Synthesis, in-silico, and in-vitro study of novel chloro methylquinazolinones as PI3K-δ inhibitors, cytotoxic agents

Elfeky, Sherin M.; Almehmadi, Samar J.; Tawfik, Samar S.

doi:10.1016/j.arabjc.2021.103614

Cited by 6 publications

(2 citation statements)

References 43 publications

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“…Molecular docking has been performed using the Molecular Operating Environment (MOE) software, according to the literature 68 . First, the MOE builder was used to build ligands in 3D conformation via 3D protonation and assigning partial charges, followed by energy minimisation using the MMFF94x force field.…”

Section: Methodsmentioning

confidence: 99%

Novel pyrimidine Schiff bases and their selenium-containing nanoparticles as dual inhibitors of CDK1 and tubulin polymerase: design, synthesis, anti-proliferative evaluation, and molecular modelling

El‐Kalyoubi

El‐Sebaey

El‐Sayed

et al. 2023

Journal of Enzyme Inhibition and Medicinal Chemistry

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Nanotechnology-based strategies can overcome the limitations of conventional cancer therapies. Hence, novel series of pyrimidine Schiff bases ( 4–9 ) were employed in the synthesis of selenium nanoparticle forms ( 4NPs–9NPs ). All selenium nano-sized forms exerted greater inhibitions than normal-sized compounds, far exceeding 5-fluorouracil activity. Compound 4 showed effective anti-proliferative activity against MCF-7(IC 50 3.14 ± 0.04 µM), HepG-2(IC 50 1.07 ± 0.03 µM), and A549(IC 50 1.53 ± 0.01 µM) cell lines, while its selenium nanoform 4NPs showed excellent inhibitory effects, with efficacy increased by 96.52%, 96.45%, and 93.86%, respectively. Additionally, 4NPs outperformed 4 in selectivity against the Vero cell line by 4.5-fold. Furthermore, 4NPs exhibited strong inhibition of CDK1(IC 50 0.47 ± 0.3 µM) and tubulin polymerase(IC 50 0.61 ± 0.04 µM), outperforming 4 and being comparable to roscovitine (IC 50 0.27 ± 0.03 µM) and combretastatin-A4(IC 50 0.25 ± 0.01 µM), respectively. Moreover, both 4 and 4NPs arrested the cell cycle at G0/G1 phase and significantly forced the cells towards apoptosis. Molecular docking demonstrated that 4 and 4NPs were able to inhibit CDK1 and tubulin polymerase binding sites.

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Section: Methodsmentioning

confidence: 99%

Novel pyrimidine Schiff bases and their selenium-containing nanoparticles as dual inhibitors of CDK1 and tubulin polymerase: design, synthesis, anti-proliferative evaluation, and molecular modelling

El‐Kalyoubi

El‐Sebaey

El‐Sayed

et al. 2023

Journal of Enzyme Inhibition and Medicinal Chemistry

Self Cite

View full text Add to dashboard Cite

show abstract

“…Molecular docking simulation was conducted using the Molecular Operating Environment (MOE) software 2009 following the literature [ 72 ]. First, ligands were built using the MOE builder, 3D protonated, partial charges assigned, and then energy-minimized using MMFF94x force field.…”

Section: Methodsmentioning

confidence: 99%

Novel Aminopyrimidine-2,4-diones, 2-Thiopyrimidine-4-ones, and 6-Arylpteridines as Dual-Target Inhibitors of BRD4/PLK1: Design, Synthesis, Cytotoxicity, and Computational Studies

El-Kalyoubi,

El-Sebaey,

Elfeky

et al. 2023

Pharmaceuticals

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Structural-based drug design and solvent-free synthesis were combined to obtain three novel series of 5-arylethylidene-aminopyrimidine-2,4-diones (4, 5a–c, 6a,b), 5-arylethylidene-amino-2-thiopyrimidine-4-ones (7,8), and 6-arylpteridines (9,10) as dual BRD4 and PLK1 inhibitors. MTT assays of synthesized compounds against breast (MDA-MB-231), colorectal (HT-29), and renal (U-937) cancer cells showed excellent-to-good cytotoxic activity, compared to Methotrexate; MDA-MB-231 were the most sensitive cancer cells. The most active compounds were tested against normal Vero cells. Compounds 4 and 7 significantly inhibited BRD4 and PLK1, with IC50 values of 0.029, 0.042 µM, and 0.094, 0.02 µM, respectively, which are nearly comparable to volasertib (IC50 = 0.017 and 0.025 µM). Compound 7 triggered apoptosis and halted cell growth at the G2/M phase, similarly to volasertib. It also upregulated the BAX and caspase-3 markers while downregulating the Bcl-2 gene. Finally, active compounds fitted the volasertib binding site at BRD4 and PLK1 and showed ideal drug-like properties and pharmacokinetics, making them promising anticancer candidates.

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A comprehensive review of small molecules targeting PI3K pathway: Exploring the structural development for the treatment of breast cancer

Dubey,

Sharma,

Gupta

et al. 2024

Bioorganic Chemistry

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Synthesis, in-silico, and in-vitro study of novel chloro methylquinazolinones as PI3K-δ inhibitors, cytotoxic agents

Cited by 6 publications

References 43 publications

Novel pyrimidine Schiff bases and their selenium-containing nanoparticles as dual inhibitors of CDK1 and tubulin polymerase: design, synthesis, anti-proliferative evaluation, and molecular modelling

Novel pyrimidine Schiff bases and their selenium-containing nanoparticles as dual inhibitors of CDK1 and tubulin polymerase: design, synthesis, anti-proliferative evaluation, and molecular modelling

Novel Aminopyrimidine-2,4-diones, 2-Thiopyrimidine-4-ones, and 6-Arylpteridines as Dual-Target Inhibitors of BRD4/PLK1: Design, Synthesis, Cytotoxicity, and Computational Studies

A comprehensive review of small molecules targeting PI3K pathway: Exploring the structural development for the treatment of breast cancer

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