Design and synthesis of novel quinazolinone–chalcone hybrids as potential apoptotic candidates targeting caspase-3 and PARP-1:<i>in vitro</i>, molecular docking, and SAR studies

Madbouly, Eman A.; Lashine, El‐Sayed M.; Al‐Karmalawy, Ahmed A.; Sebaiy, Mahmoud M.; Pratsinis, Harris; Kletsas, Dimitris; Metwally, Kamel

doi:10.1039/d2nj04053k

Cited by 17 publications

(22 citation statements)

References 90 publications

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“…The NMR ( 1 H and 13 C APT), HRMS, and FTIR spectra of the synthesized compounds were given in Supporting Information (SI) file. In addition, the IC 50 and K i plots of enzyme inhibition assay are also seen in SI file.…”

Section: Supporting Information Summarymentioning

confidence: 99%

New Diacetic Acids Containing Quinazolin‐4(3H)‐one: Synthesis, Characterization, Anticholinergic Properties, DFT Analysis and Molecular Docking Studies

Tokalı¹,

Kaya²,

Öztekіn³

et al. 2023

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In this study, a new series of quinazolin-4(3H)-ones, which constitute an important part of biologically active heterocyclic compounds, were synthesized with excellent yields (99-94 %). The structures of the synthesized compounds (1-14) were characterized with Fourier-transform infrared (FTIR), nuclear magnetic resonance ( 1 H NMR -13 C NMR), and high-resolution mass spectroscopy (HRMS). Acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibition properties were examined to evaluate the anticholinergic properties of the synthe-sized compounds. For AChE, molecules showed IC 50 in ranging of 16.27-9.12 μM and K i s in ranging of 19.20 � 0.68-4.83 � 0.19 μM. For BChE, molecules showed IC 50 in ranging of 16.77-8.50 μM and K i s in ranging of 10.35 � 2.15-3.38 � 0.25 μM. Molecular docking was performed to determine the predicted interactions between the synthesized molecules and enzymes. Additionally, Density-functional theory (DFT) studies were also carried out to clarify the electronic structures of compounds.

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Section: Supporting Information Summarymentioning

confidence: 99%

New Diacetic Acids Containing Quinazolin‐4(3H)‐one: Synthesis, Characterization, Anticholinergic Properties, DFT Analysis and Molecular Docking Studies

Tokalı¹,

Kaya²,

Öztekіn³

et al. 2023

ChemistrySelect

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“…Cell cycle regulation and the induction of programmed cell death, or apoptosis, play crucial roles in cancer development and treatment . As a result, the most potent synthetic chemical, 8e , was chosen for testing its outcomes on the cell cycle profile and apoptosis.…”

Section: Resultsmentioning

confidence: 99%

“…Cell cycle regulation and the induction of programmed cell death, or apoptosis, play crucial roles in cancer development and treatment. 53 As a result, the most potent synthetic chemical, 8e, was chosen for testing its outcomes on the cell cycle profile and apoptosis. The breast cancer cell line (MCF-7) was selected to disclose the cell-cycle profile and apoptotic power for compound 8e on this cell line against which it was cytotoxic.…”

Section: Cell Cycle and Apoptosis Analysismentioning

confidence: 99%

Ligand-Based Design on the Dog-Bone-Shaped BIBR1532 Pharmacophoric Features and Synthesis of Novel Analogues as Promising Telomerase Inhibitors with In Vitro and In Vivo Evaluations

et al. 2022

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Telomerase is an outstanding biological target for cancer treatment. BIBR1532 is a non-nucleoside selective telomerase inhibitor; however, it experiences ineligible pharmacokinetics. Herein, we aimed to design new BIBR1532-based analogues as promising telomerase inhibitors. Therefore, two novel series of pyridazine-linked to cyclopenta[b]thiophene (8a−f) and tetrahydro-1-benzothiophene (9a−f) were synthesized. A quantitative real-time polymerase chain reaction was utilized to investigate the telomerase inhibitory activity of candidates. Notably, 8e and 9e exhibited the best inhibition profiles. Moreover, 8e showed strong antitumor effects against both MCF-7 and A549 cancer cell lines. The effects of 8e on the cell cycle and apoptosis were measured. Besides, 8e was evaluated for its in vivo antitumor activity using solid Ehrlich carcinoma. The reduction in both the tumor weight and volume was greater than doxorubicin. Also, molecular docking and ADME studies were performed. Finally, a SAR study was conducted to gain further insights into the different telomerase inhibition potentials upon variable structural modifications.

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“…Two different molecular docking studies were performed to investigate the dual inhibitory activities of the novel ( 6a – l ) candidates against both EGFR (PDB ID: 1M17 [ 47 ]) and HER2 (PDB ID: 3RCD [ 18 ]) targets using the MOE 2019.0102 program [ 45 , 46 ]. The co-crystallized inhibitor of EGFR (4-anilinoquinazoline, AQ4) and that of HER2 (pyrrolo [3,2- d ]pyrimidine, 03P) were used as reference standards.…”

Section: Resultsmentioning

confidence: 99%

“…The MOE 2019.0102 [ 45 , 46 ] was used to perform two different molecular docking studies for the newly designed candidates ( 6a – l ) against both EGFR (PDB ID: 1M17 [ 47 ]) and HER2 (PDB ID: 3RCD [ 18 ]) receptors to investigate their dual inhibitory activities. The resolution values for both 1M17 and 3RCD are 2.60 and 3.21, respectively, indicating greatly acceptable and accurate X-ray structures of the two protein receptors.…”

Section: Methodsmentioning

confidence: 99%

Design, Synthesis, Biological Evaluation, and Molecular Dynamics Studies of Novel Lapatinib Derivatives

et al. 2022

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Co-expression of the epidermal growth factor receptor (EGFR, also known as ErbB1) and human epidermal growth factor receptor 2 (HER2) has been identified as a diagnostic or prognostic sign in various tumors. Despite the fact that lapatinib (EGFR/HER2 dual inhibitor) has shown to be successful, many patients do not respond to it or develop resistance for a variety of reasons that are still unclear. As a result, new approaches and inhibitory small molecules are still needed for EGFR/HER2 inhibition. Herein, novel lapatinib derivatives possessing 4-anilinoquinazoline and imidazole scaffolds (6a–l) were developed and screened as EGFR/HER2 dual inhibitors. In vitro and in silico investigations revealed that compound 6j has a high affinity for the ATP-binding regions of EGFR and HER2. All of the designed candidates were predicted to not penetrate the BBB, raising the expectation for the absence of CNS side effects. At 10 µM, derivatives possessing 3-chloro-4-(pyridin-2-ylmethoxy)aniline moiety (6i–l) demonstrated outstanding ranges of percentage inhibition against EGFR (97.65–99.03%) and HER2 (87.16–96.73%). Compound 6j showed nanomolar IC50 values over both kinases (1.8 nM over EGFR and 87.8 nM over HER2). Over EGFR, compound 6j was found to be 50-fold more potent than staurosporine and 6-fold more potent than lapatinib. A kinase selectivity panel of compound 6j showed poor to weak inhibitory activity over CDK2/cyclin A, c-MET, FGFR1, KDR/VEGFR2, and P38a/MAPK14, respectively. Structure–activity relationship (SAR) that were obtained with different substitutions were justified. Additionally, molecular docking and molecular dynamics studies revealed insights into the binding mode of the target compounds. Thus, compound 6j was identified as a highly effective and dual EGFR/HER2 inhibitor worthy of further investigation.

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Design and synthesis of novel quinazolinone–chalcone hybrids as potential apoptotic candidates targeting caspase-3 and PARP-1:in vitro, molecular docking, and SAR studies

Abstract: A new series of thirty-one quinazolinone-chalcone hybrid molecules 13-43 were designed, synthesized, and structurally characterized by different spectroscopic techniques. All the synthesized compounds were investigated for in vitro cytotoxic activity...

Cited by 17 publications

References 90 publications

New Diacetic Acids Containing Quinazolin‐4(3H)‐one: Synthesis, Characterization, Anticholinergic Properties, DFT Analysis and Molecular Docking Studies

New Diacetic Acids Containing Quinazolin‐4(3H)‐one: Synthesis, Characterization, Anticholinergic Properties, DFT Analysis and Molecular Docking Studies

Ligand-Based Design on the Dog-Bone-Shaped BIBR1532 Pharmacophoric Features and Synthesis of Novel Analogues as Promising Telomerase Inhibitors with In Vitro and In Vivo Evaluations

Design, Synthesis, Biological Evaluation, and Molecular Dynamics Studies of Novel Lapatinib Derivatives

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