New Imidazole-Based N-Phenylbenzamide Derivatives as Potential Anticancer Agents: Key Computational Insights

Abstract

An efficient atom-economical synthetic protocol to access new imidazole-based N-phenylbenzamide derivatives is described. A one-pot three-component reaction was utilized to provide a series of N-phenylbenzamide derivatives in a short reaction time (2-4 h) with an 80-85% yield. The cytotoxic evaluation revealed that derivatives 4e and 4f exhibited good activity, with IC₅₀ values between 7.5 and 11.1 μM against the tested cancer cell lines. Computational studies revealed interesting insights: the docking of the active derivatives (4e and 4f) showed a higher affinity toward the target receptor protein than the control. Molecular dynamic simulations revealed that the active derivatives form stable complexes with the ABL1 kinase protein. Moreover, the ADME and drug-likeness of the derivatives reinforced the potential of the derivatives to be taken up for further development as anticancer agents.

Keywords: ADME and drug-likeness; N-phenylbenzamide; anticancer activity; computational studies; imidazole; molecular dynamic simulations; multicomponent reaction.

FIGURE 1

Anticancer agents with imidazole and N-phenylbenzamide derivatives.

SCHEME 1

Synthesis of new imidazole-based N-phenylbenzamide derivatives 4a–j

FIGURE 2

(A) HB plots showing hydrogen bonding interaction of different ligands 4e (290:LYS, 305:GLU, 308:VAL, 378:PHE, and 400:ASP), 4f (275:VAL, 290:LYS, 292:LEU, 298:GLU, 301:GLU, 302:PHE, 305:GLU, 400: ASP, 401:PHE) and control, nilotinib (275:VAL, 290:LYS, 292:LEU, 298:GLU, 301:GLU, 302:PHE, 305:GLU, 400:ASP, and 401:PHE) with common interactive residues shown in red. (B) Overview of the 2D interactions of ABL1 kinase with ligands 4e, 4f, and nilotinib. (C) 3D molecular interactions of different ligands 4e, 4f, and control interacting with TYL kinase (5MO4) in the binding pocket.

FIGURE 3

Graphical representation of (A) RMSD plot of ABL1 kinase-4e (black), ABL1 kinase-4f (red), and ABL1 kinase–nilotinib (green) complexes deviation during 5 ns period. (B)RMSF plot with fluctuation per residues of the complexes. (C) Hydrogen bond plot depicting formation hydrogen bond of the complexes during 5,000-ps period of simulation. (D) Radius of gyration (Rg) plot representing compactness of complexes during 5,000 ps simulation. nm = nanometer, ns= nanosecond, ps = picosecond.

FIGURE 4

BOILED-Egg model of derivatives 4a–j and control (nilotinib). The yolk and the white in the model denote the BBB permeability and GI absorption, respectively. Blue dots represent the derivatives that are not effluated from CNS.