A Theoretical Study of the Dapsone Derivatives on Methemoglobin

Borges, Rosivaldo S.; Vale, Joyce Karen Lima; Schalcher, Taysa Ribeiro; Almeida, Eduardo D.; Maia, Cristiane do Socorro Ferraz; Monteiro, Marta Chagas; Orestes, Ednilsom; Silva, Albérico Borges Ferreira da

doi:10.1166/jctn.2013.3165

Cited by 4 publications

(4 citation statements)

References 13 publications

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“…Hydroxylamines can be formed from the parent and the acetylated derivative and they are potent oxidants which cause the hematologic adverse effects associated with dapsone, including methemoglobinemia and hemolytic anemia [7] , [10] , [34] , [35] , [36] . In this regard, leprosy patients presented with significantly enhanced MetHb percentage after the third dose supervised (MDT3), with values above the normal range (<2%).…”

Section: Resultsmentioning

confidence: 99%

Clinical Oxidative Stress during Leprosy Multidrug Therapy: Impact of Dapsone Oxidation

et al. 2014

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This study aims to assess the oxidative stress in leprosy patients under multidrug therapy (MDT; dapsone, clofazimine and rifampicin), evaluating the nitric oxide (NO) concentration, catalase (CAT) and superoxide dismutase (SOD) activities, glutathione (GSH) levels, total antioxidant capacity, lipid peroxidation, and methemoglobin formation. For this, we analyzed 23 leprosy patients and 20 healthy individuals from the Amazon region, Brazil, aged between 20 and 45 years. Blood sampling enabled the evaluation of leprosy patients prior to starting multidrug therapy (called MDT 0) and until the third month of multidrug therapy (MDT 3). With regard to dapsone (DDS) plasma levels, we showed that there was no statistical difference in drug plasma levels between multibacillary (0.518±0.029 µg/mL) and paucibacillary (0.662±0.123 µg/mL) patients. The methemoglobin levels and numbers of Heinz bodies were significantly enhanced after the third MDT-supervised dose, but this treatment did not significantly change the lipid peroxidation and NO levels in these leprosy patients. In addition, CAT activity was significantly reduced in MDT-treated leprosy patients, while GSH content was increased in these patients. However, SOD and Trolox equivalent antioxidant capacity levels were similar in patients with and without treatment. These data suggest that MDT can reduce the activity of some antioxidant enzyme and influence ROS accumulation, which may induce hematological changes, such as methemoglobinemia in patients with leprosy. We also explored some redox mechanisms associated with DDS and its main oxidative metabolite DDS-NHOH and we explored the possible binding of DDS to the active site of CYP2C19 with the aid of molecular modeling software.

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Section: Resultsmentioning

confidence: 99%

Clinical Oxidative Stress during Leprosy Multidrug Therapy: Impact of Dapsone Oxidation

et al. 2014

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“…DDS is extensively metabolized, and its hydroxylated metabolites are found in plasma at concentrations ranging from 0.4–1.2 mg/L 24 hours after the ingestion of 100 mg of the drug [ 6 , 42 ]. DDS-NHOH and other hydroxylated metabolites are potent oxidants cause the hematologic adverse effects associated with DDS, including methemoglobinemia and hemolytic anemia [ 6 , 7 , 41 , 43 ]. DDS-NHOH has long been considered to be the responsible for inducing methemoglobin in patients using DDS [ 44 , 45 ] besides accelerating erythrocytic destruction in rats [ 19 , 46 ] and morphological alteration in human erythrocytes [ 19 , 47 ].…”

Section: Discussionmentioning

confidence: 99%

“…The current strategy for leprosy control recommended by the World Health Organization (WHO) is based on multidrug therapy (MDT) that consists of the combination of rifampicin, clofazimine and dapsone (4,4'-diaminodiphenylsulfone, DDS) for multi-bacillary leprosy patients and rifampicin and DDS for pauci-bacillary leprosy patients [ 3 ]. DDS therapy is responsible for hematological adverse reactions, such as methemoglobinemia and anemia [ 6 , 7 ]. These effects are associated with the hydroxylamine metabolite of DDS (DDS-NHOH) that is formed through N-hydroxylation by hepatic cytochromes P450, particularly CYP2C9 and CYP2C19 [ 6 , 8 ].…”

Section: Introductionmentioning

confidence: 99%

In Vitro Protective Effect and Antioxidant Mechanism of Resveratrol Induced by Dapsone Hydroxylamine in Human Cells

Albuquerque¹,

Malcher

Amado³

et al. 2015

PLoS ONE

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Dapsone (DDS) hydroxylamine metabolites cause oxidative stress- linked adverse effects in patients, such as methemoglobin formation and DNA damage. This study evaluated the ameliorating effect of the antioxidant resveratrol (RSV) on DDS hydroxylamine (DDS-NHOH) mediated toxicity in vitro using human erythrocytes and lymphocytes. The antioxidant mechanism was also studied using in-silico methods. In addition, RSV provided intracellular protection by inhibiting DNA damage in human lymphocytes induced by DDS-NHOH. However, whilst pretreatment with RSV (10–1000 μM significantly attenuated DDS-NHOH-induced methemoglobinemia, but it was not only significantly less effective than methylene blue (MET), but also post-treatment with RSV did not reverse methemoglobin formation, contrarily to that observed with MET. DDS-NHOH inhibited catalase (CAT) activity and reactive oxygen species (ROS) generation, but did not alter superoxide dismutase (SOD) activity in erythrocytes. Pretreatment with RSV did not alter these antioxidant enzymes activities in erythrocytes treated with DDS-NHOH. Theoretical calculations using density functional theory methods showed that DDS-NHOH has a pro-oxidant effect, whereas RSV and MET have antioxidant effect on ROS. The effect on methemoglobinemia reversion for MET was significantly higher than that of RSV. These data suggest that the pretreatment with resveratrol may decrease heme-iron oxidation and DNA damage through reduction of ROS generated in cells during DDS therapy.

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“…The energy values of HOMO, LUMO, and I have also been associated with the amine groups’ reactivity and toxicity of DDS. Therefore, the amine group is the highest nucleophilic site and susceptible to oxidization [ 25 ]. These parameters will allow the generation of the donor-acceptor map (DAM), a useful tool to categorize any potential antioxidant substance as an electron donor or acceptor that permits us to better understand the possible antioxidant mechanism [ 26 ].…”

Section: Introductionmentioning

confidence: 99%

Synthesis, In Vitro, and In Silico Analysis of the Antioxidative Activity of Dapsone Imine Derivatives

et al. 2021

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Dapsone (DDS) is an antibacterial drug with well-known antioxidant properties. However, the antioxidant behavior of its derivatives has not been well explored. In the present work, the antioxidant activity of 10 dapsone derivatives 4-substituted was determined by an evaluation in two in vitro models (DPPH radical scavenging assay and ferric reducing antioxidant power). These imine derivatives 1–10 were obtained through condensation between DDS and the corresponding aromatic aldehydes 4-substuited. Three derivatives presented better results than DDS in the determination of DPPH (2, 9, and 10). Likewise, we have three compounds with better reducing activity than dapsone (4, 9, and 10). In order to be more insight, the redox process, a conceptual DFT analysis was carried out. Molecular descriptors such as electronic distribution, the total charge accepting/donating capacity (I/A), and the partial charge accepting/donating capacity (ω+/ω−) were calculated to analyze the relative donor-acceptor capacity through employing a donor acceptor map (DAM). The DFT calculation allowed us to establish a relationship between GAPHOMO-LUMO and DAM with the observed antioxidant effects. According to the results, we concluded that compounds 2 and 3 have the lowest Ra values, representing a good antioxidant behavior observed experimentally in DPPH radical capturing. On the other hand, derivatives 4, 9, and 10 display the best reducing capacity activity with the highest ω− and Rd values. Consequently, we propose these compounds as the best antireductants in our DDS imine derivative series.

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A Theoretical Study of the Dapsone Derivatives on Methemoglobin

Cited by 4 publications

References 13 publications

Clinical Oxidative Stress during Leprosy Multidrug Therapy: Impact of Dapsone Oxidation

Clinical Oxidative Stress during Leprosy Multidrug Therapy: Impact of Dapsone Oxidation

In Vitro Protective Effect and Antioxidant Mechanism of Resveratrol Induced by Dapsone Hydroxylamine in Human Cells

Synthesis, In Vitro, and In Silico Analysis of the Antioxidative Activity of Dapsone Imine Derivatives

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