Identification, characterization and in silico ADMET prediction of Roflumilast degradation products

Pinheiro, Mariana Santos; Viana, Gil Mendes; Vieira, Bárbara de Azevedo Abrahim; Souza, Alessandra Mendonça Teles de; Rodrigues, Carlos Rangel; Marins, Rita de Cássia Elias Estrela; Cabral, Lúcio Mendes; Sousa, Valéria Pereira de

doi:10.1016/j.jpba.2017.02.012

Cited by 17 publications

(5 citation statements)

References 11 publications

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“…For the toxicological profile, the cardiotoxicity was evaluated by the qualitative estimation of the hERG potassium channel inhibition in humans, which is related to ventricular arrhythmias and sudden death 32 . The prediction of hepatotoxicity considered the likelihood of causing a serum increase in alkaline phosphatase, gamma‐glutamyl transferase, lactate dehydrogenase, serum glutamic oxaloacetic transaminase, and serum glutamic pyruvic transaminase enzymes 33 . Mutagenicity was evaluated based on the Ames test.…”

Section: Methodsmentioning

confidence: 99%

“…32 The prediction of hepatotoxicity considered the likelihood of causing a serum increase in alkaline phosphatase, gamma-glutamyl transferase, lactate dehydrogenase, serum glutamic oxaloacetic transaminase, and serum glutamic pyruvic transaminase enzymes. 33 Mutagenicity was evaluated based on the Ames test. Acute toxicity was based on the amount of orally administered chemical (in mg/kg body weight) required to kill 50% of the rats tested (LD 50 ), the risk is indicated by LD 50 lower than 200−300.…”

Section: Toxicological Predictionsmentioning

confidence: 99%

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Structure‐based design of new N‐benzyl‐piperidine derivatives as multitarget‐directed AChE/BuChE inhibitors for Alzheimer's disease

Conceição,

von Ranke,

Azevedo

et al. 2023

J of Cellular Biochemistry

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The pathogenic complexity of Alzheimer's disease (AD) demands the development of multitarget‐directed agents aiming at improving actual pharmacotherapy. Based on the cholinergic hypothesis and considering the well‐established role of butyrylcholinesterase (BuChE) in advanced stages of AD, the chemical structure of the acetylcholinesterase (AChE) inhibitor drug donepezil (1) was rationally modified for the design of new N‐benzyl‐piperidine derivatives (4a−d) as potential multitarget‐direct AChE and BuChE inhibitors. The designed analogues were further studied through the integration of in silico and in vitro methods. ADMET predictions showed that 4a−d are anticipated to be orally bioavailable, able to cross the blood‐brain barrier and be retained in the brain, and to have low toxicity. Computational docking and molecular dynamics indicated the formation of favorable complexes between 4a−d and both cholinesterases. Derivative 4a presented the lowest binding free energy estimation due to interaction with key residues from both target enzymes (−36.69 ± 4.47 and −32.23 ± 3.99 kcal/mol with AChE and BuChE, respectively). The in vitro enzymatic assay demonstrated that 4a was the most potent inhibitor of AChE (IC50 2.08 ± 0.16 µM) and BuChE (IC50 7.41 ± 0.44 µM), corroborating the in silico results and highlighting 4a as a novel multitarget‐directed AChE/BuChE inhibitor.

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Section: Methodsmentioning

confidence: 99%

Section: Toxicological Predictionsmentioning

confidence: 99%

Structure‐based design of new N‐benzyl‐piperidine derivatives as multitarget‐directed AChE/BuChE inhibitors for Alzheimer's disease

Conceição,

von Ranke,

Azevedo

et al. 2023

J of Cellular Biochemistry

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“…[16][17][18] Though the identification and preparations. 19,21,22 We initiated an attempt in this regard by developing an easy,…”

Section: Introductionmentioning

confidence: 99%

“…Currently, in silico approaches are quite popular to facilitate toxicity prediction of potential DPs. They provide an added advantage against dedicated animal experiments and standardize the limits of respective DPs in pharmaceutical preparations 19,21,22 …”

Section: Introductionmentioning

confidence: 99%

Hesperidin: Enrichment, forced degradation, and structural elucidation of potential degradation products using spectral techniques

Bisen,

Rawat,

Sharma

et al. 2023

Rapid Comm Mass Spectrometry

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RationaleHesperidin (HES) is a well‐known citrus bioflavonoid phyto‐nutraceutical agent with polypharmacological properties. After 2019, HES was widely used for prophylaxis and COVID‐19 treatment. Moreover, it is commonly prescribed for treating varicose veins and other diseases in routine clinical practice. Pharmaceutical impurities and degradation products (DP) impact the drug's quality and safety and thus its effectiveness. Therefore, forced degradation studies help study drug stability, degradation mechanisms, and their DPs. This study was performed because stress stability studies using detailed structural characterization of hesperidin are currently unavailable in the literature.MethodsIn the HES enrichment method crude HES was converted to its pure form (98% purity) using column chromatography and then subjected to forced degradation under acid, base, and neutral hydrolyses followed by oxidative, reductive, photolytic, and thermal stress testing (International Conference on Harmonization guidelines). The stability‐indicating analytical method (SIAM) was developed to determine DPs using reversed‐phase high‐performance liquid chromatography (C18 column with methanol and 0.1% v/v acetic acid in deionized water [70:30, v/v] at 284 nm). Further, structural characterization of DPs was performed using liquid chromatography‐electrospray ionization‐tandem mass spectrometry (LC‐ESI‐MS/MS) and nuclear magnetic resonance (NMR) spectroscopy. In addition, in silico toxicity predictions were performed using pKCSM and DataWarior freeware.ResultsHES was found to be susceptible to acidic and basic hydrolytic conditions and yielded three DPs in each, which were detected using designed SIAM. Of six DPs, three were pseudo‐DPs (short lived), and the remaining were characterized using LC–MS/MS and NMR spectroscopy. The tentative mechanism of the formation of proposed DPs was explained. The proposed DPs were found inactive from in silico toxicity predictions.ConclusionsHesperidin was labile under acidic and basic stress conditions. The potential DPs were characterized using LC‐ESI‐MS/MS and NMR spectral techniques. The proposed mechanism of formation was hypothesized. In addition, to identify and characterize the DPs, a SIAM, which has broad biomedical applications, was successfully developed.

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“…Currently, in silico tools have been widely used to predict the toxicity endpoints of DPs (Pinheiro et al, 2017). Besides the advantage of reducing animal testing, the risk assessment of the DPs through in silico approaches is useful to establish the limits of potentially toxic compounds (ICH, 2006a; Pinheiro et al, 2017).…”

Section: Introductionmentioning

confidence: 99%

Forced degradation studies of norepinephrine and epinephrine from dental anesthetics: Development of stability‐indicating HPLC method and in silico toxicity evaluation

Abreu

Abrahim-Vieira

Souza

et al. 2020

Biomedical Chromatography

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Injectable solutions containing epinephrine (EPI) and norepinephrine (NE) are not stable, and their degradation is favored mainly by the oxidation of catechol moiety. As studies of these drugs under forced degradation conditions are scarce, herein, we report the identification of their degradation products (DP) in anesthetic formulations by the development of stability‐indicating HPLC method. Finally, the risk assessment of the major degradation products was evaluated using in silico toxicity approach. HPLC method was developed to obtain a higher selectivity allowing adequate elution for both drugs and their DPs. The optimized conditions were developed using a C18 HPLC column, sodium 1‐octanesulfonate, and methanol (80:20, v/v) as mobile phase, with a flow rate of 1.5 mL/min, UV detection at 199 nm. The analysis of standard solutions with these modifications resulted in greater retention time for EPI and NE, which allow the separation of these drugs from their respective DPs. Then, five DPs were identified and analyzed by in silico studies. Most of the DPs showed important alerts as hepatotoxicity and mutagenicity. To the best of our acknowledgment, this is the first report of a stability‐indicating HPLC method that can be used with formulations containing catecholamines.

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Identification, characterization and in silico ADMET prediction of Roflumilast degradation products

Cited by 17 publications

References 11 publications

Structure‐based design of new N‐benzyl‐piperidine derivatives as multitarget‐directed AChE/BuChE inhibitors for Alzheimer's disease

Structure‐based design of new N‐benzyl‐piperidine derivatives as multitarget‐directed AChE/BuChE inhibitors for Alzheimer's disease

Hesperidin: Enrichment, forced degradation, and structural elucidation of potential degradation products using spectral techniques

Forced degradation studies of norepinephrine and epinephrine from dental anesthetics: Development of stability‐indicating HPLC method and in silico toxicity evaluation

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