Structure of Dihydrochalcones and Related Derivatives and Their Scavenging and Antioxidant Activity against Oxygen and Nitrogen Radical Species

Bentes, Alexandre L A; Borges, Rosivaldo S.; Monteiro, Waldinei R; Macedo, Luiz Guilherme Machado de; Alves, Cláudio Nahum

doi:10.3390/molecules16021749

Cited by 50 publications

(22 citation statements)

References 29 publications

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“…These results could be confronted mainly by the stability of the semiquinone radical generated after hydrogen abstraction, such as between tyrosyl and phenol reaction. This reaction can be also related to the stability of semiquinone form, as reported in previous works (18,34,35). Therefore, the resonance structures of semiquinone free radicals generated by hydrogen abstraction of the semiquinone regioisomers of NAPSQI can be observed by the spin density distribution (Figure 3).…”

Section: Resultssupporting

confidence: 73%

A Combined Study Using Ligand‐Based Design, Synthesis, and Pharmacological Evaluation of Analogues of the Acetaminophen Ortho‐Regioisomer with Potent Analgesic Activity

et al. 2012

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A ligand-based drug design study was performed to acetaminophen regioisomers as analgesic candidates employing quantum chemical calculations at the DFT ⁄ B3LYP level of theory and the 6-31G* basis set. To do so, many molecular descriptors were used such as highest occupied molecular orbital, ionization potential, H-O bond dissociation energies, and spin densities, which might be related to quench reactivity of the tyrosyl radical to give N-acetyl-p-benzosemiquinone-imine through an initial electron withdrawing or hydrogen atom abstraction. Based on this in silico work, the most promising molecule, orthobenzamol, was synthesized and tested. The results expected from the theoretical prediction were confirmed in vivo using mouse models of nociception such as writhing, paw licking, and hot plate tests. All biological results suggested an antinociceptive activity mediated by opioid receptors. Furthermore, at 90 and 120 min, this new compound had an effect that was comparable to morphine, the standard drug for this test. Finally, the pharmacophore model is discussed according to the electronic properties derived from quantum chemistry calculations.Key words: acetaminophen, analgesic effect, ligand-based drug design, molecular modeling, opioid derivatives Received 14 December 2011, revised 14 February 2012 and accepted for publication 25 February 2012 Acetaminophen (ACP) or paracetamol is a widely used over-thecounter analgesic and antipyretic drug, and it appears to be safe when administered according to the therapeutic dosage. However, when an overdose is taken, it produces hepatic and ⁄ or renal injury in humans and in experimental animals (1,2). The pharmacological effects are generally considered to be based on the inhibition of prostaglandin synthesis (3-5). The cyclooxygenase (COX)-inhibiting activity was suggested to be related to its capacity to quench the tyrosyl radical present in prostaglandin endoperoxide synthase (PGES) (6), as shown in Figure 1.This drug is metabolized primarily by glucuronidation and sulfation. Nevertheless, a small amount is probably metabolized via a third metabolic pathway, through an oxidation by the microsomal cytochrome P450-containing mixed-function oxidase system to form Nacetyl-p-benzoquinone-imine (NAPQI). 1,4-Michael adduct of NAPQIglutathione and the corresponding cysteine conjugate and mercapturic acid breakdown products were found in human urine after the ingestion of ACP. However, hepatotoxic activity appears to be limited to compounds that are capable of forming quinoid structures, which are susceptible to both irreversible and reversible attack by soluble and non-soluble thiols (7-9).Many reports describe investigations that aim at performing structural modifications of the ACP scaffold to improve its analgesic and safety properties. Besides efforts to modulate its toxicity or to understand the toxic mechanism, important progress has been made as well by modifying the substituents to generate homologous and congeners obtained by alkylations, halogenations, and addition ...

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Section: Resultssupporting

confidence: 73%

A Combined Study Using Ligand‐Based Design, Synthesis, and Pharmacological Evaluation of Analogues of the Acetaminophen Ortho‐Regioisomer with Potent Analgesic Activity

et al. 2012

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“…THA and, to a lesser extent, PG are free radical trapping agents that exhibit antioxidant activity ( Fig. 8; Mathiesen et al, 1997;Rezk et al, 2002;Kim and Kim, 2010;Bentes et al, 2011;So and Cho, 2014). It is likely THA also has redox properties that are operational at cellular conditions and, like GSH (Rosen et al, 1984;Albano et al, 1985), might decrease the effective NAPQI concentration via reduction to APAP.…”

Section: Discussionmentioning

confidence: 99%

Enolate-Forming Phloretin Pharmacophores: Hepatoprotection in an Experimental Model of Drug-Induced Toxicity

Geohagen

Vydyanathan

Kosharskyy

et al. 2016

Journal of Pharmacology and Experimental Therapeutics

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Drug-induced toxicity is often mediated by electrophilic metabolites, such as bioactivation of acetaminophen (APAP) to N-acetylp-benzoquinone imine (NAPQI). We have shown that APAP hepatotoxicity can be prevented by 2-acetylcyclopentanone (2-ACP). This 1,3-dicarbonyl compound ionizes to form an enolate nucleophile that scavenges NAPQI and other electrophilic intermediates. In this study, we expanded our investigation of enolate-forming compounds to include analyses of the phloretin pharmacophores, 29,49,69-trihydroxyacetophenone (THA) and phloroglucinol (PG). Studies in a mouse model of APAP overdose showed that THA provided hepatoprotection when given either by intraperitoneal injection or oral administration, whereas PG was hepatoprotective only when given intraperitoneally. Corroborative research characterized the molecular pharmacology (efficacy, potency) of 2-ACP, THA, and PG in APAP-exposed isolated mouse hepatocytes. For comparative purposes, N-acetylcysteine (NAC) cytoprotection was also evaluated. Measurements of multiple cell parameters (e.g., cell viability, mitochondrial membrane depolarization) indicated that THA and, to a lesser extent, PG provided concentration-dependent protection against APAP toxicity, which exceeded that of 2-ACP or NAC. The enolateforming compounds and NAC truncated ongoing APAP exposure and thereby returned intoxicated hepatocytes toward normal viability. The superior ability of THA to protect is related to multifaceted modes of action that include metal ion chelation, free radical trapping, and scavenging of NAPQI and other soft electrophiles involved in oxidative stress. The rank order of potency for the tested cytoprotectants was consistent with that determined in a parallel mouse model. These data suggest that THA or a derivative might be useful in treating drug-induced toxicities and other conditions that involve electrophile-mediated pathogenesis.

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“…In phloretin, two aromatic phenol rings (ring A and B), hydroxyl groups and a carbonyl group are responsible for a wide spectrum of pharmacological effects. The antioxidant pharmacophore of phloretin is 2 0 ,6 0 -dihydroxyacetophenone, in which the contribution of carbonyl and OH groups of ring A enhances its activity, whereas, the substitution of one hydroxyl moiety by a sugar (as in the case of phloridzin) reduces the activity compared to phloretin (Bentes et al 2011;Rezk et al 2002).…”

Section: Chemistrymentioning

confidence: 98%

Health effects of phloretin: from chemistry to medicine

et al. 2017

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Dihydrochalcones are a class of secondary metabolites, whose demand in biological and pharmacological applications is rapidly growing. Phloretin is one of the best known and abundant dihydrochalcone characterized by the presence of 2,6-dihydroxyacetophenone pharmacophore. It is a versatile molecule with anticancer, antiosteoclastogenic, antifungal, antiviral, anti-inflammatory, antibacterial and estrogenic activities and able to increase the fluidity of biological membranes and penetration of administered drugs. In this review we have performed a critical evaluation of available literature as far as phloretin beneficial effects and activation/block of intracellular signal cascade are of concern. In addition, we supply useful information on its chemical properties, sources and bioavailability.

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Structure of Dihydrochalcones and Related Derivatives and Their Scavenging and Antioxidant Activity against Oxygen and Nitrogen Radical Species

Cited by 50 publications

References 29 publications

A Combined Study Using Ligand‐Based Design, Synthesis, and Pharmacological Evaluation of Analogues of the Acetaminophen Ortho‐Regioisomer with Potent Analgesic Activity

A Combined Study Using Ligand‐Based Design, Synthesis, and Pharmacological Evaluation of Analogues of the Acetaminophen Ortho‐Regioisomer with Potent Analgesic Activity

Enolate-Forming Phloretin Pharmacophores: Hepatoprotection in an Experimental Model of Drug-Induced Toxicity

Health effects of phloretin: from chemistry to medicine

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