Insights into the crystal structure of two newly synthesized quinoxalines derivatives as potent inhibitor for <i>c</i>-Jun <i>N</i>-terminal kinases

Abad, Nadeem; Bakri, Youness El; Lai, Chin‐Hung; Karthikeyan, S.; Ramli, Youssef; Ferfra, S.; Mague, Joel T.; Essassi, El Mokhtar

doi:10.1080/07391102.2020.1844049

Cited by 7 publications

(5 citation statements)

References 43 publications

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“…The molecular docking simulation results in 100 different conformations of the complex [28–38] . Among them, the best‐docked position of the protein‐ligand complex was found based on binding energy.…”

Section: Resultsmentioning

confidence: 99%

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Synthesis, Crystal Structure, Computational Investigation of Vanillin Azine Derivative as Potent Blocker of the N‐Terminal Ras‐Binding Domain (RBD) in Human a‐Raf Kinase

Mohamed,

Karthikeyan,

Ahsin

et al. 2024

ChemistrySelect

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Vanillin is the main component of natural vanilla extract and is responsible for its flavoring properties. Besides its well‐known applications as an additive in food and cosmetics. In this, we have synthesized a new vanillin derivative. Its structure was characterized by IR, MS, NMR and confirmed by single‐crystal X‐ray analysis. The asymmetric unit of the title molecule consists of two independent half molecules, each having crystallographically imposed centrosymmetry. Reticular layers approximately parallel to the bc plane are generated from one molecule through O−H⋅⋅⋅N hydrogen bonds. The layers are linked by the second molecule through O−H⋅⋅⋅O hydrogen bonds to form a 3‐D network structure. We carried out density functional investigations to understand the compound‘s molecular reactivity and chemical stability. Frontier molecular orbital (FMO) analysis, global reactivity, and Fukui parameters were calculated at the B3LYP/6‐31+G(d,p) method. In 20 % to 30 % of human malignancies, RAS genes are activated ontogenetically by point mutations. New strategies to block this oncogenic protein are needed since it has proven difficult to create efficient RAS inhibitors. The above‐titled compound shows better structural activity relationship studies against Ras‐binding domine, based on this molecular docking simulation as well as the drug‐likeness analysis carried out for our newly synthesized compound.

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Section: Resultsmentioning

confidence: 99%

“…The molecular docking simulation results in 100 different conformations of the complex. [28][29][30][31][32][33][34][35][36][37][38] Among them, the bestdocked position of the protein-ligand complex was found based on binding energy. In this case, the binding energy was found to be À 5.08 kcal/mol (Figure 7).…”

Section: Molecular Dockingmentioning

confidence: 99%

Synthesis, Crystal Structure, Computational Investigation of Vanillin Azine Derivative as Potent Blocker of the N‐Terminal Ras‐Binding Domain (RBD) in Human a‐Raf Kinase

Mohamed,

Karthikeyan,

Ahsin

et al. 2024

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“…Quinoxaline derivatives made up of a fused benzene ring and pyrazine ring constitute an important class of heterocyclic compounds which, even when part of a complex molecule, possess a wide spectrum of biological activities (Abad et al, 2020). Quinoxaline derivatives have been synthesized by several methods (Chen et al, 2021;Ramli et al, 2010) and possess interesting properties such as anti-bacterial (Ammar et al, 2020), anti-inflammatory (Meka & Chintakunta, 2023), anticancer (Jain et al, 2019) and kinase inhibition (Oyallon et al, 2018).…”

Section: Chemical Contextmentioning

confidence: 99%

“…In a continuation of our ongoing research in this area (Abad et al, 2020), we have synthesized the title compound (I) by reacting ethyl bromide with 6-nitro-1,4-dihydroquinoxaline-2,3-dione and potassium carbonate in the presence of tetra-nbutyl ammonium bromide as catalyst. We report herein the synthesis, crystal structure and Hirshfeld surface analysis and the density functional theory (DFT) computational calculations carried out at the B3LYP/6-311G(d,p) level for comparing with the experimentally determined molecular structure in the solid state of the title compound.…”

Section: Chemical Contextmentioning

confidence: 99%

Crystal structure and Hirshfeld surface analysis of 3-ethoxy-1-ethyl-6-nitroquinoxalin-2(1H)-one

Yousra,

El Ghayati,

Hökelek

et al. 2023

Acta Cryst E

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The asymmetric unit of the title compound, C12H13N3O4, consists of two molecules differing to a small degree in their conformations. In the crystal, layers of molecules are connected by weak C—H...O hydrogen bonds and slipped π-stacking interactions. These layers lie parallel to (10\overline{1}) and are stacked along the normal to that plane. Hirshfeld surface analysis indicates that the most important contributions for the crystal packing arise from H...H (43.5%) and H...O/O...H (30.8%) contacts. The density functional theory (DFT) optimized structure of the title compound at the B3LYP/ 6–311 G(d,p) level agrees well with the experimentally determined molecular structure in the solid state.

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“…Quinoxaline is a privileged scaffold and one of the main blocks of different anticancer agents as it has been proven to be selective adenosine triphosphate (ATP) competitive as well as a bioisostere to benzimidazole, quinazolinones, isoquinolinones, phenanthridone, or phthalazinones, which are the basic scaffolds of the plurality of PARP-1 inhibitors [ 25 , 26 , 27 ]. In addition, sulfonyl and sulfonamide moieties conjugated to different heterocyclic ring systems have been reported as one of the most privileged scaffolds to inhibit the growth of various human cancer cell lines via different modes of action [ 28 , 29 ].…”

Section: Introductionmentioning

confidence: 99%

New Quinoxaline-Based Derivatives as PARP-1 Inhibitors: Design, Synthesis, Antiproliferative, and Computational Studies

et al. 2022

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Herein, 2,3-dioxo-1,2,3,4-tetrahydroquinoxaline was used as a bio-isosteric scaffold to the phthalazinone motif of the standard drug Olaparib to design and synthesize new derivatives of potential PARP-1 inhibitory activity using the 6-sulfonohydrazide analog 3 as the key intermediate. Although the new compounds represented the PARP-1 suppression impact of IC50 values in the nanomolar range, compounds 8a, 5 were the most promising suppressors, producing IC50 values of 2.31 and 3.05 nM compared to Olaparib with IC50 of 4.40 nM. Compounds 4, 10b, and 11b showed a mild decrease in the potency of the IC50 range of 6.35–8.73 nM. Furthermore, compounds 4, 5, 8a, 10b, and 11b were evaluated as in vitro antiproliferative agents against the mutant BRCA1 (MDA-MB-436, breast cancer) compared to Olaparib as a positive control. Compound 5 exhibited the most significant potency of IC50; 2.57 µM, whereas the IC50 value of Olaparib was 8.90 µM. In addition, the examined derivatives displayed a promising safety profile against the normal WI-38 cell line. Cell cycle, apoptosis, and autophagy analyses were carried out in the MDA-MB-436 cell line for compound 5, which exhibited cell growth arrest at the G2/M phase, in addition to induction of programmed apoptosis and an increase in the autophagic process. Molecular docking of the compounds 4, 5, 8a, 10b, and 11b into the active site of PARP-1 was carried out to determine their modes of interaction. In addition, an in silico ADMET study was performed. The results evidenced that compound 5 could serve as a new framework for discovering new potent anticancer agents targeting the PARP-1 enzyme.

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Insights into the crystal structure of two newly synthesized quinoxalines derivatives as potent inhibitor for c-Jun N-terminal kinases

Cited by 7 publications

References 43 publications

Synthesis, Crystal Structure, Computational Investigation of Vanillin Azine Derivative as Potent Blocker of the N‐Terminal Ras‐Binding Domain (RBD) in Human a‐Raf Kinase

Synthesis, Crystal Structure, Computational Investigation of Vanillin Azine Derivative as Potent Blocker of the N‐Terminal Ras‐Binding Domain (RBD) in Human a‐Raf Kinase

Crystal structure and Hirshfeld surface analysis of 3-ethoxy-1-ethyl-6-nitroquinoxalin-2(1H)-one

New Quinoxaline-Based Derivatives as PARP-1 Inhibitors: Design, Synthesis, Antiproliferative, and Computational Studies

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