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Review

Metabolic-Hydroxy and Carboxy Functionalization of Alkyl Moieties in Drug Molecules: Prediction of Structure Influence and Pharmacologic Activity

1
Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, University of Science and Technology of Fujairah, Fufairah 00971, UAE
2
College of Medicine, Sharjah Institute for Medical Research, University of Sharjah, Sharjah 00971, UAE
*
Author to whom correspondence should be addressed.
Molecules 2020, 25(8), 1937; https://doi.org/10.3390/molecules25081937
Received: 6 February 2020 / Revised: 1 April 2020 / Accepted: 7 April 2020 / Published: 22 April 2020
Alkyl moieties—open chain or cyclic, linear, or branched—are common in drug molecules. The hydrophobicity of alkyl moieties in drug molecules is modified by metabolic hydroxy functionalization via free-radical intermediates to give primary, secondary, or tertiary alcohols depending on the class of the substrate carbon. The hydroxymethyl groups resulting from the functionalization of methyl groups are mostly oxidized further to carboxyl groups to give carboxy metabolites. As observed from the surveyed cases in this review, hydroxy functionalization leads to loss, attenuation, or retention of pharmacologic activity with respect to the parent drug. On the other hand, carboxy functionalization leads to a loss of activity with the exception of only a few cases in which activity is retained. The exceptions are those groups in which the carboxy functionalization occurs at a position distant from a well-defined primary pharmacophore. Some hydroxy metabolites, which are equiactive with their parent drugs, have been developed into ester prodrugs while carboxy metabolites, which are equiactive to their parent drugs, have been developed into drugs as per se. In this review, we present and discuss the above state of affairs for a variety of drug classes, using selected drug members to show the effect on pharmacologic activity as well as dependence of the metabolic change on drug molecular structure. The review provides a basis for informed predictions of (i) structural features required for metabolic hydroxy and carboxy functionalization of alkyl moieties in existing or planned small drug molecules, and (ii) pharmacologic activity of the metabolites resulting from hydroxy and/or carboxy functionalization of alkyl moieties. View Full-Text
Keywords: alkyl moieties; hydroxy functionalization; carboxy functionalization; prodrug metabolic activation; primary and auxiliary pharmacophores; auxophores alkyl moieties; hydroxy functionalization; carboxy functionalization; prodrug metabolic activation; primary and auxiliary pharmacophores; auxophores
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MDPI and ACS Style

El-Haj, B.M.; Ahmed, S.B.M. Metabolic-Hydroxy and Carboxy Functionalization of Alkyl Moieties in Drug Molecules: Prediction of Structure Influence and Pharmacologic Activity. Molecules 2020, 25, 1937. https://doi.org/10.3390/molecules25081937

AMA Style

El-Haj BM, Ahmed SBM. Metabolic-Hydroxy and Carboxy Functionalization of Alkyl Moieties in Drug Molecules: Prediction of Structure Influence and Pharmacologic Activity. Molecules. 2020; 25(8):1937. https://doi.org/10.3390/molecules25081937

Chicago/Turabian Style

El-Haj, Babiker M., and Samrein B.M. Ahmed. 2020. "Metabolic-Hydroxy and Carboxy Functionalization of Alkyl Moieties in Drug Molecules: Prediction of Structure Influence and Pharmacologic Activity" Molecules 25, no. 8: 1937. https://doi.org/10.3390/molecules25081937

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