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

El‐Haj, Babiker M.; Ahmed, Samrein B M; Garawi, Mousa A; Ali, Heyam Saad

doi:10.3390/molecules23092119

Cited by 21 publications

(17 citation statements)

References 71 publications

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“…The chemical classification of NSAIDS is given in the first part of this review series [12]. The two NSAIDS considered in this section, ibuprofen and tolmetin are of the arylalkanoic acid class.…”

Section: Nsaidsmentioning

confidence: 99%

“…Loss of pharmacologic activity has been observed for ibuprofen upon metabolic hydroxylation of the isobutyl group at C1, C2, and C3 ( Figure 3). In analogy with the O-demethylation of the methoxy-group-containing NSAIDS discussed in the first part of this review series [12], both pharmacodynamic and pharmacokinetic effects may account for the ibuprofen isobutyl-hydroxy metabolites' loss of pharmacologic activity. The SAR of ibuprofen dictates that the branched isobutyl moiety is essential for optimum COX-inhibitory effect; in this context, n-butyl substitution has led to significant loss of activity [101].…”

Section: Nsaidsmentioning

confidence: 99%

“…At this pKa value, a sulfonylurea anion is formed that is essential for interaction with the pancreatic β-cell subtypes (SUR1, SURA1, and SUR2A) through ion-ion and ion-dipole bindings [103]. Generally, metabolic change at auxiliary pharmacophores or auxophores is associated with retention of pharmacologic activity [12]. However, a discrepancy is observed for some members of the first-generation sulfonylurea antidiabetics in this respect.…”

Section: Sulfonylurea Oral Antidiabeticsmentioning

confidence: 99%

“…In the first part of this review series [12], we classified the pharmacophore as primary and auxiliary (secondary or logistic) based on the "message/address" concept suggested by Dr. Portoghese [119]. The case of fexofenadine development as a metabolite drug of terfenadine ( Figure 24) due to the cardiotoxicity of the latter has prompted us to extend the definition of an auxiliary pharmacophore.…”

Section: Primary and Auxiliary Pharmacophoresmentioning

confidence: 99%

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

El‐Haj

Ahmed

2020

Molecules

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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.

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Section: Nsaidsmentioning

confidence: 99%

Section: Nsaidsmentioning

confidence: 99%

Section: Sulfonylurea Oral Antidiabeticsmentioning

confidence: 99%

Section: Primary and Auxiliary Pharmacophoresmentioning

confidence: 99%

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

El‐Haj

Ahmed

2020

Molecules

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“…While no further in vitro or in vivo studies have been reported for compound A however we anticipated that the presence of OMe group (activated by the +M effect of pyrazole ring) exposed outside at the para ‐position could be a metabolic burden of these molecules. It is known that drugs or bioactive agents containing a methoxy group generally undergo metabolism involving the demethylation of the methoxy group in the presence of cytochrome P450 (CYP) isoenzymes [10,11] . To avoid this issue we designed an alternative pyrazole based framework B (Figure 1) in which the methoxy phenyl moiety was moved to the nitrogen atom with the shifting of OMe group from para ‐ to the ortho ‐position.…”

Section: Introductionmentioning

confidence: 99%

In Silico and Biological Evaluation of N‐(2‐methoxyphenyl) Substituted Pyrazoles Accessed via a Sonochemical Method

Rao

Vardhini³

et al. 2021

ChemistrySelect

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In view of remarkable biological properties including anticancer activities of N-aryl pyrazoles we have explored N-(2-methoxyphenyl) substituted pyrazoles and related derivatives as potential cytotoxic agents. In silico methods were adopted to understand/predict the biochemical and physiological effects, toxicity, and biological profiles of these compounds thereby assessing the potential drug-likeness of the hit molecule. The target compounds were conveniently prepared via a sonochemical method involving the CÀ N bond forming reactions in the presence of CuI in DMSO. A library of N-aryl pyrazole derivatives were synthesized via coupling of iodoarenes with pyrazole whereas the use of other N-heteroarene such as imidazole and pyrrole in place of pyrazole afforded the corresponding product. The in vitro evaluation of all these compounds was carried out against MDAMB-231 and MCF-7 cell lines and subsequently against SIRT1. The pyrazole derivative 3 c showed encouraging growth inhibition of both MDAMB-231 and MCF-7 cell lines (59 and 48 % at 10 μM, respectively) and inhibition of SIRT1 (IC 50 ∼ 6.21 � 0.42 μM) in vitro. The molecular docking studies suggested H-bonding (involving OMe group), Van der Waals and hydrophobic interactions of 3 c with important amino acid residues in the catalytic domain of SIRT1. Overall, cell-based as well as enzyme assay, molecular modelling, in silico ADME/TOX prediction and in vitro stability studies suggested 3 c as a potential hit molecule.

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Late‐Stage C−H Activation of Drug (Derivative) Molecules with Pd(ll) Catalysis

Shim

2023

Chemistry A European J

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This review comprehensively analyses representative examples of Pd(II)‐catalyzed late‐stage C−H activation reactions and demonstrates their efficacy in converting C−H bonds at multiple positions within drug (derivative) molecules into diverse functional groups. These transformative reactions hold immense potential in medicinal chemistry, enabling the efficient and selective functionalization of specific sites within drug molecules, thereby enhancing their pharmacological activity and expanding the scope of potential drug candidates. Although notable articles have focused on late‐stage C−H functionalization reactions of drug‐like molecules using transition‐metal catalysts, reviews specifically focusing on late‐stage C−H functionalization reactions of drug (derivative) molecules using Pd(II) catalysts are required owing to their prominence as the most widely utilized metal catalysts for C−H activation and their ability to introduce a myriad of functional groups at specific C−H bonds. The utilization of Pd‐catalyzed C−H activation methodologies demonstrates impressive success in introducing various functional groups, such as cyano (CN), fluorine (F), chlorine (Cl), aromatic rings, olefin, alkyl, alkyne, and hydroxyl groups, to drug (derivative) molecules with high regioselectivity and functional‐group tolerance. These breakthroughs in late‐stage C−H activation reactions serve as invaluable tools for drug discovery and development, thereby offering strategic options to optimize drug candidates and drive the exploration of innovative therapeutic solutions.

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

Cited by 21 publications

References 71 publications

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

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

In Silico and Biological Evaluation of N‐(2‐methoxyphenyl) Substituted Pyrazoles Accessed via a Sonochemical Method

Late‐Stage C−H Activation of Drug (Derivative) Molecules with Pd(ll) Catalysis

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