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Synthesis, Cytotoxicity, ADMET and Molecular Docking Studies of Some Quinoline-Pyrimidine Hybrid Compounds: 3-(2-Amino-6-arylpyrimidin-4- yl)-4-hydroxy-1-methylquinolin-2(1H)-ones

Author(s):

Duong Ngoc Toan*, Nguyen Dinh Thanh*, Mai Xuan Truong and Dinh Thuy Van   Pages 1 - 15 ( 15 )

Abstract:


Aims: Synthesis of 3-(2-amino-6-arylpyrimidin-4-yl)-4-hydroxy-1-methylquinolin-2(1H)-ones and estimation their anticancer activities on HepG2 and KB cancer lines.

Background: Many derivatives of quinoline-2-on have been consider to synthesize and evaluate their biological properties by organic chemists due to their various biological effects, including antibacterial, antioxidant, anti-inflammatory, anticancer activities. Quinolinepyrimidine hybrid compounds exhibited various biological activities, such as antituberculosis, antibacterial, anticancer, antifungal, etc. The connection of 4-hydroxyquinoline-2-one with 2-amino-pyrimidine could initiate the new activities.

Objective: α,β-Unsaturated ketones of 3-acetyl-4-hydroxy-N-methylquinolin-2-one were prepared. Novel 2-amino-6-aryl-4-(4′-hydroxy-Nmethylquinolin- 2′-on-3′-yl)pyrimidines have been synthesized by reaction of these corresponding α,β-unsaturated ketones with guanidine hydrochloride. Human hepatocellular carcinoma HepG2 and squamous cell carcinoma KB cancer lines were used for screening their cytotoxicity.

Method: 3-Acetyl-4-hydroxy-N-methylquinolin-2-one was prepared from N-methylaniline and diethyl malonate. Reaction of (un)substituted benzaldehydes with this 4-hydroxyquinoline-2-one produced corresponding substituted α ,β-unsaturated ketones in the presence of piperidine as catalyst. 2-Amino-6-aryl-4-(4′-hydroxy-N-methylquinolin-2′-on-3′-yl)pyrimidines have been synthesized from these α,β-unsaturated ketones of 3-acetyl-4-hydroxy-N-methylquinolin-2-one by reaction of corresponding α ,β-unsaturated ketones with guanidine hydrochloride. All obtained pyrimidines were screened for anticancer activity using MTT bio-assay method.

Result: Seven substituted (E)-4-hydroxy-3-(3-(aryl)acryloyl)-1-methylquinolin-2(1H)-ones were prepared and converted to corresponding substituted 2-amino-6-aryl-4-(4′-hydroxy-N-methylquinolin-2′-on-3′-yl)pyrimidines with yields of 58−74%. All the synthesized pyrimidines were screened for their in vitro anticancer activity against human hepatocellular carcinoma HepG2 and squamous cell carcinoma KB cancer lines. Compounds 6b and 6e had the best activity in the series, with IC50 values equal to 1.32 and 1.33 μM, respectively. ADMET properties showed that compounds 6b, 6e, and 6f possessed the drug-likeness behavior. Cross-docking results indicated that residues GLN778(A), DT8(C), DT9(D), DA12(F), and DG13(F) in the binding pocket as potential ligand binding hot-spot residues for compounds 6b, 6e, and 6f.

Conclusion: New substituted 2-amino-6-aryl-4-(4′-hydroxy-N-methylquinolin-2′-on-3′-yl)pyrimidines were obtained and displayed significant inhibition against human hepatocellular carcinoma HepG2 and squamous cell carcinoma KB cancer lines.

Keywords:

3-Acetyl-4-hydroxyquinolin-2(1H)-one, cytotoxicity, KB cell line, HepG2 cell line, 2-aminopyrimidine, α, β- unsaturated ketones.

Affiliation:

Faculty of Chemistry, Thai Nguyen University of Education, 20 Luong Ngoc Quyen, Thai Nguyen, Faculty of Chemistry, VNU University of Science (Vietnam National University, Ha Noi), 19 Le Thanh Tong, Hoan Kiem, Ha Noi, Faculty of Chemistry, Thai Nguyen University of Education, 20 Luong Ngoc Quyen, Thai Nguyen, Faculty of Chemistry, Thai Nguyen University of Education, 20 Luong Ngoc Quyen, Thai Nguyen



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