Macitentan: An overview of its degradation products, process-related impurities, and in silico toxicity.

Pinto, Enrico; Souza, de; Velozo, Carolina Trajano; Viana, Gil Mendes; Cabral, Lúcio Mendes; Sousa, Valéria Pereira de

doi:10.1016/j.comtox.2022.100255

Cited by 4 publications

(4 citation statements)

References 32 publications

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“…46 Additionally, the compounds are not P-glycoprotein 1 (PGP−) substrates, a pump regulating some xenobiotic compounds. 47 By avoiding the design of polyhydroxylated aurones (HBD between 0 and 2) and based on this theoretical prediction method, we expect to obtain compounds with good bioavailability that do not suffer from extensive metabolization, which often hampers the success of natural flavonoids in preclinical in vivo evaluations. 48−50 Therefore, considering the low lipophilicity and bioavailability of polyphenolic flavonoids and the higher potency against SARS-CoV-2 replication found for the methylflavonols 6 and 7, we prioritized the design of aurones with methoxy (OCH 3 ) groups over hydroxy (OH) groups (Figure 3).…”

Section: ■ Results and Discussionmentioning

confidence: 99%

“…Additionally, the compounds are not P-glycoprotein 1 (PGP−) substrates, a pump regulating some xenobiotic compounds . By avoiding the design of polyhydroxylated aurones (HBD between 0 and 2) and based on this theoretical prediction method, we expect to obtain compounds with good bioavailability that do not suffer from extensive metabolization, which often hampers the success of natural flavonoids in preclinical in vivo evaluations. − …”

Section: Resultsmentioning

confidence: 99%

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Aurones: A Promising Scaffold to Inhibit SARS-CoV-2 Replication

Caleffi,

Rosa,

de Souza

et al. 2023

J. Nat. Prod.

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Aurones are a small subgroup of flavonoids in which the basic C6–C3–C6 skeleton is arranged as (Z)-2-benzylidenebenzofuran-3(2H)-one. These compounds are structural isomers of flavones and flavonols, natural products reported as potent inhibitors of SARS-CoV-2 replication. Herein, we report the design, synthesis, and anti-SARS-CoV-2 activity of a series of 25 aurones bearing different oxygenated groups (OH, OCH3, OCH2OCH3, OCH2O, OCF2H, and OCH2C6H4R) at the A- and/or B-rings using cell-based screening assays. We observed that 12 of the 25 compounds exhibit EC50 < 3 μM (8e, 8h, 8j, 8k, 8l, 8m, 8p, 8q, 8r, 8w, 8x, and 8y), of which five presented EC50 < 1 μM (8h, 8m, 8p, 8q, and 8w) without evident cytotoxic effect in Calu-3 cells. The substitution of the A- and/or B-ring with OCH3, OCH2OCH3, and OCF2H groups seems beneficial for the antiviral activity, while the corresponding phenolic derivatives showed a significant decrease in the anti-SARS-CoV-2 activity. The most potent compound of the series, aurone 8q (EC50 = 0.4 μM, SI = 2441.3), is 2 to 3 times more effective than the polyphenolic flavonoids myricetin (2) and baicalein (1), respectively. Investigation of the five more active compounds as inhibitors of SARS-CoV-2 3CLpro based on molecular dynamic calculations suggested that these aurones should detach from the active site of 3CLpro, and, probably, they could bind to another SARS-CoV-2 protein target (either receptor or enzyme).

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Section: ■ Results and Discussionmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Aurones: A Promising Scaffold to Inhibit SARS-CoV-2 Replication

Caleffi,

Rosa,

de Souza

et al. 2023

J. Nat. Prod.

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“…These parameters include the issue of permeation of the blood-brain barrier (BBB), the interaction as a substrate of a protein that is present in the intestinal and capillary epithelium cells, acting as a pump of xenobiotic compounds (P-gp protein), and the interaction as a substrate/inhibitor of five significant isoforms of cytochrome P450 (CYP1A2, CYP2C19, CYP2C9, CYP2D6, and CYP3A4). [54] The results presented in Table 3 indicated that all twelve chalcones were considered substrates of CYP2C19, CYP2C9, and CYP3A4. Compound 11 was the only one to present BBB permeation and was considered the substrate of CYP1A2, the isoform responsible for the metabolism of amine groups.…”

Section: In Silico Prediction Of Drug-likeness Physicochemical Proper...mentioning

confidence: 99%

Synthesis and evaluation of hybrid sulfonamide‐chalcones with potential antileishmanial activity

de Oliveira,

de Souza,

de Almeida

et al. 2023

Archiv der Pharmazie

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Leishmaniasis is an emerging tropical infectious disease caused by a protozoan parasite of the genus Leishmania. In this work, the molecular hybridization between a trimethoxy chalcone and a sulfonamide group was used to generate a series of sulfonamide‐chalcones. A series of eight sulfonamide‐chalcone hybrids were made with good yields (up to 95%). These sulfonamide‐chalcones were tested against promastigotes of Leishmania amazonensis and cytotoxicity against mouse macrophages, which showed good antileishmanial activity with IC50 = 1.72–3.19 µM. Three of them (10c, 10g, and 10h) were also highly active against intracellular amastigotes and had a good selectivity index (SI > 9). Thus, those three compounds were docked in the cytosolic tryparedoxin peroxidase (cTXNPx) enzyme of the parasite, and molecular dynamics simulations were carried out. This enzyme was selected as a target protein for the sulfonamide‐chalcones due to the fact of the anterior report, which identified a strong and stable interaction between the chalcone NAT22 (6) and the cTXNPx. In addition, a prediction of the drug‐likeness, and the pharmacokinetic profile of all compounds were made, demonstrating a good profile of those chalcones.

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“…Hence, a predictive ADMET study was conducted using the OSIRIS Property Explorer tool [41] to estimate the toxicity profile and druglikeness of the best 10 hits to propose whether they can pass as being orally active drugs [42]. The following pharmacokinetic properties were examined: molecular weight and solubility (log S), which are determinants of the degree to which a compound can penetrate the biological membrane [39]; hydrophilicity (log P) to estimate the dissolution of compounds in a liquid membrane; topological polar surface area (TPSA) associated with membrane permeability [43]; and drug score, a single value from the combination of all the properties listed above [44] and toxicity risk combining irritant, tumorigenic, mutagenic, and reproductive risks [45]. Druglikeness, a value that determines the consistency in properties of a compound as a drug candidate, was also examined [46].…”

Section: In Silico Druglikeness Predictionmentioning

confidence: 99%

In Silico Design of Potential Small-Molecule Antibiotic Adjuvants against Salmonella typhimurium Ortho Acetyl Sulphydrylase Synthase to Address Antimicrobial Resistance

Elebiju,

Oduselu,

Ogunnupebi

et al. 2024

Pharmaceuticals

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The inhibition of O-acetyl sulphydrylase synthase isoforms has been reported to represent a promising approach for the development of antibiotic adjuvants. This occurs via the organism developing an unpaired oxidative stress response, causing a reduction in antibiotic resistance in vegetative and swarm cell populations. This consequently increases the effectiveness of conventional antibiotics at lower doses. This study aimed to predict potential inhibitors of Salmonella typhimurium ortho acetyl sulphydrylase synthase (StOASS), which has lower binding energy than the cocrystalized ligand pyridoxal 5 phosphate (PLP), using a computer-aided drug design approach including pharmacophore modeling, virtual screening, and in silico ADMET (Absorption, Distribution, Metabolism, Excretion, and Toxicity) evaluation. The screening and molecular docking of 4254 compounds obtained from the PubChem database were carried out using AutoDock vina, while a post-screening analysis was carried out using Discovery Studio. The best three hits were compounds with the PubChem IDs 118614633, 135715279, and 155773276, possessing binding affinities of −9.1, −8.9, and −8.8 kcal/mol, respectively. The in silico ADMET prediction showed that the pharmacokinetic properties of the best hits were relatively good. The optimization of the best three hits via scaffold hopping gave rise to 187 compounds, and they were docked against StOASS; this revealed that lead compound 1 had the lowest binding energy (−9.3 kcal/mol) and performed better than its parent compound 155773276. Lead compound 1, with the best binding affinity, has a hydroxyl group in its structure and a change in the core heterocycle of its parent compound to benzimidazole, and pyrimidine introduces a synergistic effect and consequently increases the binding energy. The stability of the best hit and optimized compound at the StOASS active site was determined using RMSD, RMSF, radius of gyration, and SASA plots generated from a molecular dynamics simulation. The MD simulation results were also used to monitor how the introduction of new functional groups of optimized compounds contributes to the stability of ligands at the target active site. The improved binding affinity of these compounds compared to PLP and their toxicity profile, which is predicted to be mild, highlights them as good inhibitors of StOASS, and hence, possible antimicrobial adjuvants.

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Macitentan: An overview of its degradation products, process-related impurities, and in silico toxicity.

Cited by 4 publications

References 32 publications

Aurones: A Promising Scaffold to Inhibit SARS-CoV-2 Replication

Aurones: A Promising Scaffold to Inhibit SARS-CoV-2 Replication

Synthesis and evaluation of hybrid sulfonamide‐chalcones with potential antileishmanial activity

In Silico Design of Potential Small-Molecule Antibiotic Adjuvants against Salmonella typhimurium Ortho Acetyl Sulphydrylase Synthase to Address Antimicrobial Resistance

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