Novel 4-thiophenyl-pyrazole, pyridine, and pyrimidine derivatives as potential antitumor candidates targeting both EGFR and VEGFR-2; design, synthesis, biological evaluations, and<i>in silico</i>studies

Al-Muntaser, Samia M.; Al‐Karmalawy, Ahmed A.; El‐Naggar, Abeer M.; Khalil, A. M.; El‐Sattar, Nour E. A. Abd; Abbass, Eslam M.

doi:10.1039/d3ra00416c

Cited by 21 publications

(12 citation statements)

References 57 publications

(79 reference statements)

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“…This comparative analysis highlights the acceptable binding affinity of ( 3 ), supporting its potential for further development as an effective VEGFR-2 inhibitor. The 2D interaction diagram of ( 3 ) (Figure ) displayed a common binding pattern with the key residues ASP1046 and GLU885 in the VEGFR-2 active site, comparable to the reference compounds. ,− (Figures – ). The analysis revealed eight types of bonds formed between compound ( 3 ) and the receptor, including two conventional hydrogen bonds with ASP1046, pi–anion bonds with GLU885 and LYS868, alkyl bonds with ILE1044, LEU1019 and VAL898, pi–alkyl bonds with VAL899 and VAL916, a pi–sulfur bond with CYS1045, a pi–σ bond with LE889, and van der Waals bonds with VAL848, ILE888, and ILE892.…”

Section: Resultsmentioning

confidence: 71%

“…This score suggests a strong affinity of compound ( 3 ) toward the VEGFR-2 receptor, indicating its potential as a VEGFR-2 inhibitor. When compared to established reference compounds, ,− ( 3 ) demonstrated a competitive binding affinity, closely aligning with Axitinib (−9.3 kcal/mol) and Sunitinib (−9.3 kcal/mol). Although its score was lower than that of Sorafenib (−11.0 kcal/mol), it outperformed that of Tamoxifen (−7.1 kcal/mol).…”

Section: Resultsmentioning

confidence: 88%

“…The E LUMO values of −2.3997, −1.8806, and −0.7115 eV depict these respective energy states. The Δ E gap of 3.2230 eV is indicative of the molecule’s kinetic stability, with a small gap suggesting promising reactivity in comparison to 4.55 eV for Sorafenib, 4.19 eV for Erlotinib, and 7.22 eV for Lenvatinib. − Moreover, the chemical hardness (η) of 1.6115 eV highlights the molecule’s resistance to electron exchange and its overall stability. Specifically, it quantifies the energy required to add or remove an electron from the system.…”

Section: Resultsmentioning

confidence: 99%

“…This characteristic aligns with the molecule’s elevated electrophilicity index, indicating that it not only attracts electrons strongly but also actively engages in electrophilic reactions, portraying a dynamic reactivity profile. The combination of a higher global electronegativity, electrophilicity index, and lower chemical hardness collectively suggests that the molecule is predisposed to engaging in chemical reactions, particularly those involving electron transfer, while exhibiting stability in its electronic structure. − …”

Section: Resultsmentioning

confidence: 99%

“…The molecule ( 3 ) was converted to 3D PDB format by OpenBabel and then to 3D PDBQT format using AutoDockTools. Sorafenib (CID: 216239), Axitinib (CID: 6450551), Sunitinib (CID: 5329102), and Tamoxifen (CID: 2733526) were used as reference compounds. ,− To facilitate the molecular docking study, a grid box was generated to cover all target active site residues described in the literature; details of the molecular docking active site residues and grid box parameters are shown in Table .…”

Section: Methodsmentioning

confidence: 99%

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Synthesis, Characterizations, and Quantum Chemical Investigations on Imidazo[1,2-a]pyrimidine-Schiff Base Derivative: (E)-2-Phenyl-N-(thiophen-2-ylmethylene)imidazo[1,2-a]pyrimidin-3-amine

Azzouzi,

Azougagh,

Ouchaoui

et al. 2023

ACS Omega

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In this study, (E)-2-phenyl-N-(thiophen-2ylmethylene)imidazo[1,2-a]pyrimidin-3-amine (3) is synthesized, and detailed spectral characterizations using 1 H NMR, 13 C NMR, mass, and Fourier transform infrared (FT-IR) spectroscopy were performed. The optimized geometry was computed using the density functional theory method at the B3LYP/6-311++G(d,p) basis set. The theoretical FT-IR and NMR ( 1 H and 13 C) analysis are agreed to validate the structural assignment made for (3). Frontier molecular orbitals, molecular electrostatic potential, Mulliken atomic charge, electron localization function, localized orbital locator, natural bond orbital, nonlinear optical, Fukui functions, and quantum theory of atoms in molecules analyses are undertaken and meticulously interpreted, providing profound insights into the molecular nature and behaviors. In addition, ADMET and drug-likeness studies were carried out and investigated. Furthermore, molecular docking and molecular dynamics simulations have been studied, indicating that this is an ideal molecule to develop as a potential vascular endothelial growth factor receptor-2 inhibitor.

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Section: Resultsmentioning

confidence: 71%

Section: Resultsmentioning

confidence: 88%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

See 3 more Smart Citations

Synthesis, Characterizations, and Quantum Chemical Investigations on Imidazo[1,2-a]pyrimidine-Schiff Base Derivative: (E)-2-Phenyl-N-(thiophen-2-ylmethylene)imidazo[1,2-a]pyrimidin-3-amine

Azzouzi,

Azougagh,

Ouchaoui

et al. 2023

ACS Omega

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Exploring the Antioxidant Potency of New Naphthalene‐Based Chalcone Derivatives: Design, Synthesis, Antioxidant Evaluation, Docking Study, DFT Calculations

Balamon,

El‐Bordany,

Mahmoud

et al. 2023

Chemistry & Biodiversity

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A new naphthalene‐based chalcone derivative was successfully synthesized through the condensation of 2,4‐dichlorobenzaldehyde with 2‐acetylnaphthalene. This chalcone, denoted as compound 1, demonstrated a versatile reactivity upon treatment with both nitrogen and carbon nucleophiles, and yielded diverse heterocyclic scaffolds such as pyrazoline, thiazole, pyrimidine, pyran, and pyridine derivatives. The pyrazoline aldehyde derivative 7 was further derivatized to produce the hydrazide‐hydrazone 13, namely, (1H‐pyrazol‐1‐yl)methylene)acetohydrazide, which was exploited to synthesize derivatives of 2‐oxo‐2H‐chromene‐3‐carbohydrazide 14, 2‐(4‐oxo‐4,5‐dihydrothiazol‐2‐yl)acetohydrazide 15, and 3‐(4‐nitrophenyl)acrylohydrazide 16. All the newly synthesized compounds were characterized spectroscopic data. Furthermore, these heterocyclic derivatives were screened for their antioxidant capacities using the DPPH radical assay. The results showed that compounds 5 and 10 are the most potent antioxidants with IC50 comparable to that of ascorbic acid. Meanwhile, compounds 2, 12, 13, 14, 15, and 16 exhibited moderate antioxidant activities. Thus, these heterocycles could emerge as promising antioxidant drugs for the treatment of oxidative stress‐related diseases. Finally, molecular docking was conducted to study the binding affinity for the most potent antioxidant compounds 5, 10, and ascorbic acid inside the active pocket of Human Peroxiredoxin 5. DFT calculations and global descriptors were calculated for the most potent compounds to correlate the relation between chemical structure and reactivity.

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Exploring the Antiproliferative Potency of Pyrido[2,3‐d]Pyrimidine Derivatives: Studies on Design, Synthesis, Anticancer Evaluation, SAR, Docking, and DFT Calculations

Abd‐Alsalam,

Hafez,

Assay

et al. 2024

Chemistry & Biodiversity

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Herein, an efficient method for the synthesis of a new series of pyrido[2,3‐d]pyrimidine derivatives has been adopted through the reaction of hydrazinyl pyrido[2,3‐d] pyrimidine derivative (1) with different electrophilic species, such as ethyl cyanoacetate and different 1,3 diketone derivatives, gave the corresponding derivatives (2‐5). Meanwhile, pyrido[2,3‐d][1,2,4]triazolo[4,3‐a]pyrimidines (6‐11) were synthesized via reaction of hydrazine derivative 1 with phenylisothiocyanate, potassium thiocyanate, and carbon disulfide. Compound 1 was also submitted to react with different carbonyl compounds to afford pyrido‐pyrimidine derivatives (12‐15). All the newly synthesized compounds were tested in vitro for their antiproliferative activities against HCT‐116 and MCF‐7 cell lines. Compounds 2, 3, 7, and 8 displayed very strong inhibitory activity against the two cell lines compared with the standard drug doxorubicin. Furthermore, a docking study of the most active compounds was performed with the thymidylate synthase enzyme (PDB: Code 6qxg). Moreover, DFT calculation was carried out for the most biologically active compounds and a reference drug (Doxorubicin) using the B3LYP/6‐31G+(d,p) level of theory. The calculated EHOMO and ELUMO energies were used to calculate the global reactivity parameters. Finally, Molecular electrostatic potential (MEP) and structure activity relationship (SAR) were studied to correlate the relation between chemical structure and reactivity.

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Novel 4-thiophenyl-pyrazole, pyridine, and pyrimidine derivatives as potential antitumor candidates targeting both EGFR and VEGFR-2; design, synthesis, biological evaluations, andin silicostudies

Abstract: Novel 4-thiophenyl-pyrazole, pyridine, and pyrimidine derivatives as potential dual EGFR/VEGFR-2 inhibitors with promising antimicrobial activity as well.

Cited by 21 publications

References 57 publications

Synthesis, Characterizations, and Quantum Chemical Investigations on Imidazo[1,2-a]pyrimidine-Schiff Base Derivative: (E)-2-Phenyl-N-(thiophen-2-ylmethylene)imidazo[1,2-a]pyrimidin-3-amine

Synthesis, Characterizations, and Quantum Chemical Investigations on Imidazo[1,2-a]pyrimidine-Schiff Base Derivative: (E)-2-Phenyl-N-(thiophen-2-ylmethylene)imidazo[1,2-a]pyrimidin-3-amine

Exploring the Antioxidant Potency of New Naphthalene‐Based Chalcone Derivatives: Design, Synthesis, Antioxidant Evaluation, Docking Study, DFT Calculations

Exploring the Antiproliferative Potency of Pyrido[2,3‐d]Pyrimidine Derivatives: Studies on Design, Synthesis, Anticancer Evaluation, SAR, Docking, and DFT Calculations

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