Rational design-aided discovery of novel 1,2,4-oxadiazole derivatives as potential EGFR inhibitors

Unadkat, Vishal; Rohit, Shishir; Parikh, Paranjay; Sanna, Vinod K.; Singh, Sanjay

doi:10.1016/j.bioorg.2021.105124

Cited by 5 publications

(3 citation statements)

References 26 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Upon the initiation of the simulation, we observed an initial fluctuation in the RMSD values, which can be attributed to the equilibration process. However, subsequent to this initial phase, the complex displayed a remarkable level of stability throughout the 30 ns (ns) simulation. − The mean RMSD value indicates a consistently low deviation from that of the initial conformation. These findings suggest that the (3 )-VEGFR-2 complex achieved a well-equilibrated state and maintained a highly stable structure over the course of the simulation.…”

Section: Resultsmentioning

confidence: 99%

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

View full text Add to dashboard Cite

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.

show abstract

Section: Resultsmentioning

confidence: 99%

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

View full text Add to dashboard Cite

show abstract

“…We have previously reported the synthesis of a series of heterocyclic compounds having 1,2,4-oxadiazole scaffold ( Figure 1 ), 24–26 which was obtained by reaction of 4-amino-2-chlorobenzonitrile ( 1 ) with respective acid chloride ( 2 ). The reaction was carried out using triethylamine (TEA) as a base to afford the target amide ( 3 ).…”

Section: Methodsmentioning

confidence: 99%

“…Our previous study screened a library of heterocyclic molecules and identified a set of fourteen molecules exhibiting EGFR inhibition. 24 , 25 In this study, we have performed a molecular docking study on all the fourteen compounds that revealed the four most active compounds/molecules. Finally, these four compounds were chosen for molecular dynamics study and ADME profiling to understand their drug-like properties.…”

Section: Introductionmentioning

confidence: 99%

Identification of 1,2,4-Oxadiazoles-Based Novel EGFR Inhibitors: Molecular Dynamics Simulation-Guided Identification and in vitro ADME Studies

Unadkat¹,

Rohit²,

Parikh³

et al. 2022

OTT

Self Cite

View full text Add to dashboard Cite

Background In this work, we have identified heterocyclic derivatives with 1,2,4 oxadiazole scaffold mimicking the functions of tyrosine kinase inhibitors. Fourteen molecules that displayed the best fit were picked from the library of compounds and studied under in-silico and in-vitro conditions. Four compounds were selected for further cytotoxicity and ADME (Absorption, Distribution, Metabolism, Elimination) profiling showing IC 50 (from 8–13 µM) values against EGFR positive cancer cell line (MCF7). Methods A molecular dynamics simulation study was performed to understand the correlation of non-covalent binding energies with biological activity. The drug-like properties of the selected four compounds (7a, 7b, 7e, and 7m) were evaluated by in-vitro ADME studies. Compounds 7a, 7b , and 7m were the active compounds in the molecular dynamics simulations study. Further, EGFR binding activity was confirmed with EGFR WT and EGFR T790M kinase assay using a luminescence-based method. Results These compounds ( 7a, 7b , and 7m ) showed activity against EGFR WT and mutant EGFR T790M , exhibiting IC 50 values of <10 and <50 micromolar, respectively. These compounds also possess moderate aqueous solubility in 40–70 µg/mL at pH 7.4 and 30–100 µg/mL at pH 4.0. Further, 7a, 7b , and 7m showed balanced lipophilicity with Log D values ranging from 1–3. They demonstrated a good correlation in Caco-2 permeability with Apparent permeability (Papp) 1 to 5 × 10 −6 cm/s in comparison with 7e , which was found to be highly lipophilic (Log D >5) and showed high permeability (Papp 17 × 10 −6 cm/s). Lastly, all these compounds were moderately stable in liver microsomes at alkaline pH with a half-life of 30–60 min, while at a highly acidic pH (2.0), the compounds were stable up to 15–20 min. Conclusion Overall, in-vitro ADME results of these molecules showed good drug-like properties, which are well correlated with the in-silico ADME data, making them ideal for developing an oral drug delivery formulation.

show abstract

A comprehensive review of recent advances in the biological activities of 1,2,4‐oxadiazoles

Hendawy

2022

Archiv der Pharmazie

View full text Add to dashboard Cite

Nitrogen heterocycles play an essential role in medication development. The 1,2,4‐oxadiazole heterocycle has been extensively studied, yielding a large variety of molecules with varied biological functions. The 1,2,4‐oxadiazole shows bioisosteric equivalency with ester and amide moieties. In recent years, the 1,2,4‐oxadiazole nucleus has received a lot of attention in medicinal chemistry. It was thought to be a pharmacophore component in the production of biologically intriguing drugs. This review presents a comprehensive overview of the recent achievements in the biological activities of 1,2,4‐oxadiazoles as potential antimicrobial, anticancer, anti‐inflammatory, neuroprotective, and antidiabetic agents. The structure–activity relationship and mechanisms of action are also reviewed.

show abstract

Rational design-aided discovery of novel 1,2,4-oxadiazole derivatives as potential EGFR inhibitors

Cited by 5 publications

References 26 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

Identification of 1,2,4-Oxadiazoles-Based Novel EGFR Inhibitors: Molecular Dynamics Simulation-Guided Identification and in vitro ADME Studies

A comprehensive review of recent advances in the biological activities of 1,2,4‐oxadiazoles

Contact Info

Product

Resources

About