Hydroxynaphthalenecarboxamides and substituted piperazinylpropandiols, two new series of BRAF inhibitors. A theoretical and experimental study

Campos, Ludmila Estefanía; Garibotto, Francisco Matías; Angelina, Emilio; Kos, Jiří; Goněc, Tomáš; Marvanova, Pavlina; Vettorazzi, Marcela Cristina; Oravec, Michal; Jendrzejewska, Izabela; Jampílek, Josef; Alvarez, Sergio E.; Enriz, Ricardo D.

doi:10.1016/j.bioorg.2020.104145

Cited by 10 publications

(9 citation statements)

References 47 publications

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“…Combined studies using molecular modeling techniques (docking calculations, MD simulation, and analysis per residue) were previously used by us in other biological systems. [70][71][72][73][74] CONFLICT OF INTERESTS…”

Section: Molecular Mechanics Generalized Born Surface Area (Mm-gbsa) Free-energy Decompositionmentioning

confidence: 96%

Quinazoline‐tethered hydrazone: A versatile scaffold toward dual anti‐TB and EGFR inhibition activities in NSCLC

Emam

Dahal

Singh

et al. 2021

Archiv der Pharmazie

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Globally, lung cancer and tuberculosis are considered to be very serious and complex diseases. Evidence suggests that chronic infection with tuberculosis (TB) can often lead to lung tumors; therefore, developing drugs that target both diseases is of great clinical significance. In our study, we designed and synthesized a suite of 14 new quinazolinones (5a-n) and performed biological investigations of these compounds in Mycobacterium tuberculosis (MTB) and cancer cell lines. In addition, we conducted a molecular modeling study to determine the mechanism of action of these compounds at the molecular level. Compounds that showed anticancer activity in the preliminary screening were further evaluated in three cancer cell lines (A549, Calu-3, and BT-474 cells) and characterized in an epidermal growth factor receptor (EGFR) binding assay. Cytotoxicity in noncancerous lung fibroblast cells was also evaluated to obtain safety data. Our theoretical and experimental studies indicated that our compounds showed a mechanism of action similar to that of erlotinib by inhibiting the EGFR tyrosine kinase. In turn, the antituberculosis activity of these compounds would be produced by the inhibition of enoyl-ACP-reductase. From our findings, we were able to identify two potential lead compounds (5i and 5l) with dual activity and elevated safety toward noncancerous lung fibroblast cells. In addition, our data identified three compounds with excellent anti-TB activities (compounds 5i, 5l, and 5n).

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Section: Molecular Mechanics Generalized Born Surface Area (Mm-gbsa) Free-energy Decompositionmentioning

confidence: 96%

Quinazoline‐tethered hydrazone: A versatile scaffold toward dual anti‐TB and EGFR inhibition activities in NSCLC

Emam

Dahal

Singh

et al. 2021

Archiv der Pharmazie

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“…40,41 In 2011, vemurafenib, a pyrolo-pyrimidine based diphenyl sulfonamide derivative 42 of type I 1/2 , (aC-OUT/ DFG-IN) 43 received FDA approval for rst oral BRAF V600E inhibitor. 44,45 Encorafenib (LGX-818), a pyrazolo-pyrimidine based phenyl sulfonamide derivative, 39 was approved by the FDA in June 2018 for the treatment of BRAF V600E/K mutated cancer. Patients with metastatic melanoma can take a combination of encorafenib and binimetinib (inhibitors of BRAF and MEK).…”

Section: Different Binding Modes Of Braf Protein With Inhibitorsmentioning

confidence: 99%

“…[34][35][36][37] 1.3 Pyrimidine-sulfonamide hybrids BRAF inhibitors Dabrafenib mesylate type I 1/2 , (aC-OUT/DFG-IN) inhibitor is an FDA-approved pyrimidine-thiazole based diphenyl sulfonamide derivative for the treatment of metastatic melanoma in patients with BRAF V600E mutation. 38,39 Dabrafenib was rst developed by GlaxoSmithKline (GSK) under the name GSK2118436. It is an ATP-competitive inhibitor of BRAF kinases.…”

Section: Different Binding Modes Of Braf Protein With Inhibitorsmentioning

confidence: 99%

Gaussian field-based 3D-QSAR and molecular simulation studies to design potent pyrimidine–sulfonamide hybrids as selective BRAF^V600Einhibitors

et al. 2022

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“…In order to evaluate in more details the molecular interactions of different molecular complexes, in the last stage of our study we carried out QTAIM calculations. This methodology was successfully applied in previous works [60][61][62][63][64][65]. Indeed, we have formerly reported and described the molecular interactions established in the active site of AChE and BChE when complexed with the well-known cholinesterase inhibitors RIV [66,67] and galantamine [68][69][70][71] and other ligands with great structural variability, including alkaloids [69,70], carbamates [67], 4-[(alkoxycarbonyl)amino]benzoates [66], and N-benzyl-2-phenylethanamine derivatives [72].…”

Section: Molecular Modeling Studiesmentioning

confidence: 99%

“…Previously we have used QTAIM calculations as a complementary technique for dynamic approaches. We have proved that QTAIM calculations are a useful tool in the study of enzyme-ligand complexes with different structural complexity, since they provide accurate information of molecular interactions that take part in complexes formation [62]. In addition, we have recently applied this technique to the study of different complexes of both AChE and BChE [66,67].…”

Section: Qtaim Calculationsmentioning

confidence: 99%

Novel Sulfonamide-Based Carbamates as Selective Inhibitors of BChE

Magar

Parravicini

Štěpánková

et al. 2021

IJMS

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A series of 14 target benzyl [2-(arylsulfamoyl)-1-substituted-ethyl]carbamates was prepared by multi-step synthesis and characterized. All the final compounds were tested for their ability to inhibit acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) in vitro, and the selectivity index (SI) was determined. Except for three compounds, all compounds showed strong preferential inhibition of BChE, and nine compounds were even more active than the clinically used rivastigmine. Benzyl {(2S)-1-[(2-methoxybenzyl)sulfamoyl]-4-methylpentan-2-yl}carbamate (5k), benzyl {(2S)-1-[(4-chlorobenzyl)sulfamoyl]-4-methylpentan-2-yl}carbamate (5j), and benzyl [(2S)-1-(benzylsulfamoyl)-4-methylpentan-2-yl]carbamate (5c) showed the highest BChE inhibition (IC50 = 4.33, 6.57, and 8.52 µM, respectively), indicating that derivatives 5c and 5j had approximately 5-fold higher inhibitory activity against BChE than rivastigmine, and 5k was even 9-fold more effective than rivastigmine. In addition, the selectivity index of 5c and 5j was approx. 10 and that of 5k was even 34. The process of carbamylation and reactivation of BChE was studied for the most active derivatives 5k, 5j. The detailed information about the mode of binding of these compounds to the active site of both BChE and AChE was obtained in a molecular modeling study. In this study, combined techniques (docking, molecular dynamic simulations, and QTAIM (quantum theory of atoms in molecules) calculations) were employed.

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Hydroxynaphthalenecarboxamides and substituted piperazinylpropandiols, two new series of BRAF inhibitors. A theoretical and experimental study

Cited by 10 publications

References 47 publications

Quinazoline‐tethered hydrazone: A versatile scaffold toward dual anti‐TB and EGFR inhibition activities in NSCLC

Quinazoline‐tethered hydrazone: A versatile scaffold toward dual anti‐TB and EGFR inhibition activities in NSCLC

Gaussian field-based 3D-QSAR and molecular simulation studies to design potent pyrimidine–sulfonamide hybrids as selective BRAF^V600Einhibitors

Novel Sulfonamide-Based Carbamates as Selective Inhibitors of BChE

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Hydroxynaphthalenecarboxamides and substituted piperazinylpropandiols, two new series of BRAF inhibitors. A theoretical and experimental study

Cited by 10 publications

References 47 publications

Quinazoline‐tethered hydrazone: A versatile scaffold toward dual anti‐TB and EGFR inhibition activities in NSCLC

Quinazoline‐tethered hydrazone: A versatile scaffold toward dual anti‐TB and EGFR inhibition activities in NSCLC

Gaussian field-based 3D-QSAR and molecular simulation studies to design potent pyrimidine–sulfonamide hybrids as selective BRAFV600Einhibitors

Novel Sulfonamide-Based Carbamates as Selective Inhibitors of BChE

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Gaussian field-based 3D-QSAR and molecular simulation studies to design potent pyrimidine–sulfonamide hybrids as selective BRAF^V600Einhibitors