Synthesis And Biological Activities Of Quinolin-2(1H)-One Derivatives

The 2-oxoquinoline skeleton was chosen as an active pharmacal core to screen for new potential antitumor compounds and NA inhibitors by the introduction of various functional groups, such as aminophosphonate, arylaminothiazoles, thiazole schiff bases and 2-(2-hydrazinyl)thiazole. In this paper 5 series of anticancer angents and 2 series of NA inhibitors were designed and synthesized.The compounds A were obtained by the key intermediate 2-oxo-1,2-dihydroquinoline-3-carbaldehyde(G) and compounds B, C, D and E were acquired by the key intermediate 3-(2-bromo-4,4-dimethylpentanoyl)quinolin-2(1H)-one(J). Potential anticancer activities of compounds A, B, C, D and E were investigated against three or four human cancer cell lines and anti-influenza activity of compounds C and E were also tested as NA inhibitors.(1) Synthesis and anticancer activity of diethyl((2-oxo-1,2-dihydroquinolin-3-yl)(arylamino)methyl)phosphonate(A)2-Oxoquinoline skeleton was chosen as an active pharmacal core to screen for new potential antitumor compounds by the introduction of various functional aminophosphonate group. A series of diethyl((2-oxo-1,2-dihydroquinolin-3-yl)(arylamino)methyl)phosphonate(A) were synthesized and evaluated their potential anticancer activity against four human cancer cell lines in vitro. The cytotoxic inhibition screening results showed that the introduction of α-aminophosphonate on 2-oxoquinoline should markedly improve the antitumor activity. Compounds A21 and A24 displayed remarkable activity against A549, MCF-7 and U2 OS with IC50 values below 10 μM. In vitro pharmacological analysis demonstrated that compounds A21 exerted its anticancer activity against the HeLa cell line by inducing apoptosis, arresting cell cycle at the S and G2 phases.(2) Synthesis and anticancer activity of 3-((4-(tert-butyl)-2-(arylamino)thiazol-5-yl) methyl)quinolin-2(1H)-one(B)Based on our previous work, herein we aim to design and synthesize a series of new 2-oxoquinoline derivatives with improved antitumor activity by the introduction of various arylaminothiazoles. A series of diethyl 3-((4-(tert-butyl)-2-(arylamino)thiazol-5-yl)methyl) quinolin-2(1H)-one(B) were synthesized and evaluated their potential anticancer activity against three human cancer cell lines in vitro. This cytotoxic inhibition screening results revealed that compounds B3, B7 and B28 displayed potent inhibition activity against MCF-7 cell lines with IC50 values of 0.4±0.1 μM, 1.1±0.1 μM and 1.8±0.6 μM, respectively. In vitro pharmacological analysis demonstrated that cell cycle arrest in the G1 and G2 stages contributed to the antitumor effects of compounds B7 on HeLa cells.(3) Synthesis and biological activity of(E)-3-((4-(tert-butyl)-2-((2-hydroxybenzylidene) amino)thiazol-5-yl)methyl)quinolin-2(1H)-one(C) and 3-((4-(tert-butyl)-2-((2-hydroxybenzyl)amino)thiazol-5-yl)methyl)quinolin-2(1H)-one(D)Based on our previous work, 2-oxoquinoline was selected as pharmacal core to design and synthesize a series of new 2-oxoquinoline derivatives bearing thiazoles schiff bases as antitumor agents and NA inhibitors. Therefore, a series of(E)-3-((4-(tert-butyl)-2-((2-hydroxybenzylidene) amino)thiazol-5-yl)methyl)quinolin-2(1H)-one(C) were synthesized and evaluated their potential anticancer activity against three human cancer cell lines and NA inhibitory activity. In order to overcome the instability of Schiff base, compounds(D) were synthesized by the reduction of C=N. The cytotoxic inhibition screening results showed that compounds C3 and C5 displayed better anticancer activity against HeLa cell lines with IC50 values of 8.2±0.9 μM and 11.1±1.5 μM, respectively. Compared with compounds C, most of compounds D had cytotoxicity gainst HeLa and MCF-7 cell lines, but showed weak inhibition for A549 cell lines. The acridine orange/ethidium bromide staining, Hoechst 33342 staining and flow cytometry were also employed in the study to reveal the mechanism of compound D1, which indicated that it can induce cell apoptosis in HeLa cells and arrest cell cycle at the G2 phase.The results of NA inhibitory activity revealed that all compounds C showed inhibition effects on influenza H1N1 virus. Docking study indicated that compound C10 can not only binds to the NA action region, but also occupies the active site region 430-cavity and it could be used as a good representative for further studies.(4) Synthesis and biological activity of(E)-3-((4-(t-butyl)-2-(2-benzylidene-hydrazinyl) thiazol-5-yl)methyl)quinolin-2(1H)-ones(E)Based on our previous work of synthesis and biological evaluation of thiazole derivatives, it is considered that simultaneous administration of 2-oxoquinoline and 2-(2-hydrazinyl)thiazole structures in a single molecule, would lead to a rapid onset of biological activity. So a series of diethyl 3-((4-(t-butyl)-2-(2-benzylidene-hydrazinyl)thiazol-5-yl)methyl)quinolin-2(1H)-ones(E) were synthesized and evaluated their potential anticancer activity and NA inhibitory activity. This cytotoxic inhibition screening results showed that compounds E1, E10 and E11 displayed potent cytotoxic activities against HeLa cell lines with IC50 values below 5 μM and compounds E9, E11, E14, E15 and E21 exhibited good cytotoxic activities against A549 cell lines with IC50 values below 10 μM. The mechanism of compound E10 was preliminarily investigated by acridine orange/ethidium bromide staining, Hoechst 33342 staining and flow cytometry, which indicated that the compound can induce cell apoptosis in HeLa cells and arrest cell cycle at the G2 phase.All compounds E showed inhibition effects on influenza H1N1 virus, in which compound E12 exhibited moderate NA inhibitory activity with IC50 of 44.66 μM. Docking study indicated that compound E12 has important interactions with some key residues and binds to 430-cavity adjacent to NA active site.