Biological evaluation, docking and molecular dynamic simulation of some novel diaryl urea derivatives bearing quinoxalindione moiety

Abstract

In this study a series of diarylurea derivatives containing quinoxalindione group were biologically evaluated for their cytotoxic activities using MTT assay against MCF-7 and HepG2 cell lines. Antibacterial activities of these compounds were also evaluated by Microplate Alamar Blue Assay (MABA) against three Gram-negative (Escherichia coli, Pseudomonas aeruginosa and Salmonella typhi), three Gram-positive (Staphylococcus aureus, Bacillus subtilis and Listeria monocitogenes) and one yeast-like fungus (Candida albicans) strain. Furthermore, molecular docking was carried out to study the binding pattern of the compounds to the active site of B-RAF kinase (PDB code: 1UWH). Molecular dynamics simulation was performed on the best ligand (16e) to investigate the ligand binding dynamics in the physiological environment. Cytotoxic evaluation revealed the most prominent cytotoxicity for 6 compounds with IC50 values of 10-18 μM against two mentioned cell lines. None of the synthesized compounds showed significant antimicrobial activity. The obtained results of the molecular docking study showed that all compounds fitted in the binding site of enzyme with binding energy range of -11.22 to -12.69 kcal/mol vs sorafenib binding energy -11.74 kcal/mol as the lead compound. Molecular dynamic simulation indicated that the binding of ligand (16e) was stable in the active site of B-RAF during the simulation.

Charge-Transfer Complex of Linifanib with 2,3-dichloro-3,5-dicyano-1,4-benzoquinone: Synthesis, Spectroscopic Characterization, Computational Molecular Modelling and Application in the Development of Novel 96-microwell Spectrophotometric Assay

“…42 Because of the therapeutic importance of LFB, the chemistry of its binding to different organic targets has been a subject of considerable research. 43,44 Owing to the presence of multiple N-based functional groups, LFB molecules can be readily immobilized on a metal substrate for immersible biosensors or on gold nanoparticle (AuNP) nanocarriers for targeted controlled drug delivery (CDD), as shown recently for various highly toxic chemotherapeutic drugs, like gemcitabine, 45 dabrafenib, 46 azacitidine and decitabine. 47 However, the CT reaction of LFB has not been reported.…”

Exploring the interaction between epidermal growth factor receptor tyrosine kinase and some of the synthesized inhibitors using combination of in-silico and in-vitro cytotoxicity methods

“…Cancer is one of the global health problems. Significant progress has been observed in cancer research in the last ten years(27). Considering the adverse complications and resistance to the current chemotherapeutic agents, development of more efficient anticancer agents with less harm has remained as an important subject in drug design(27).…”

“…Significant progress has been observed in cancer research in the last ten years(27). Considering the adverse complications and resistance to the current chemotherapeutic agents, development of more efficient anticancer agents with less harm has remained as an important subject in drug design(27). The findings of this study provide an integral part of the pre-clinical investigation of our compounds that can be further developed as anticancer agents against tumors, with excellent oral absorption.…”

“…MD simulations were performed using the GROMACS package 5.3.1(26). The “pdb2gmx” program was used to generate the topology file for protein using the G43a1 united-atom force field(27). The systems inserted into dodecahedron box and was solvated with the single point charge (SPC216) water model(28).…”

Role of heterocycles in inhibition of VEGFR-2 – a recent update (2019–2022)

“…Quinoxaline, a bioisostere, is considered as an important nucleus for many anticancer drugs, 25,26 and also quinoxaline derivatives were reported to exhibit potent VEGFR-2 inhibitory activity. 27,28 Based on these facts, M. M. Alanazi et al reported 3-methylquinoxaline derivatives as VEGFR-2 inhibitors. 29 Initially, the synthesized compounds were investigated for their anticancer activity wherein N-t -butylbenzamide derivative 15 (Fig.…”