreversible), and pharmacogenetics. Issues related to drug toxicity include drug-drug interactions, drug-food interactions, and the roles of chemical moieties of drug candidates in drug discovery and development. The maturation of the field of P450 and drug toxicity has been facilitated by advances in analytical chemistry, computational capability, biochemistry and enzymology, and molecular and cell biology. Problems still arise with P450s and drug toxicity in drug discovery and development, and in the pharmaceutical industry the interaction of scientists in medicinal chemistry, drug metabolism, and safety assessment is critical for success.

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“…6. Some of the transformations are discussed elsewhere in this review, and others are presented in detail elsewhere [57, [142][143][144][145][146][147].…”

Section: Toxicophoresmentioning

confidence: 99%

A history of the roles of cytochrome P450 enzymes in the toxicity of drugs

Guengerich

2020

Toxicol Res.

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“…Their presence can precipitate severe immune reactions, organ toxicity (especially liver), drug-drug interactions or genotoxicity. [153] Alternatively, a metabolite of a parent species might retain pharmacological activity (Figure 15), which can potentially extend the duration of action of a drug. The metabolic activation of chemical species has been successfully exploited in the development of prodrugs.…”

Section: Brief Overviewmentioning

confidence: 99%

Into the Fray! A Beginner's Guide to Medicinal Chemistry

Veale

2021

ChemMedChem

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Modern medicinal chemistry is a complex, multidimensional discipline that operates at the interface of the chemical and biological sciences. The medicinal chemistry contribution to drug discovery is typically described in the context of the wellrecited linear progression of the drug discovery pipeline. However, compound optimization is idiosyncratic to each project, and clear definitions of hit and lead molecules and the subsequent progress along the pipeline becomes easily blurred. In addition, this description lacks insight into the entangled relationship between chemical and pharmacological properties, and thus provides limited guidance on how innovative medicinal chemistry strategies can be applied to solve optimization problems, regardless of the stage in the pipeline. Through discussion and illustrative examples, this article seeks to provide insights into the finesse of medicinal chemistry and the subtlety of balancing chemical properties pharmacology. In so doing, it aims to serve as an accessible and simple-to-digest guide for anyone who wishes to learn about the underlying principles of medicinal chemistry, in a context that has been decoupled from the pipeline description.

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“…Pyrazole, a five-membered 1,2-diazole, is found in a number of widely used drugs such as celecoxib and lonazolac [ 4 ]. The pyrazole nucleus is less susceptible to oxidative metabolism than other five-membered heterocycles [ 5 ]. Derivatives of this diazole have been reported as antimicrobial agents in a number of publications by us [ 6 , 7 , 8 , 9 , 10 , 11 ] and others [ 12 , 13 ].…”

Section: Introductionmentioning

confidence: 99%

Synthesis and Antimicrobial Studies of Coumarin-Substituted Pyrazole Derivatives as Potent Anti-Staphylococcus aureus Agents

Alnufaie

Alsup

et al. 2020

Molecules

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In this paper, synthesis and antimicrobial studies of 31 novel coumarin-substituted pyrazole derivatives are reported. Some of these compounds have shown potent activity against methicillin-resistant Staphylococcus aureus (MRSA) with minimum inhibitory concentration (MIC) as low as 3.125 µg/mL. These molecules are equally potent at inhibiting the development of MRSA biofilm and the destruction of preformed biofilm. These results are very significant as MRSA strains have emerged as one of the most menacing pathogens of humans and this bacterium is bypassing HIV in terms of fatality rate.

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Metabolism and Bioactivation: It’s Time to Expect the Unexpected

Cited by 25 publications

References 39 publications

A history of the roles of cytochrome P450 enzymes in the toxicity of drugs

A history of the roles of cytochrome P450 enzymes in the toxicity of drugs

Into the Fray! A Beginner's Guide to Medicinal Chemistry

Synthesis and Antimicrobial Studies of Coumarin-Substituted Pyrazole Derivatives as Potent Anti-Staphylococcus aureus Agents

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