N-{2-[(2-chlorothieno[3,2-d]pyrimidin-4-yl)amino]ethyl}-3-methoxybenzamide: design, synthesis, crystal structure, antiproliferative activity, DFT, Hirshfeld surface analysis and molecular docking study

Abstract

The compound N-{2-[(2-chlorothieno[3,2-d]pyrimidin-4-yl)amino]ethyl}-3-methoxybenzamide (8) was synthesized by the condensation of 3-methoxybenzoic acid (7) with N¹-(2-chlorothieno[3,2-d]pyrimidin-4-yl)ethane-1,2-diamine (6). This intermediate was prepared from methyl 3-aminothiophene-2-carboxylate (1) by the condensation with urea, chlorination with phosphorus oxychloride and then condensation with ethane-1,2-diamine. The crystal structure of the title compound was determined and the crystal of the title compound belongs to the tetragonal system, space group P4(3) with a = 9.4694(10) Å, b = 9.4694(10) Å, c = 18.886(3) Å, α = 90°, β = 90°, γ = 90°. The optimized geometric bond lengths and bond angles obtained by using density functional theory (DFT) have been compared with X-ray diffraction values. The calculated HOMO and LUMO energies showed the character of the title compound. The molecular electrostatic potential (MEP) surface map of the related molecule was investigated with theoretical calculations at the B3LYP/6-311 + G(d,p) levels. A quantitative analysis of the intermolecular interactions in the crystal structures has been performed using Hirshfeld surface analysis. In addition, the title compound possesses marked inhibition against the proliferation of human colon cancer cell line HT-29 (IC₅₀ = 1.76 μM), human lung adenocarcinoma cell line A549 (IC₅₀ = 1.98 μM) and human gastric cancer cell line MKN45 (IC₅₀ = 2.32 μM), displaying promising anticancer activitiy. The molecular docking studies revealed that the title compound may exhibit activity inhibiting PDB:3D15.

Communicated by Ramaswamy H. Sarma

Keywords:

• Thieno[3,2-d]pyrimidine
• synthesis
• X-ray diffraction
• antiproliferative activity
• Hirshfeld surface analysis

Disclosure statement

No potential conflict of interest was reported by the authors.

Additional information

Funding

This work is supported by the team of syngas catalytic conversion of Shaanxi University of Technology, the national natural science foundation of China (project no. 21373132, 21603133, 21807068), project of education department of Shaanxi province (20JK0565, 20JK0552), Shaanxi provincial science and technology department project (2019JM471, 2020JM602), the project of Shaanxi University of Technology(SLGKY2009), the Young Talent fund of University Association for Science and Technology in Shaanxi, China (20180607).