Synthesis, cytotoxicity, and molecular docking of substituted 3‐(2‐methylbenzofuran‐3‐yl)‐5‐(phenoxymethyl)‐1,2,4‐oxadiazoles

Abstract

A series of new benzofuran/oxadiazole hybrids (8a-n) was synthesized from 2H-chromene-3-carbonitriles (3a-c) through the multistep synthetic methodology, and these hybrids are known to exhibit anticancer activities. All the compounds were evaluated for their in vitro cytotoxicity against the HCT116 and MIA PaCa2 cell lines. Compounds 6a (IC 50 : 9.71 ± 1.9 μM), 6b (IC 50 : 7.48 ± 0.6 μM), and 6c (IC 50 : 3.27 ± 1.1 μM) displayed a significant cytotoxic activity, whereas compounds 8d and 8e exhibited good activity against both cell lines. The depletion of glycogen synthase kinase-3β (GSK3β) induces apoptosis through the inhibition of basal NF-κB activity in HCT116 colon cancer cells and MIA PaCa2 pancreatic cancer cells. Molecular docking of compounds 6a, 6b, 6c, 8d, and 8e with GSK3β demonstrated the best binding affinity, correlating with the biological activity assay. Furthermore, the structure-activity relationship of these novel compounds reveals promising features for their use in anticancer therapy. K E Y W O R D S 1,2,4-oxadiazole, benzofuran, cytotoxicity, docking studies, glycogen synthase kinase-3β 2 of 12 | MOKENAPELLI ET AL.

4-Dimethylaminopyridine (DMAP), A Superior Mediator for Morita–Balylis–Hillman Reaction-Triggered Annulative Condensation of Salicylaldehydes and Acrylonitrile to Form 3-Cyano-2<i>H</i>-chromenes

“…The NMR data for the known compounds 3a, 25) 3b, 65) 3c, 66) 3d, 22) 3e, 39) 3g, 65) 3h, 25) 3i, 65) 3j, 66) 3k, 25) 3q, 65) 3s, 20) 3t, 67) 3u, 68) 3w, 20) 3x, 20) and 4 59),60) were in good agreement with the literature values (see Supplementary Materials for the spectra). 25) The "General procedure" with 6-methoxysalicylaldehyde 1a (152 mg), and silica gel column chromatography using hexane/EtOAc ( 65) The "General procedure" with 6-methylsalicylaldehyde 1b (136 mg), and silica gel column chromatography using hexane/EtOAc (10/1) gave the title compound (50.1 mg, 29%) as a white solid; 1 H-NMR (CDCl3) δ: 7.39 (1H, br s), 7.16 (1H, t, J=7.9 Hz), 6.81 (1H, d, J=7.9…”

Structure-Based Designing, Solvent Less Synthesis of 1,2,3,4-Tetrahydropyrimidine-5-carboxylate Derivatives: A Combined In Vitro and In Silico Screening Approach

“…Compound 5c forms hydrogen bonds from oxygen of ester linkage with Ser454 and Arg197, respectively. Oxygen of ester linked carbonyl form hydrogen bonds with Lys199 and Arg197 shown in Figure 12 A–E [ 24 , 27 ].…”

“…All the synthesized compounds were drawn into 2D conformers by using ChemDraw Professional (Version 19.1.0.8, Perkin Elmer, Waltham, MA, USA), then these structures were imported to chem3D Ultra (Version 19.1.0.8, Perkin Elmer, Waltham, MA, USA). All the energy minimizations and other structural conformations, such as bond order, assigning missing bonds, explicit hydrogens and flexible torsional if absent in synthesized compounds, were optimized by using MM2 force field-Steepest Descent Algorithm in chem3D [ 27 , 55 ]. The crystal structure of target protein was downloaded from Protein Data Bank (PDB) at the Research Collaboratory for Structural Bioinformatics (RCSB, , accessed on 13–17 January 2021).…”

“…As studies revealed that MVD showed the best binding affinity in the form of Mol dock score as compared to other docking software like Surflex, Glide, Autodock Vina and FlexX [ 22 , 60 ]. Pose comprising top docked conformation was examined by using MolDock Score [GRID] algorithm, number of runs taken as 10, maximum iterations were 1500, population size of 50, with energy threshold of 100 having grid resolution 0.30 Å [ 23 , 24 , 25 , 26 , 27 , 58 , 61 , 62 ]. The MolDock score, length and number of hydrogen bonds involved along with residues involved in hydrogen bonding are listed for all the biological activities.…”

Exploring the Synergistic Anticancer Potential of Benzofuran–Oxadiazoles and Triazoles: Improved Ultrasound- and Microwave-Assisted Synthesis, Molecular Docking, Hemolytic, Thrombolytic and Anticancer Evaluation of Furan-Based Molecules

“…Sulfonamide scaffolds of benzofuran–imidazopyridines showed anticancer activity against ovarian cancer, MCF-7, lung cancer and colon cancer [ 24 ]. Benzofuran–oxadiazole hybrids exhibited significant cytotoxicity against pancreatic cancer and colon cancer cell lines in vitro [ 25 ]. The 2-aryl benzo furan–appended 4-aminoquinazoline structural motifs significantly inhibited the epidermal growth factor receptortyrosine kinase phosphorylation in vitro against human lung cancer, cervical cancer, colorectal adenocarcinoma and hepatocellular carcinoma cell lines [ 26 ].…”