Screening of quinoline, 1,3-benzoxazine, and 1,3-oxazine-based small molecules against isolated methionyl-tRNA synthetase and A549 and HCT116 cancer cells including an in silico binding mode analysis

• Published in: Organic & biomolecular chemistry 2015-09, Vol.13 (36), p.9381-9387
• Main Authors: Bharathkumar, Hanumantharayappa, Mohan, Chakrabhavi Dhananjaya, Rangappa, Shobith, Kang, Taehee, Keerthy, H K, Fuchs, Julian E, Kwon, Nam Hoon, Bender, Andreas, Kim, Sunghoon, Basappa, Rangappa, Kanchugarakoppal S
• Format: Article
• Language: English
• Subjects: Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Benzoxazines - chemical synthesis; Benzoxazines - chemistry; Benzoxazines - pharmacology; Cell Line, Tumor; Cell Proliferation - drug effects; Computer Simulation; Dose-Response Relationship, Drug; Drug Screening Assays, Antitumor; Enzyme Inhibitors - chemical synthesis; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - pharmacology; Humans; Methionine-tRNA Ligase - antagonists & inhibitors; Methionine-tRNA Ligase - metabolism; Molecular Structure; Oxazines - chemical synthesis; Oxazines - chemistry; Oxazines - pharmacology; Quinolines - chemical synthesis; Quinolines - chemistry; Quinolines - pharmacology; Structure-Activity Relationship
• ISSN: 1477-0520; 1477-0539
• DOI: 10.1039/c5ob00791g

Elevated activity of methionyl-tRNA synthetase (MRS) in many cancers renders it a possible drug target in this disease area, as well as in a series of parasitic diseases. In the present work, we report the synthesis and in vitro screening of a library of 1,3-oxazines, benzoxazines and quinoline scaffolds against human MRS. Among the compounds tested, 2-(2-butyl-4-chloro-1-(4-phenoxybenzyl)-1H-imidazol-5-yl)-5-(4-methoxyphenyl)-1-oxa-3-azaspiro[5.5]undecane (compound 21) and 2-(2-butyl-4-chloro-1-(4-nitrobenzyl)-1H-imidazol-5-yl)-2,4-dihydro-1H-benzo[d][1,3]oxazine (compound 8) were found to be potent inhibitors of MRS. Additionally, these compounds significantly suppressed the proliferation of A549 and HCT116 cells with IC50 values of 28.4, 17.7, 41.9, and 19.8 μM respectively. Molecular docking studies suggested that the ligand binding orientation overlaps with the original positions of both methionine and adenosine of MRS. This suggests the binding of compound 21 against MRS, which might lead the inhibitory activity towards cancer cells.