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Review

Linking Aromatic Hydroxy Metabolic Functionalization of Drug Molecules to Structure and Pharmacologic Activity

1
Department of Pharmaceutical Sciences, College of Pharmacy, Ajman University, Ajman, UAE
2
College of Medicine, Sharjah Institute for Medical Research, University of Sharjah, Sharjah, UAE
3
Department of Pharmaceutics, Dubai Pharmacy College, Dubai, UAE
*
Author to whom correspondence should be addressed.
Molecules 2018, 23(9), 2119; https://doi.org/10.3390/molecules23092119
Received: 7 July 2018 / Revised: 10 August 2018 / Accepted: 13 August 2018 / Published: 23 August 2018
Drug functionalization through the formation of hydrophilic groups is the norm in the phase I metabolism of drugs for the modification of drug action. The reactions involved are mainly oxidative, catalyzed mostly by cytochrome P450 (CYP) isoenzymes. The benzene ring, whether phenyl or fused with other rings, is the most common hydrophobic pharmacophoric moiety in drug molecules. On the other hand, the alkoxy group (mainly methoxy) bonded to the benzene ring assumes an important and sometimes essential pharmacophoric status in some drug classes. Upon metabolic oxidation, both moieties, i.e., the benzene ring and the alkoxy group, produce hydroxy groups; the products are arenolic in nature. Through a pharmacokinetic effect, the hydroxy group enhances the water solubility and elimination of the metabolite with the consequent termination of drug action. However, through hydrogen bonding, the hydroxy group may modify the pharmacodynamics of the interaction of the metabolite with the site of parent drug action (i.e., the receptor). Accordingly, the expected pharmacologic outcome will be enhancement, retention, attenuation, or loss of activity of the metabolite relative to the parent drug. All the above issues are presented and discussed in this review using selected members of different classes of drugs with inferences regarding mechanisms, drug design, and drug development. View Full-Text
Keywords: aromatic hydroxy metabolites; arenolic drug metabolites; metabolic O-dealkylation; metabolic aromatic-ring hydroxylation; primary and auxiliary pharmacophores; auxophores; metabolic modification of drug activity aromatic hydroxy metabolites; arenolic drug metabolites; metabolic O-dealkylation; metabolic aromatic-ring hydroxylation; primary and auxiliary pharmacophores; auxophores; metabolic modification of drug activity
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MDPI and ACS Style

El-Haj, B.M.; Ahmed, S.B.M.; Garawi, M.A.; Ali, H.S. Linking Aromatic Hydroxy Metabolic Functionalization of Drug Molecules to Structure and Pharmacologic Activity. Molecules 2018, 23, 2119. https://doi.org/10.3390/molecules23092119

AMA Style

El-Haj BM, Ahmed SBM, Garawi MA, Ali HS. Linking Aromatic Hydroxy Metabolic Functionalization of Drug Molecules to Structure and Pharmacologic Activity. Molecules. 2018; 23(9):2119. https://doi.org/10.3390/molecules23092119

Chicago/Turabian Style

El-Haj, Babiker M., Samrein B.M. Ahmed, Mousa A. Garawi, and Heyam S. Ali 2018. "Linking Aromatic Hydroxy Metabolic Functionalization of Drug Molecules to Structure and Pharmacologic Activity" Molecules 23, no. 9: 2119. https://doi.org/10.3390/molecules23092119

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