Novel quinazolines bearing 1,3,4-thiadiazole-aryl urea derivative as anticancer agents: design, synthesis, molecular docking, DFT and bioactivity evaluations

Abstract

A novel series of 1-(5-((6-nitroquinazoline-4-yl)thio)-1,3,4-thiadiazol-2-yl)-3-phenylurea derivatives 8 were designed and synthesized to evaluate their cytotoxic potencies. The structures of these obtained compounds were thoroughly characterized by IR, ¹H, and ¹³C NMR, MASS spectroscopy and elemental analysis methods. Additionally, their in vitro anticancer activities were investigated using the MTT assay against A549 (human lung cancer), MDA-MB231 (human triple-negative breast cancer), and MCF7 (human hormone-dependent breast cancer). Etoposide was used as a reference marketed drug for comparison. Among the compounds tested, compounds 8b and 8c demonstrated acceptable antiproliferative activity, particularly against MCF7 cells. Considering the potential VEGFR-2 inhibitor potency of these compounds, a molecular docking study was performed for the most potent compound, 8c, to determine its probable interactions. Furthermore, computational investigations, including molecular dynamics, frontier molecular orbital analysis, Fukui reactivity descriptor, electrostatic potential surface, and in silico ADME evaluation for all compounds were performed to illustrate the structure-activity relationship (SAR).

Keywords: Anticancer; In silico ADME; MTT assay; Molecular docking; Quinazoline.

Fig. 1

Structures of FDA-approved EGFR and VEGFR-2 inhibitor drugs featuring quinazoline, thiadiazole, and urea moieties

Fig. 2

Design strategy of the target 1-(5-((6-nitroquinazolin-4-yl)thio)-1,3,4-thiadiazol-2-yl)-3-phenylurea derivatives as anticancer agents

Scheme 1

Synthetic route toward 6-nitroquinazoline conjugated with 1,3,4-thiadiazole and diaryl-urea 8a-l

Fig. 3

Frontier molecular orbitals of studied ligands

Fig. 4

Fukui functions for a nucleophilic attack f⁺(r) b electrophilic attack f⁻ (r) c dual descriptor (Δf), and d radical attack f⁰ for 8c ligand at B3LYP/6–31 g (d, p) level. The green and blue regions show positive and negative values of these functions

Fig. 5

The quantitative ESP analysis on the molecular vdW surface of studied ligands. The unit is in kcal/mol. The green and magenta spheres represent surface local minima and maxima of ESP values, respectively

Fig. 6.

3dimensional (3D) binding interactions of compound 8c. The hydrophobic interactions and hydrogen bonds are indicated as black dotted and blue lines, respectively

Fig. 7

RMSD plot for the backbone atoms (a), RMSF plot of the complex (b), and the number of hydrogen bonds between the protein target VEGFR2 and compound 8c