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Design, Synthesis, and Anticancer Activity Studies of Novel Quinoline-Chalcone Derivatives

Yong-feng guan.

1 School of Chemical Engineering, Zhengzhou University, Zhengzhou 450001, China; moc.621@961fyg

Xiu-Juan Liu

2 Key Laboratory of Advanced Drug Preparation Technologies (Ministry of Education), Institute of Drug Discovery & Development, School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou 450001, China; moc.361@YYW021JXL (X.-J.L.); moc.361@56026556871yxy (X.-Y.Y.); moc.361@17576589671 (W.-B.L.); nc.ude.uzz@bygnahz (Y.-B.Z.)

Xin-Ying Yuan

3 School of Basic Medical Sciences, Zhengzhou University, Zhengzhou 450001, China; moc.361@85186830671 (Y.-R.L.); moc.621@01109991xgy (G.-X.Y.); moc.361@626iyxt (X.-Y.T.)

Guang-Xi Yu

Xin-yi tian, yan-bing zhang, sai-yang zhang, associated data.

Data of the compounds is available from the authors.

The chalcone and quinoline scaffolds are frequently utilized to design novel anticancer agents. As the continuation of our work on effective anticancer agents, we assumed that linking chalcone fragment to the quinoline scaffold through the principle of molecular hybridization strategy could produce novel compounds with potential anticancer activity. Therefore, quinoline-chalcone derivatives were designed and synthesized, and we explored their antiproliferative activity against MGC-803, HCT-116, and MCF-7 cells. Among these compounds, compound 12e exhibited a most excellent inhibitory potency against MGC-803, HCT-116, and MCF-7 cells with IC 50 values of 1.38, 5.34, and 5.21 µM, respectively. The structure–activity relationship of quinoline-chalcone derivatives was preliminarily explored in this report. Further mechanism studies suggested that compound 12e inhibited MGC-803 cells in a dose-dependent manner and the cell colony formation activity of MGC-803 cells, arrested MGC-803 cells at the G2/M phase and significantly upregulated the levels of apoptosis-related proteins (Caspase3/9 and cleaved-PARP) in MGC-803 cells. In addition, compound 12e could significantly induce ROS generation, and was dependent on ROS production to exert inhibitory effects on gastric cancer cells. Taken together, all the results suggested that directly linking chalcone fragment to the quinoline scaffold could produce novel anticancer molecules, and compound 12e might be a valuable lead compound for the development of anticancer agents.

1. Introduction

Chalcone is a natural product template which shows many versatile pharmacological activities especially anticancer activities [ 1 , 2 , 3 ]. Due to its simple chemistry and ease of synthesis, a large number of chalcone derivatives was discovered with variety of promising biological activity [ 4 ]. In fact, chalcone compounds have shown good therapeutic effects and clinical application potential as anticancer drugs for the treatment of human cancers [ 5 , 6 , 7 ]. In addition, chalcone fragment was also frequently utilized to design novel agents with other anticancer moieties to enhance the biological efficacy by the molecular hybridization strategy [ 8 , 9 , 10 , 11 , 12 , 13 , 14 , 15 ]. 4-Aminochalcone derivative 1 [ 12 ] displayed excellent inhibitory activity against NCI-H460, A549, and H1975 cells with IC 50 values of 2.3, 3.2, and 5.7 μM, respectively. Compound 1 was able to trigger ROS-mediated apoptosis in time- and concentration-dependent manners in NCI-H460 cells. In addition, compound 1 also displayed a better safety profile in animal models. Chalcone dithiocarbamate derivative 2 [ 13 ] was reported as a LSD1 inhibitor with an IC 50 value of 0.14 μM. Compound 2 exhibited potent anticancer activity against MOLT-4 cells (IC 50 = 0.87 μM) and was significantly effective in suppressing the growth of MOLT-4 xenograft tumor mouse model. Compound 3 [ 14 ] was successfully designed by the structural combination of the 1,3,5-triazine and chalcone fragments via a diether linker with potent antiproliferative activity against the MCF-7 and HCT116 cells (GI 50 = 0.127 and 0.116 μM, respectively). Additionally, compound 3 could potently inhibit the activity of cellular DHFR and TrxR in HCT-116 cells. [ 1 , 2 , 4 ] Triazolo [1,5- a ] pyrimidine–chalcone derivative 4 [ 15 ] inhibited MGC-803 cells at the nanomolar level (GI 50 = 0.64 μM) and exhibited its anti-proliferative potency via inducing autophagy and increasing ROS level ( Figure 1 ). Therefore, chalcone fragment might be a valuable and core moiety to design anticancer agents. In this work, we continued our efforts on the discovery of chalcone derivatives as potential anticancer activity.

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Structures of chalcone derivatives as anticancer agents previously reported.

Quinolines, as one class of N -containing heterocycles, have numerous advantages over other non-nitrogenous, which are widely used as “parental” compounds to synthesize molecules with variety of promising biological activity [ 16 , 17 , 18 , 19 ]. The quinoline motifs are frequently found in many compounds that show potent anticancer activity with different mechanisms [ 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 ]. Anlotinib [ 23 ] (multi-kinase inhibitor) and Bosutinib [ 24 ] (Src-Abl inhibitor), which are quinoline-based protein kinase inhibitors, have been approved for the treatment of human cancers. Quinoline–chalcone derivative 5 [ 25 ] as a potent tubulin inhibitor showed excellent anticancer potency with IC 50 values at nanomolar levels. In addition, compound 5 could arrest the cell cycle at the G2/M phase, induce apoptosis, depolarize mitochondria, and induce ROS generation in K562 cells. Quinoline chalcone 6 [ 26 ] is effective in exhibiting potent activity against HL60 cells with an IC 50 values of 0.59 μM. Novel phenylsulfonylurea derivative 7 [ 27 ] as an anticancer agent exhibited potent cytotoxicity activity against HepG-2, A549, and MCF-7 cells (IC 50 = 2.71, 7.47, and 6.55 μM, respectively) as well as moderate PI3K/mTOR dual inhibitory activity ( Figure 2 ). Therefore, in this work, we use the quinoline moiety as the core scaffold of molecules to discover novel quinoline-based anticancer agents.

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Structures of quinoline derivatives as anticancer agents previously reported.

Molecular hybridization strategy is extensively used in drug design and discovery based on the combination of different bioactive moieties to produce new hybrids with the improved activities [ 28 ]. These interesting findings about chalcones and quinolines as anticancer agents led to molecular hybridization strategy of chalcone and quinoline scaffolds to generate novel anticancer agents. In this work, as the continuation of our work on the development of anticancer agents, we designed and synthesized novel quinoline-chalcone derivatives as anticancer activity ( Figure 3 ).

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Design of novel quinoline-chalcone derivatives as anticancer agents.

2. Results and Discussion

2.1. chemistry.

Target quinoline-chalcone derivatives were synthesized by outlined procedures in Scheme 1 . Commercially available 4-aminoacetophenone ( 8 ) reacted with aromatic aldehydes 9a – 9j to afford compounds 10a – 10j in the presence of NaOH in EtOH at 25 °C. Substitution reaction between compounds 10a – 10j with commercially available 4-chloro-2-methylquinoline ( 11 ) gave target compounds 12a – 12j in the presence of HCl in EtOH at 80 °C. In addition, Compounds 12a , 12b , 12e , and 12f then reacted with iodomethane or iodoethane in the presence of KOH in acetonitrile at 80 °C to give compounds 13a – 13f . All the compounds were characterized by means of NMR and HREI-mass spectra which are showed in the Supplementary Materials .

2.2. Antiproliferative Activity and Structure Activity Relationship Analysis

According to the latest statistics from the International Agency for Research on Cancer (IARC), in 2020, the number of newly diagnosed patients of colorectal cancer, gastric cancer, and breast cancer ranked second, third, and fourth in China, respectively [ 29 ]. Therefore, the in vitro antiproliferative activities of new target compounds 12a – 12j and 13a – 13f were evaluated against MGC-803 cell line (human gastric cancer cells), HCT-116 cell line (human colon cancer cells), and MCF-7 (human breast cancer cells), with the 5-fluorouracil (5-Fu ) as a positive control. The following Table 1 depicted the results of antiproliferative activity.

In vitro antiproliferative activity of compounds 12a – 12j and 13a – 13f against MGC-803, HCT-116, and MCF-7 cells.

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a In vitro antiproliferative activity was assayed by exposure for 48 h.

As shown in Table 1 , most of quinoline-chalcone derivatives displayed potent antiproliferative activity against MGC-803, HCT-116 and MCF-7 cells with IC 50 values <20 µM. Particularly, compound 12e exhibited most excellent inhibitory potency against MGC-803, HCT-116, and MCF-7 cells with IC 50 values of 1.38, 5.34, and 5.21 µM, respectively, which were much lower than that of 5-Fu (IC 50 values = 6.22 µM, 10.4 μM, and 11.1 μM, respectively), which indicated that compound 12e was effective in inhibiting the activity of three kinds of tumor cells. In addition, most of compounds was more sensitive to MGC-803 cells than that of HCT-116 and MCF-7 cells. Therefore, the structure–activity relationships were discussed according to the results of antiproliferative activity of MGC-803 cells. As shown in Table 1 , the types and positions of substituents (R 1 ) on chalcone group (A ring) have an important influence on its antiproliferative activity. Compared with 12f , compounds 12a – 12e with electron-donating groups of A ring exhibited enhanced activity than compounds without substitution groups of A ring, but compounds 12g and 12i , with electron-withdrawing groups of A ring, despaired the antiproliferative activity more potent than that of compound 12f . In addition, the position of substituents (R 1 ) is also important. The inhibitory activity of compounds was less potent when the substituents (R 1 ) were at the 3-position of chalcone group (A ring) than that of the substituents (R 1 ) were at the 3-position of A ring (compounds 12b vs. 12c , 12g vs. 12i , and 12h vs. 12j ). However, compound 12e with a 3,4,5-triOCH 3 substituent of chalcone group (A ring) exhibited better activity. The relationships between the electron-donating groups and electron-withdrawing groups of chalcone group (A ring) and the inhibitory potency on MGC-803 cells were 3,4,5-triOCH 3 > 3,4-diOCH 3 > 4-CH 3 > 4-Br > 4-OCH 3 > 3-OCH 3 > 3-Br > H > 4-Cl > 3-Cl. Next, the influence of R 2 was further explored. As shown in Table 1 , the inhibitory activity of compounds 13a – 13f was decreased when the H group was replaced by CH 3 or CH 3 CH 2 substituent (compounds 13a vs. 12f , 13b vs. 12a , 13c vs. 12d , 13d vs. 12g , 13e vs. 12e , and 13f vs. 12e ), indicating that the substituents of R 2 could not improve the inhibitory potency.

Based on above the antiproliferative activity results of compounds, we can conclude that linking quinoline fragment to the chalcone scaffold produces new hybrids with potential anticancer activity. The types and positions of substituents (R 1 ) on chalcone group (A ring) make a great influence on the inhibitory potency of compounds. Substituents of R 2 impaired the inhibitory potency of compounds ( Figure 4 ).

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Summary of the structure-activity relationships.

2.3. Compound 12e Inhibited Gastric Cancer Cells

Compound 12e in this series of compounds showed the most excellent inhibitory activity against MGC-803 cells. The cell viability of the MGC-803 cells was significantly decreased after the treatment with different concentrations of compound 12e for 48 h ( Figure 5 D). The cell inhibition rate of the high concentration treatment group increased by more than 60%. Cell proliferation inhibition could be caused by cell cycle arrestment. As shown in Figure 5 A,C, the results of cell cycle analysis showed that gastric cancer cells MGC-803 could arrest the cells in G2/M phase. The percentage of cells was upregulated by 20%. Compound 12e also showed significant activity on inhibiting the activity of cell colony formation ( Figure 5 B). With long-term low concentration treatment of compound 12e , the formatted colony was significantly decreased from the concentration of 900 nM. The detection of apoptosis-related proteins showed that the levels of cleaved-Caspase3/9 and cleaved-PARP, the markers of apoptosis, were significantly upregulated ( Figure 5 E). In conclusion, compound 12e could inhibit gastric cancer cells by arresting cells in G2/M phase and inducing apoptosis of MGC-803 cells.

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Compound 12e inhibited gastric cancer cells. ( A , C ) Cell-cycle distribution detection, MGC-803 cells were treated with indicated concentrations of compound 12e for 48 h; ( B ) Cell colonies formatted, MGC-803 cells were treated indicated concentrations of compound 12e for 7 d; ( D ) Cell viability of MGC-803 cells, cells were treated indicated concentrations of compound 12e for 48 h; and ( E ) Apoptosis related proteins, MGC-803 cells were treated indicated concentrations of compound 12e for 48 h.

2.4. Compound 12e Inhibited Gastric Cancer Cells through the Generation of Reactive Oxygen Species (ROS)

It has been reported in the literature that the molecular skeleton of chalcone can induce the production of ROS [ 12 , 15 ]. The assay labeling ROS using DCFH-DA probe revealed that compound 12e could effectively induce ROS generation at concentrations as low as 500 nM ( Figure 6 A). To investigate the direct relationship between the induction of ROS generation and tumor cell inhibition by compound 12e , gastric cancer cells (MGC-803 and SGC-7901 cells) were treated with the ROS inhibitor NAC in combination with compound 12e . As shown in Figure 6 B,C, the results showed that the presence of NAC significantly reversed the cytostatic effect caused by compound 12e . The above results suggested that compound 12e could significantly induce ROS generation and was dependent on ROS production to exert inhibitory effects on gastric cancer cells.

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Compound 12e induced ROS generation. ( A ) The levels of ROS in MGC-803 cells, cells were treated indicated concentrations of compound 12e for 48 h, then ROS was labeled by DCFH-DA. ( B , C ) Cell viabilities of two gastric cancer cells, cells were treated with indicated concentrations of compound 12e and/or NAC for 48 h. Date were expressed as mean ± SD, n = 3. Three individual experiments were implemented for per group. ** p < 0.01, *** p < 0.001 vs. control.

3. Materials and Methods

All the chemical reagents were purchased from commercial suppliers (Energy chemical Company, Shanghai, China). Melting points were determined on an X-5 micromelting apparatus (Fukai Instrument, Beijing, China). NMR spectra data was recorded with a Bruker DPX 400 MHz spectrometer (Bruker, Billerica, MA, USA). High-resolution mass spectra (HRMS) data was obtained using a Waters Micromass Q-TOF Micromass spectrometer (Waters, Manchester, UK) by electrospray ionization (ESI).

3.1. Synthesis of Compounds 10a – 10j

A solution of commercially available 4-aminoacetophenone 8 (1.0 mmol, 1.0 eq), aromatic aldehyde 9a – 9j (1.0 mmol, 1.0 eq), NaOH (2.0 mmol, 2.0 eq) and were added into 20 mL EtOH at 25 °C. After 6 h, 20 mL water was added to the reaction mixture, giving yellow solid. Then, the crude product was obtained by filtration without further purification.

3.2. Synthesis of Compounds 12a – 12j and 13a – 13f

A solution of compounds 10a – 10j (1.0 mmol, 1.0 eq), 4-chloro-2-methylquinoline 11 (1.0 mmol, 1.0 eq) were added into 10 mL EtOH at 80 °C in the presence of HCl. After 8 h, organic phases were evaporated to obtain crude products, and then were purified to give compounds 12a – 12j by column chromatography. A solution of compounds 12a , 12b , 12e , 12f , and 12e (1.0 mmol, 1.0 eq), iodomethane or iodoethane (2.0 mmol, 2.0 eq), and KOH (2.0 mmol, 2.0 eq) were added into 10 mL acetonitrile at 80 °C. After 6 h, the reaction was quenched with water and the crude product extracted with ethyl acetate three times, organic phases were evaporated to obtain crude products, then were purified to give compounds 13a – 13f by column chromatography (PE:EA = 5:1).

(E)-1-(4-((2-methylquinolin-4-yl)amino)phenyl)-3-(p-tolyl)prop-2-en-1-one ( 12a ). Yellow powder, Yield, 68%, m.p.124–126 °C. 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.31 (s, 1H), 8.30 (dd, J = 8.5, 1.4 Hz, 1H), 8.24–8.18 (m, 2H), 7.94 (d, J = 15.6 Hz, 1H), 7.87 (d, J = 8.3 Hz, 1H), 7.82–7.76 (m, 2H), 7.73 (d, J = 7.3 Hz, 1H), 7.71–7.67 (m, 1H), 7.56–7.51 (m, 1H), 7.50 (s, 1H), 7.48 (s, 1H), 7.33–7.23 (m, 3H), 2.56 (s, 3H), 2.36 (s, 3H). 13 C NMR (100 MHz, DMSO-d 6 ) δ 187.52, 159.42, 149.29, 147.00, 146.09, 143.55, 140.90, 132.64, 131.52, 130.93, 130.01, 129.96, 129.26, 129.08, 124.85, 122.68, 121.47, 119.93, 119.06, 106.02, 25.60, 21.55. HRMS m/z calcd. for C 26 H 23 N 2 O, [M + H] + : 379.1805, found: 379.1812.

(E)-3-(4-methoxyphenyl)-1-(4-((2-methylquinolin-4-yl)amino)phenyl)prop-2-en-1-one ( 12b ). Yellow powder, Yield, 64%, m.p.111–113 °C. 1 H NMR (400 MHz, DMSO- d 6 ) δ 9.29 (s, 1H), 8.29 (dd, J = 8.5, 1.4 Hz, 1H), 8.24–8.16 (m, 2H), 7.89–7.82 (m, 4H), 7.74–7.66 (m, 2H), 7.50 (dd, J = 10.1, 7.1 Hz, 3H), 7.24 (s, 1H), 7.07–6.99 (m, 2H), 3.83 (s, 3H), 2.55 (d, J = 2.3 Hz, 3H). 13 C NMR (100 MHz, DMSO- d 6 ) δ 187.46, 159.42, 149.38, 146.23, 144.70, 138.42, 131.92, 130.65, 129.96, 129.05, 128.04, 124.84, 122.69, 119.90, 119.56, 119.24, 119.17, 113.09, 110.95, 105.81, 55.95, 25.57. HRMS m / z calcd. for C 26 H 23 N 2 O 2 , [M + H] + : 395.1754, found: 395.1758.

(E)-3-(3-methoxyphenyl)-1-(4-((2-methylquinolin-4-yl)amino)phenyl)prop-2-en-1-one ( 12c ). Yellow powder, Yield, 66%, m.p.173–175 °C. 1 H NMR (400 MHz, DMSO- d 6 ) δ 9.32 (s, 1H), 8.29 (dd, J = 8.5, 1.4 Hz, 1H), 8.26–8.19 (m, 2H), 8.00 (d, J = 15.6 Hz, 1H), 7.87 (dd, J = 8.5, 1.3 Hz, 1H), 7.75–7.68 (m, 2H), 7.57–7.48 (m, 4H), 7.44 (dt, J = 7.8, 1.4 Hz, 1H), 7.38 (t, J = 7.8 Hz, 1H), 7.26 (s, 1H), 7.03 (ddd, J = 8.1, 2.6, 1.0 Hz, 1H), 3.85 (s, 3H), 2.56 (s, 3H). 13 C NMR (100 MHz, DMSO- d 6 ) δ 193.40, 160.16, 159.44, 143.53, 137.15, 137.08, 131.12, 131.06, 130.37, 130.04, 129.86, 128.97, 128.70, 124.94, 122.68, 122.03, 119.97, 119.08, 118.93, 114.81, 114.69, 113.64, 55.42, 25.49. HRMS m / z calcd. for C 26 H 23 N 2 O 2 , [M + H] + : 395.1754, found: 395.1760.

(E)-3-(3,4-dimethoxyphenyl)-1-(4-((2-methylquinolin-4-yl)amino)phenyl)prop-2-en-1-one ( 12d ). Yellow powder, Yield, 69%, m.p.153–155 °C. 1 H NMR (400 MHz, DMSO- d 6 ) δ 9.30 (s, 1H), 8.30 (dd, J = 8.5, 1.4 Hz, 1H), 8.25–8.18 (m, 2H), 7.92–7.83 (m, 2H), 7.75–7.66 (m, 2H), 7.57 (d, J = 2.0 Hz, 1H), 7.54–7.46 (m, 3H), 7.39 (dd, J = 8.4, 2.0 Hz, 1H), 7.25 (s, 1H), 7.03 (d, J = 8.4 Hz, 1H), 3.88 (s, 3H), 3.83 (s, 3H), 2.55 (s, 3H). 13 C NMR (100 MHz, DMSO- d 6 ) δ 187.40, 159.40, 151.61, 149.53, 149.26, 146.84, 146.16, 144.02, 131.73, 130.88, 129.97, 129.08, 128.20, 124.84, 124.32, 122.68, 120.02, 119.90, 119.11, 112.04, 111.05, 105.87, 56.22, 56.07, 25.59. HRMS m / z calcd. for C 27 H 25 N 2 O 3 , [M + H] + : 425.1860, found: 425.1869.

(E)-1-(4-((2-methylquinolin-4-yl)amino)phenyl)-3-(3,4,5-trimethoxyphenyl)prop-2-en-1-one ( 12e ). Brown power, Yield, 60%, m.p.122–124 °C. 1 H NMR (400 MHz, DMSO- d 6 ) δ 9.36 (s, 1H), 8.30 (dd, J = 8.5, 1.4 Hz, 1H), 8.26–8.20 (m, 2H), 7.95 (d, J = 15.5 Hz, 1H), 7.86 (d, J = 8.3 Hz, 1H), 7.75–7.65 (m, 2H), 7.54–7.48 (m, 3H), 7.25 (d, J = 3.5 Hz, 3H), 3.88 (s, 6H), 3.73 (s, 3H), 2.55 (s, 3H). 13 C NMR (100 MHz, DMSO- d 6 ) δ 187.46, 153.60, 152.85, 144.00, 140.09, 131.49, 131.01, 130.91, 130.01, 129.03, 124.90, 122.68, 121.65, 119.92, 119.05, 106.89, 105.21, 60.63, 56.62, 56.19, 25.56. HRMS m / z calcd. for C 28 H 27 N 2 O 4 , [M + H] + : 455.1965, found: 455.1975.

(E)-1-(4-((2-methylquinolin-4-yl)amino)phenyl)-3-phenylprop-2-en-1-one ( 12f ). Yellow powder, Yield, 58%, m.p.265-267 °C. 1 H NMR (400 MHz, DMSO- d 6 ) δ 11.10 (s, 1H), 8.89 (d, J = 8.5 Hz, 1H), 8.34 (d, J = 8.6 Hz, 2H), 8.17 (d, J = 8.4 Hz, 1H), 8.05–7.98 (m, 2H), 7.92 (dd, J = 6.7, 3.0 Hz, 2H), 7.83–7.76 (m, 2H), 7.74 (dd, J = 6.7, 4.8 Hz, 2H), 7.52–7.44 (m, 3H), 7.04 (s, 1H), 2.69 (s, 3H). 13 C NMR (100 MHz, DMSO- d 6 ) δ 192.85, 160.84, 153.04, 151.68, 149.78, 136.85, 135.87, 131.12, 130.30, 129.59, 129.45, 128.90, 128.72, 128.54, 127.31, 126.55, 123.61, 123.54, 120.28, 114.25, 25.33. HRMS m / z calcd. for C 25 H 21 N 2 O, [M + H] + : 365.1648, found: 365.1655.

(E)-3-(4-chlorophenyl)-1-(4-((2-methylquinolin-4-yl)amino)phenyl)prop-2-en-1-one ( 12g ). Yellow powder, Yield, 58%, m.p.203–205 °C. 1 H NMR (400 MHz, DMSO- d 6 ) δ 11.07 (s, 1H), 8.86 (d, J = 8.6 Hz, 1H), 8.34 (d, J = 8.2 Hz, 2H), 8.15 (d, J = 8.5 Hz, 1H), 7.99 (dd, J = 22.2, 7.4 Hz, 4H), 7.79 (s, 1H), 7.74 (d, J = 6.3 Hz, 2H), 7.71 (s, 1H), 7.54 (d, J = 8.2 Hz, 2H), 7.04 (s, 1H), 2.68 (s, 3H). 13 C NMR (100 MHz, DMSO- d 6 ) δ 188.29, 155.64, 153.94, 143.14, 142.67, 138.98, 135.67, 135.61, 134.27, 134.14, 131.13, 130.85, 129.48, 127.25, 124.78, 124.20, 123.10, 120.26, 117.24, 101.84, 20.32. HRMS m / z calcd. for C 25 H 20 ClN 2 O, [M + H] + : 399.1259, found: 399.1261.

(E)-3-(4-bromophenyl)-1-(4-((2-methylquinolin-4-yl)amino)phenyl)prop-2-en-1-one ( 12h ). Yellow powder, Yield, 67%, m.p.133–135 °C. 1 H NMR (400 MHz, DMSO- d 6 ) δ 9.32 (s, 1H), 8.29 (dd, J = 8.5, 1.4 Hz, 1H), 8.24–8.18 (m, 2H), 8.03 (d, J = 15.6 Hz, 1H), 7.87 (d, J = 8.5 Hz, 3H), 7.73–7.65 (m, 4H), 7.53 (d, J = 7.4 Hz, 1H), 7.51–7.47 (m, 2H), 7.26 (s, 1H), 2.56 (s, 3H). 13 C NMR (100 MHz, DMSO- d 6 ) δ 192.55, 187.43, 142.10, 136.81, 135.12, 134.69, 132.35, 131.71, 131.59, 131.15, 131.07, 130.26, 130.02, 129.03, 128.92, 124.93, 122.70, 122.34, 118.83, 106.50, 25.56. HRMS m / z calcd. for C 25 H 20 BrN 2 O, [M + H] + : 443.0754, found: 443.0756.

(E)-3-(3-chlorophenyl)-1-(4-((2-methylquinolin-4-yl)amino)phenyl)prop-2-en-1-one ( 12i ). Yellow powder, Yield, 63%, m.p.212–214 °C. 1 H NMR (400 MHz, DMSO- d 6 ) δ 9.55 (s, 1H), 8.35 (dd, J = 16.5, 8.3 Hz, 1H), 8.26–8.06 (m, 3H), 7.86 (ddd, J = 11.1, 6.2, 2.6 Hz, 2H), 7.77–7.61 (m, 2H), 7.56–7.46 (m, 5H), 7.35 (t, J = 2.2 Hz, 1H), 7.23 (d, J = 23.6 Hz, 1H), 2.55 (d, J = 5.1 Hz, 3H). 13 C NMR (100 MHz, DMSO- d 6 ) δ 187.37, 159.37, 149.33, 147.46, 146.10, 141.69, 137.67, 134.28, 131.15, 131.11, 131.07, 130.39, 129.94, 129.02, 128.31, 128.27, 124.82, 124.17, 123.02, 120.06, 118.91, 106.32, 25.60. HRMS m / z calcd. for C 25 H 20 ClN 2 O, [M + H] + : 399.1259, found: 399.1266.

(E)-3-(3-bromophenyl)-1-(4-((2-methylquinolin-4-yl)amino)phenyl)prop-2-en-1-one ( 12j ). Yellow powder, Yield, 64%, m.p.219–221 °C. 1 H NMR (400 MHz, DMSO- d 6 ) δ 9.33 (d, J = 9.0 Hz, 1H), 8.29–8.22 (m, 3H), 8.08 (d, J = 15.6 Hz, 1H), 7.87 (dd, J = 8.2, 3.8 Hz, 2H), 7.74–7.62 (m, 3H), 7.55–7.47 (m, 3H), 7.41 (q, J = 7.6 Hz, 2H), 7.27 (s, 1H), 2.55 (d, J = 4.8 Hz, 3H). 13 C NMR (100 MHz, DMSO- d 6 ) δ 187.34, 159.43, 149.31, 147.30, 145.99, 141.69, 137.92, 133.30, 131.40, 131.17, 131.13, 129.98, 129.11, 128.68, 124.90, 124.10, 122.90, 122.69, 119.98, 118.91, 106.28, 25.61. HRMS m / z calcd. for C 25 H 20 BrN 2 O, [M + H] + : 443.0754, found: 443.0761.

(E)-1-(4-(methyl(2-methylquinolin-4-yl)amino)phenyl)-3-phenylprop-2-en-1-one ( 13a ). Brown power, Yield, 57%, m.p.160–162 °C. 1 H NMR (400 MHz, DMSO- d 6 ) δ 8.07–7.99 (m, 3H), 7.92–7.82 (m, 3H), 7.73 (ddd, J = 8.4, 6.8, 1.5 Hz, 1H), 7.70–7.61 (m, 2H), 7.49–7.41 (m, 5H), 6.78–6.71 (m, 2H), 3.52 (s, 3H), 2.69 (s, 3H). 13 C NMR (100 MHz, DMSO- d 6 ) δ 188.47, 155.66, 153.97, 144.68, 142.52, 138.93, 135.74, 135.10, 134.31, 131.24, 130.82, 129.46, 129.41, 127.30, 124.81, 124.11, 122.33, 120.24, 117.19, 101.79, 25.92, 20.34. HRMS m / z calcd. for C 26 H 23 N 2 O, [M + H] + : 379.1805, found: 379.1809.

(E)-1-(4-(methyl(2-methylquinolin-4-yl)amino)phenyl)-3-(p-tolyl)prop-2-en-1-one ( 13b ). Yellow powder, Yield, 55%, m.p. 86–88 °C. 1 H NMR (400 MHz, DMSO- d 6 ) δ 8.06–7.99 (m, 3H), 7.83 (d, J = 15.6 Hz, 1H), 7.76–7.70 (m, 3H), 7.68–7.60 (m, 2H), 7.50–7.42 (m, 2H), 7.25 (d, J = 7.9 Hz, 2H), 6.78–6.71 (m, 2H), 3.52 (s, 3H), 2.69 (s, 3H), 2.34 (s, 3H). 13 C NMR (100 MHz, DMSO- d 6 ) δ 192.74, 160.79, 152.99, 151.74, 138.61, 137.05, 133.07, 131.08, 130.30, 129.99, 129.62, 129.54, 129.31, 127.51, 127.36, 126.51, 123.64, 123.52, 120.20, 114.33, 25.31, 21.52, 21.30. HRMS m / z calcd. for C 27 H 25 N 2 O, [M + H] + : 392.1889, found: 393.1964.

(E)-3-(4-methoxyphenyl)-1-(4-(methyl(2-methylquinolin-4-yl)amino)phenyl)prop-2-en-1-one ( 13c ). Yellow powder, Yield, 63%, m.p.114–116 °C. 1 H NMR (400 MHz, DMSO- d 6 ) δ 8.05–7.98 (m, 3H), 7.80 (d, J = 8.8 Hz, 2H), 7.76–7.69 (m, 2H), 7.68–7.61 (m, 2H), 7.48–7.42 (m, 2H), 7.00 (d, J = 8.8 Hz, 2H), 6.78–6.70 (m, 2H), 3.81 (s, 3H), 3.52 (s, 3H), 2.68 (s, 3H). 13 C NMR (100 MHz, DMSO- d 6 ) δ 192.63, 187.44, 161.58, 160.94, 149.48, 143.10, 137.74, 131.60, 130.95, 130.84, 130.43, 129.28, 126.53, 123.74, 123.45, 119.91, 114.88, 114.68, 114.44, 114.06, 55.78, 55.60, 25.14. HRMS m / z calcd. for C 27 H 25 N 2 O 2 , [M + H] + : 409.1911, found: 409.1919.

(E)-3-(4-chlorophenyl)-1-(4-(methyl(2-methylquinolin-4-yl)amino)phenyl)prop-2-en-1-one ( 13 d ). Yellow powder, Yield, 67%, m.p.159–161 °C. 1 H NMR (400 MHz, DMSO- d 6 ) δ 8.03 (dd, J = 8.2, 5.8 Hz, 3H), 7.94–7.87 (m, 3H), 7.73 (ddd, J = 8.4, 6.8, 1.5 Hz, 1H), 7.68–7.62 (m, 2H), 7.54–7.49 (m, 2H), 7.48–7.43 (m, 2H), 6.74 (d, J = 9.0 Hz, 2H), 3.53 (s, 3H), 2.69 (s, 3H). 13 C NMR (100 MHz, DMSO- d 6 ) δ 192.30, 160.83, 153.10, 151.63, 149.80, 135.96, 134.80, 133.47, 131.27, 131.15, 130.29, 129.62, 129.06, 128.74, 127.22, 126.53, 123.60, 123.53, 120.31, 114.22, 40.74. HRMS m / z calcd. for C 26 H 22 ClN 2 O, [M + H] + : 413.1415, found: 413.1420.

(E)-1-(4-(methyl(2-methylquinolin-4-yl)amino)phenyl)-3-(3,4,5-trimethoxyphenyl)prop-2-en-1-one ( 13e ). Yellow powder, Yield, 61%, m.p.162–164 °C. 1 H NMR (400 MHz, DMSO- d 6 ) δ 8.10–7.98 (m, 3H), 7.84 (d, J = 15.5 Hz, 1H), 7.73 (ddd, J = 8.4, 6.8, 1.5 Hz, 1H), 7.67–7.58 (m, 2H), 7.51–7.43 (m, 2H), 7.18 (s, 2H), 6.79–6.71 (m, 2H), 3.85 (s, 6H), 3.71 (s, 3H), 3.53 (s, 3H), 2.69 (s, 3H). 13 C NMR (100 MHz, DMSO- d 6 ) δ 187.17, 160.78, 153.57, 152.79, 149.70, 143.36, 131.07, 130.99, 130.28, 129.55, 126.46, 123.77, 123.48, 121.84, 120.14, 119.91, 114.57, 114.42, 107.48, 106.75, 60.61, 60.53, 56.58, 56.14, 25.32. HRMS m / z calcd. for C 29 H 29 N 2 O 4 , [M + H] + : 469.2122, found: 469.213.

(E)-1-(4-(ethyl(2-methylquinolin-4-yl)amino)phenyl)-3-(3,4,5-trimethoxyphenyl)prop-2-en-1-one ( 13f ). Yellow powder, Yield, 62%, m.p.148–150 °C. 1 H NMR (400 MHz, DMSO- d 6 ) δ 8.01 (dd, J = 8.3, 6.4 Hz, 2H), 7.85–7.70 (m, 2H), 7.63–7.57 (m, 1H), 7.55–7.46 (m, 1H), 7.45 (d, J = 8.6 Hz, 1H), 7.17 (s, 1H), 6.84–6.76 (m, 1H), 6.68 (d, J = 8.8 Hz, 1H), 6.63–6.57 (m, 1H), 4.00 (q, J = 7.0 Hz, 1H), 3.94 (q, J = 7.0 Hz, 1H), 3.84 (s, 3H), 3.70 (s, 2H), 3.63 (d, J = 5.6 Hz, 3H), 3.41 (d, J = 5.2 Hz, 3H), 2.70 (d, J = 7.4 Hz, 3H), 1.23 (dt, J = 21.2, 7.0 Hz, 3H). 13 C NMR (100 MHz, DMSO- d 6 ) δ 186.97, 160.87, 153.57, 151.83, 150.24, 149.91, 143.17, 139.92, 131.16, 131.01, 130.21, 129.64, 128.09, 126.53, 124.09, 123.73, 121.89, 121.14, 114.07, 106.73, 60.60, 56.57, 47.26, 25.38, 13.32. HRMS m / z calcd. for C 30 H 31 N 2 O 4 , [M + H] + : 483.2278, found: 483.2290.

3.3. Cell Culture

Cell lines used were cultured in humidified incubator at 37 °C and 5% CO 2 . The RPMI-1640 medium was supplemented with 10% fetal bovine serum, penicillin (100 U/mL), and streptomycin (0.1 mg/mL). All the cells were obtained from the Cell Bank of Type Culture Collection of Chinese Academy of Sciences (Shanghai, China).

3.4. MTT Assay

Cell lines were seeded into 126-well plates and incubated for 24 h. Then, cells were treated with different concentrations of compounds. Additionally, after another 48 h, MTT reagent (20 μL per well) was added and then incubated at 37 °C for 4 h. Formazan was then dissolved with DMSO. Absorbencies of formazan solution were measured at 4120 nm. The IC 50 values of tested compounds were calculated by SPSS version 17.0.

3.5. Western Blotting Analysis

Gastric cancer cells were seeded in dishes and treated with 12e or DMSO. After 48 h, MGC-803 cells were collected and then lysed. The denatured lysates of each group were electrophoretic separated in SDS-PAGE. Proteins were then transferred onto PVDF membranes from gels. After blocking for 2 h, membranes were incubated with primary antibodies conjugation. Then, the membranes were washed and incubated with 2nd antibodies. At last, specific proteins were detected.

3.6. General Methods

In this work, some other assays including colony formation assay were referred to our previous work [ 30 , 31 ].

4. Conclusions

Chalcone and quinoline are common scaffolds found in many compounds with many versatile pharmacological activities, especially anticancer activities. In this work, we assumed that linking chalcone fragment to the quinoline scaffold through the principle of molecular hybridization strategy could produce novel compounds with potential anticancer activity. Therefore, quinoline-chalcone derivatives were designed and synthesized, and we explored their antiproliferative activity against MGC-803, HCT-116, and MCF-7 cells. Among these compounds, compound 12e exhibited a most excellent inhibitory potency against MGC-803, HCT-116, and MCF-7 cells, with IC 50 values of 1.38, 5.34, and 5.21 µM, respectively, which were much lower than that of 5-FU (IC 50 values = 6.22, 10.4, and 11.1 μM, respectively). Further mechanism studies suggested that compound 12e inhibited the cell colony formation activity of MGC-803 cells in a dose-dependent manner. Meanwhile, compound 12e could arrest MGC-803 cells at the G2/M phase and significantly upregulate levels of apoptosis-related proteins (Caspase3/9 and cleaved-PARP) in MGC-803 cells. In addition, compound 12e could significantly induce ROS generation, and was dependent on ROS production to exert inhibitory effects on gastric cancer cells. Taken together, all the results suggested that compound 12e might be a valuable lead compound for the development of anticancer agents.

An external file that holds a picture, illustration, etc.
Object name is molecules-26-04899-sch001.jpg

Synthesis of compounds 12a – 12j and 13a – 13f . Reagents and conditions: ( a ) EtOH, NaOH, 25 °C, 6 h; ( b ) EtOH, HCl, 80 °C, 8 h; and ( c ) iodomethane or iodoethane, KOH, acetonitrile, 80 °C, 8 h.

Supplementary Materials

The supplementary materials are available online.

Author Contributions

S.-Y.Z., W.L., and J.S. designed the research and contributed to revision of manuscript; Y.-F.G., X.-J.L., W.-B.L., and G.-X.Y. performed the synthetic work; X.-Y.Y., Y.-R.L., Y.-B.Z. and X.-Y.T. were responsible for the direction of the biological research; and Y.-F.G. contributed to writing of the manuscript. All authors have read and agreed to the published version of the manuscript.

This work was supported by the National Natural Sciences Foundations of China (U2004123 for Sai-Yang Zhang) and China Postdoctoral Science Foundation (No. 2019M632812 for Sai-Yang Zhang) and the Henan Scientific Innovation Talent Team, Department for Education (No. 19ITSTHN001 for Wen Zhao, China). Henan Association of Science and Technology (No. 2020HYTP056 for Sai-Yang Zhang, China) and Science and Technology Department of Henan Province (No. 20202310144, for Sai-Yang Zhang, China). The open fund of state key laboratory of Pharmaceutical Biotechnology, Nan-jing University, China (Grant no. KF-GN-202101).

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Data availability statement, conflicts of interest.

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Recent Developments of Quinoline Derivatives and their Potential Biological Activities

Affiliation.

  • 1 Laboratoire de Chimie Organique et Analytique, Equipe de Chimie Organique et Organometallique Appliquees, Faculte des Sciences et Techniques, Universite Sultan Moulay Slimane, BP 523, 23000 Beni-Mellal, Morocco.
  • PMID: 33327918
  • DOI: 10.2174/1570179417666201216162055

Heterocyclic compounds containing the quinoline ring play a significant role in organic synthesis and therapeutic chemistry. Polyfunctionalized quinolines have attracted the attention of many research groups, especially those who work on drug discovery and development. These derivatives have been widely explored by the research biochemists and are reported to possess wide biological activities. This review focuses on the recent progress in the synthesis of heterocyclic compounds based-quinoline and their potential biological activities.

Keywords: Quinoline derivatives; SARS-CoV-2; biological activity; heterocyclic compounds; synthesis; therapeutic chemistry.

Copyright© Bentham Science Publishers; For any queries, please email at [email protected].

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  • Anti-Infective Agents / chemistry
  • Anti-Infective Agents / therapeutic use*
  • Heterocyclic Compounds / chemistry
  • Heterocyclic Compounds / therapeutic use*
  • Quinolines / chemistry*
  • Anti-Infective Agents
  • Heterocyclic Compounds

quinoline synthesis research paper

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quinoline synthesis research paper

RSC Advances

Recent advances in the synthesis of quinolines: a review.

* Corresponding authors

a Department of Chemistry, School of Sciences, Gujarat University, Ahmedabad, Gujarat, India E-mail: [email protected] Fax: +91-079-26308545 Tel: +91-079-26300969

Quinolines have become important compounds because of their variety of applications in medicinal, synthetic organic chemistry as well as in the field of industrial chemistry. In recent years there are greater societal expectations that chemists should produce greener and more sustainable chemical processes. This review article gives information about the green and clean syntheses using alternative reaction methods for the synthesis of quinoline derivatives. The article includes synthesis by microwave, using clay or some other catalyst which could be recycled and reused, one-pot reaction, solvent-free reaction conditions, using ionic liquids, ultrasound promoted synthesis and photocatalytic synthesis (UV radiation).

Graphical abstract: Recent advances in the synthesis of quinolines: a review

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quinoline synthesis research paper

S. M. Prajapati, K. D. Patel, R. H. Vekariya, S. N. Panchal and H. D. Patel, RSC Adv. , 2014,  4 , 24463 DOI: 10.1039/C4RA01814A

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  • Published: 19 March 2022

Synthesis of new series of quinoline derivatives with insecticidal effects on larval vectors of malaria and dengue diseases

  • Kadarkarai Murugan 1 , 2 ,
  • Chellasamy Panneerselvam 3 ,
  • Jayapal Subramaniam 2 ,
  • Manickam Paulpandi 2 ,
  • Rajapandian Rajaganesh 2 ,
  • Murugan Vasanthakumaran 4 ,
  • Jagannathan Madhavan 5 ,
  • S. Syed Shafi 5 ,
  • Mathath Roni 2 ,
  • Johan S. Portilla-Pulido 6 , 7 ,
  • Stelia C. Mendez 6 ,
  • Jonny E. Duque 7 ,
  • Lan Wang 8 ,
  • Al Thabiani Aziz 3 ,
  • Balamurugan Chandramohan 2 ,
  • Devakumar Dinesh 2 ,
  • Shanmughavel Piramanayagam 9 &
  • Jiang-Shiou Hwang 10 , 11 , 12  

Scientific Reports volume  12 , Article number:  4765 ( 2022 ) Cite this article

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Mosquito borne diseases are on the rise because of their fast spread worldwide and the lack of effective treatments. Here we are focusing on the development of a novel anti-malarial and virucidal agent with biocidal effects also on its vectors. We have synthesized a new quinoline (4,7-dichloroquinoline) derivative which showed significant larvicidal and pupicidal properties against a malarial and a dengue vector and a lethal toxicity ranging from 4.408 µM/mL (first instar larvae) to 7.958 µM/mL (pupal populations) for Anopheles stephensi and 5.016 µM/mL (larva 1) to 10.669 µM/mL (pupae) for Aedes aegypti . In-vitro antiplasmodial efficacy of 4,7-dichloroquinoline revealed a significant growth inhibition of both sensitive strains of Plasmodium falciparum with IC 50 values of 6.7 nM (CQ-s) and 8.5 nM (CQ-r). Chloroquine IC 50 values, as control, were 23 nM (CQ-s), and 27.5 nM (CQ-r). In vivo antiplasmodial studies with P. falciparum infected mice showed an effect of 4,7-dichloroquinoline compared to chloroquine. The quinoline compound showed significant activity against the viral pathogen serotype 2 (DENV-2). In vitro conditions and the purified quinoline exhibited insignificant toxicity on the host system up to 100 µM/mL. Overall, 4,7-dichloroquinoline could provide a good anti-vectorial and anti-malarial agent.

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Introduction.

Vector-borne maladies are providing a serious threat to the well-being and public health around the world. Malaria, or dschungle fever, a tropical parasitic illness caused by the eukaryotic protest Plasmodium spp., provides one of the most significant infections on the planet 1 . An assessed 3.3 billion of the world human population lives in areas with risk of Malaria infection 2 is contaminated with its mosquito vector Anopheles spp. Despite being preventable and treatable, malaria continues to provide severe effects on public health and livelihood in the tropical world 3 , 4 .

According to the World Health Organization 5 , almost two million people in the Americas suffered from dengue virus infection in 2019, and more recent data showed that four billion people suffer from dengue and related viruses such as Zika and Chikungunya in 128 countries worldwide 6 .

Quinoline provides a well studied compound and shows potential biological activities against vector borne diseases 7 , 8 . Quinoline provided the first anti-malarial medicine. It is a special kind of alkaloid originating from the herbal tree Cinchona 9 . By altering the places of the chemical aldehyde groups, quinoline increases its pesticidal properties 10 . Chloroquine provides well known clinical uses because of its viability and its generally safe application 11 . Attributable to huge natural bioactivities, quinoline compounds have attracted increasingly more consideration in combinatorial and bioactivity research 12 , 13 .

Quinoline subsidiaries have widespread biopharmaceutical applications 14 (Fig.  1 ). Analysts have just decided numerous helpful bioactivities of quinoline subordinates, including among others mitigative effects, against bacteria 15 , 16 , hostility to viruses 17 and cell reinforcement 18 . Therapeutic scientists incorporated an assortment of quinoline compounds with various natural compounds by introducing different dynamic gatherings to the quinoline moiety, utilizing engineering techniques and the possible utilization of quinoline subsidiaries in different fields of science, pesticide development and biomedicine 19 , 20 , 21 . Since 2011, several quinoline compounds have shown Epidermal Growth Factor Receptor (EGFR) inhibition 22 .

figure 1

( a ) 4,7-Dichloroquinoline design inspired by the natural molecule, chloroquine. ( b ) 4,7-Dichloroquinoline design inspired by the natural molecule, chloroquine. ( c ) 4,7-Dichloroquinoline design inspired by the natural molecule, chloroquine.

Among the heterocyclic compounds, 4,7-dichloroquinoline is a hydroxychloroquine intermediate for the treatment of different types of malaria 23 . Recently, numerous examinations are carried out with hydroxychloroquine for the therapeutic/forestall of pandemic COVID 19 24 . Likewise, the above said molecule was significant for the understanding of life performances 25 , 26 .

We synthesized a N 1 -(7-chloroquinoline-4-yl) ethane-1,2-diamine derivative by the method of Shafi et al. 8 against A. stephensi providing no harmful impacts on the environment as well on non-target organisms (see Nyberg et al. 27 ). As the plasmodium parasite becomes more resistant to quinoline based anti-malarial drugs, it becomes even more important to design a potent anti-malarial molecule 28 , 29 .

Hence, finding new compounds to treat malaria is urgently needed for the treatment of dangerous mosquito borne diseases 30 , 31 . This work provides a general overview of quinoline advantages for the discovery of more efficient compounds 32 , 33 . In continuation of the study for the preparation of a 4-diamine substituted-7-dichloroquinoline compounds against vector borne diseases 34 we report herein the anti-malarial and anti-dengue potential of a novel quinoline compound.

The quinoline skeleton is utilized for some important engineered agrochemicals and to plan manufactured mixtures providing several pharmacological effects. Quinoline and its related compounds belongs to a significant class of antimalarial sedates that affect the parasite’s hemoglobin breakdown pathway. Earlier studies reported that for some time this compound was utilizing quinoline to battle malaria 35 . Along these lines, it is significant to re-look into the antimalarial movement of existing quinoline libraries or blend some unique quinoline subsidiaries with improved action. A methodical and broad investigation is needed to find a compelling antimalarial compound structure 4-aminoquinoline based framework 36 . In the present research, we have orchestrated several analogs of 4,7-dichloroquinoline and screened against jungle fever parasites, dengue (DENV-2) and their respective mosquito vectors. Also, we reported the synthesis of N2-2-((7-chloroquinolin-4-yl) amino) ethyl)-N4, N6-bis(4-nitrophenyl)-1,3,5-triazine-2,4,6-triamine. Whose synthesis have been planned for the bi-substituted cyanuric chloride using p-nitroaniline incorporated N1-(7-chloroquinoline–4–yl) ethane-1,2–diamine. Synthesized molecules can be analyzed by IR, 1 HNMR, 13 C, mass and elemental analysis to characterize their molecular structure. This is a new compound that is easily synthesized by substituting cyanuric chloride to provide s-triazine derivatives. Substituted quinolines are historically among the most important antimalarial drugs and are expected to achieve a substantial reduction of malaria infections.

Materials and methods

Biogenesis of n1-(7-chloroquinoline -4-yl) ethane-1,2-diamine.

A form of 4,7 dichloroquinoline (1.8 g, 0.01 mol) and ethylene diamine (0.06 g, 0.01 mol) was evaluated through thin layer chromatography (TLC) at the end of a chemical reaction. Filtration was used to remove the crystals of 4-substituted 7-chloroquinoline. After acetone treatment the end compound was recrystallized twice providing N1-(7-chloroquinoline-4-yl) ethane-1,2-diamine (CAS Number-5407-57-8).

N1-(7-chloroquinoline-4-yl) ethane-1,2-diamine in silico analysis

The synthesized compound N1-(7-chloroquinoline-4-yl) ethane-1,2-diamine was analyzed for its cytotoxic potential using the Osiris protocol from its official website ( https://www.organic-chemistry.org/prog/peo/ ). Parts of the Lipinski rule of five important parameters were utilized for quantification in order to trace their biological functions.

Anopheles stephen s i and Aedes aegypti cultures

Developmental instars of Anopheles stephensi and Aedes aegypti eggs were maintained at the following conditions of the laboratory: 27 ± 2 °C, 75–85% R.H. and 14 h:10 h (L:D) photoperiod.

Toxicity effects on developmental instars of Aedes aegypti and A. stephensi

The mosquitoes A. aegypti and A. stephensi were cultured and maintained following Murugan et al. 37 . For toxicology studies, 25 individuals of both A. stephensi and A. aegypti larva (1st, 2nd, 3rd, and 4th) and pupae were placed for a 24 h treatment in a tank filled with 500 mL of distilled water at concentrations of 4,7-dichloroquinoline (2, 4, 6, 8 and 10 ppm) 38 . In each treatment, 3 replications were carried out, in addition to negative controls. Mortality rate in percentage was studied applying the following formula:

Antiplasmodial cell culture assays on P. falciparum

CQ-sensitive strain 3D7 and CQ-resistant strain INDO of Plasmodium falciparum were used to test the antimalarial activity of 4,7-dichloroquinoline. They were maintained according to the method described by Murugan et al. 39 . Formulations of 4,7-dichloroquinoline in DMSO were evaluated by the procedure of Murugan et al. 40 , modified after Smilkstein et al. 41 . Microscopic examination of Giemsa stained smear samples of normal Plasmodium falciparum exposed to 4,7-dichloroquinoline was following Bagavan et al. 42 .

In vivo antiplasmodial assays on P. falciparum

Following the method of Murugan et al. 43 , male albino mice (weight 27–30 g) were tested. They were maintained as reported by Murugan et al. 43 . For each experiment, three albino mice were used to test the antimalarial potential of the synthesized compound, 4,7-dichloroquinoline following a four-day inhibition technique by Murugan et al. 43 . Chloroquine (Sigma-Aldrich, Germany) was used as a positive control drug with normal saline (0.9%) at 5 mg/kg, while the negative control group was treated with 1 mL deionized water. The parasites inoculated in mice were noticed after 4 days of infection through microscopic observations of the blood 44 . Chemosuppression (%) was analyzed for every concentration of the parasitemia following the method of Argotte et al. 45 .

Infection and toxicity towards cells

We procured Vero cells from the National Center for Cell Science (NCCS Maharashtra, India). The medium used for cultivation (EMEM) contained 10% fetal bovine serum and was incubated at 37 °C in a 5% CO 2 atmosphere. We decreased the serum concentration to 2% when viral cultures were used. As described by Murugan et al. 43 Dengue virus type-2 (DEN-2) New Guinea C strain was raised through adopting the cell line and were retrieved after the expression of cytopathic effects (CPE), commonly seven days after infection. Infected viral cells were stored at – 70 °C. Cytotoxicity assays and viral quantification assays were following Sujitha et al. 46 with minor modification.

Statistical analysis

Data from Probit analysis allowed the analysis of the effective lethal concentrations of the mosquito larvicidal and pupicidal experiments 47 . From the drug concentration–response curves the IC 50 s of Plasmodium were calculated. In vivo antimalarial data were checked for normality and analysed using ANOVA with two factors (i.e. dose and treatment). DEN-2 PFU and cytotoxicity data were determined by ANOVA followed by the HSD test of Tukey with the following probabilities (P = 0.05). All analyses were commonly carried out with the SPSS software package version 16.0.

Results and discussion

N1-(7-chloroquinoline-4-yl) ethane-1, 2-diamine effects analyzed by in-silico approaches.

The synthesized compound showed no tumorigenic, irritative, nor reproductively significant effects in silico. Besides, LogP and LogS values (Table 1 ) indicated that the synthesized compound was hydrophilic with a high probability of being distributed along with hydrophilic environments such as insect lymph or cellular cytosol. Molinspiration analysis indicated that the values regarding, GPCR ligand, kinase inhibitor, nuclear receptor ligand, ion channel modulator, protease inhibitor and enzyme inhibitor scores were high. Molinspiration analysis generally indicated that the larger the value of the score was, the more the compound would have biological effects. Therefore, according to in silico analysis, N1-(7-chloroquinoline-4-yl) ethane-1,2-diamine is likely to affect ion channels, kinases, and some important enzymes. The above results could be related to acute toxicity on young instars of A. aegypti and A. stephensi and highly increased the growth inhibition of Plasmodium falciparum 48 . The in silico study highlighted that quinoline derivatives (BT24) effectively inhibited all four dengue serotypes (1–4) of infected Vero cells by compound (BT24) binding to the active site of the DENV-2 protease. On the other hand, no cytotoxic in silico results could be corroborated by the effect of Vero cell line studies. The drug likeness value is similar to quinolineb (− 1.65, data not shown) as the compounds are closely related. As a result, the compound could be used for the above mentioned applications.

Toxicity effect of 4,7-dichloroquinoline on A. aegypti and A. stephensi

In agreement with the current research, Saini et al. 49 studied the antimalarial potential of quinoline-pyrazolo pyridine derivatives. Mosquitocidal results revealed that the synthesized 4,7-dichloroquinoline was highly toxic to developmental stages of malarial and dengue vectors providing LC 50 values ranging from 4.408 µM/mL (larva I) to 7.958 µM/mL (pupa) for the chosen malaria vector and 5.016 µM/mL (larva I) to 10.669 µM/mL (pupa) for the dengue vector (Table 2 ). Recently, Rueda et al. 50 demonstrated both adulticidal and larvicidal activity of A. aegypti when exposed to synthesized α-amino nitriles. Shao et al. 51 showed for hexahydroimidazo [1,2-α] pyridine derivatives that they had excellent pesticidal properties against aphid species. Furthermore, Sun et al. 52 highlighted that piperazinedione derivatives were highly toxic on the root-knot nematode Meloidogyne incognita . The K1 strain being resistant against chloroquine (CQ) was shown by Gayam and Ravi 53 and that cinnamoylated chloroquine hybrid analogues showed highest antimalarial activity. Lastly, Kondaparia et al. 54 found that 4-aminoquinolines showed considerable antimalarial activity on Plasmodium falciparum . It was proposed that death rate caused by 4,7-dichloroquinoline for the different life stages of larval populations of both A. stephensi and A. aegypti may be due to the upregulation of electronegative ions which provided better biological activity on target pests 55 . Indeed, Rahuman et al. 56 reported that Zingiber officinale derived molecules showed toxicity on the 4th larval stages of the dengue vectors belonging to Culex species.

Antiplasmodial activities

As a result of antiplasmodial assays, when compared to chloroquine, the synthesized 4,7-dichloroquinoline expressed significant growth inhibition against both CQ-resistant (CQ-r) and CQ-sensitive (CQ-s) strains of P. falciparum (Fig.  2 ). Similarly, Kumawat et al. 57 investigated 7-Chloro-4-aminoquinoline derivatives causing moderate growth inhibition on CQ-sensitive P. falciparum (RKL-2). Also, Faruk Khan 58 noticed that the cyclen 4-Aminoquinoline anlog, bisquinoline, exhibited in vitro and in vivo antiplasmodial properties on D6 W2 chloroquine-sensitive and chloroquine-resistant strains of P. falciparum with IC 50 values of 7.5 nM (D6 CQ-sensitive) and 19.2 nM (W2 CQ-resistance). Very recently, Pinheiro et al. 59 showed that quinoline and non-quinoline derivatives were highly effective against both P. falciparum W2 chloroquine-resistant strains of P. falciparum in infected mice. Quinoline drugs exhibited potential inhibitory effect of proteolysis, DNA replication, RNA synthesis and heme polymerization in Plasmodium spp 60 , 61 . Additionally, Aboelnaga and El-Sayed 62 reported that 7-chloroquinoline derivatives showed significant anticancer activity on cervical (Hela) cancer cell lines, human breast cancer (MCF-7) and colon carcinoma (HCT-116). Protein kinase inhibitors, topo isomerase inhibitors, carbonic anhydrase inhibitors, Hsp90 inhibitors are the anticancer mechanisms of quinoline derivatives 63 . Aderibigbe et al. 64 found that polymer loaded aminoquinoline were highly potent against the strain of P. falciparum which was chloroquine-sensitive. A new quinoline derivative, thiazolyl hydrazone were synthesized as effective antifungal and anticancer agents by Erguc et al. 65 .

figure 2

In vitro growth inhibition of chloroquine-sensitive and chloroquine-resistant strains of Plasmodium falciparum post-treatment with 4,7-dichloroquinoline and chloroquine. T-bars represent standard deviations.

Dose-dependent chemosuppression against P. falciparum was demonstrated by Peters’ 4-day chemo-suppressive activity assay (Fig.  3 ). After 4 days of 4,7-dichloroquinoline treated groups exhibited the percentage of parasitemia 10.6 ± 0.8% at 300 mg/kg/day than that of the control drug chloroquine (CQ) 1.0 ± 0.0% 37 , 66 . Tang et al. 67 showed antimalarial activities against the P. falciparum strain K173 with EC 50 values ranging from 0.38 to 0.43 mg/kg. Manohar et al. 68 found that 4-Aminoquinoline-pyrimidine hybrids exhibited 80% parasitemia suppression as compared to CQ (20%). Finally, Sahu et al. 69 found that low doses of tigecycline (3.7 mg/kg) showed 77–91% of parasitaemia suppression. Inhibition of parasitaemia of 77–91% was provided by 3.7 mg/kg dose of tigecycline for 4 consecutive days. Furthermore, the authors reported that in vivo treatment with tigecycline in combination with sub-curative doses of CQ provided 100% mortality of P. falciparum in infected mice.

figure 3

In vivo growth inhibition of Plasmodium falciparum parasites infecting albino mice post-treatment with 4,7-dichloroquinoline. Positive control (chloroquine 5 mg/kg/day) led to mean parasitemia of 1.0 ± 0.0% at day 4. T-bars represent standard deviations. Above each column, different letters indicate significant differences (ANOVA, Tukey's HSD, P  < 0.05).

Cytotoxicity effect of 4,7-dichloroquinoline on Vero cells

In the present study, the viability of Vero cells was incorporated in various concentrations of 4,7-dichloroquinoline 70 . We observed that there were no adverse morphological differences in the treated groups when compared to control Vero cells (Figs.  4 , 5 ). For example, Tseng et al. 71 studied that the new derivatives of synthesized 2-aroyl-3-arylquinoline compounds provided substantial cytotoxicity against Huh-7 cells with less than 20% viability at doses of 100 μM of 4,7-dichloroquinoline. Cell death above a concentration of 60 μM of 4-methyl pyrimido (5,4-c) quinoline-2,5(1H, 6H)-dione on MDCK cells were shown by Paulpandi et al. 34 . Recently, Beesetti et al. 72 highlighted that quinoline derivatives, BT24 effectively inhibit DENV-2 protease with IC 50 of 0.5 μM.

figure 4

Cytotoxic effects of 4,7-dichloroquinoline on Vero cells.

figure 5

Vero cell viability after the treatment with different concentrations of 4,7-dichloroquinoline.

Antiviral effects of 4,7-dichloroquinoline on dengue and zika virus

Antiviral results showed that the synthesized compound, 4,7-dichloroquinoline tested at 10–40 μg/mL significantly inhibited dengue virus (DENV-2), with a reduction of PFU abundance 73 (see also Fig.  6 ). Furthermore, a plaque assay displayed after an individual exposure and with a minimum dosis that 4,7-dichloroquinoline effectively inhibited the production of dengue viruses. Post 48 h treatment duration of the viral production was 91 PFU/mL in the control, whereas it was 19 PFU/mL, after the treatment of in 4,7-dichloroquinoline at a concentration of 40 μL/mL (Fig.  7 ). Similarly, Guardia et al. 74 discovered that quinoline derivatives highly inhibited DENV-2 with IC 50 values ranging from 3.03 to 0.49 μM, respectively. Very recently, Devaux et al. 75 found that chloroquine/hydroxychloroquine significantly inhibited pandemic SARS-CoV-2. Furthermore, chloroquine highly inhibited HCoV-229E replication in epithelial lung cell cultures 76 . It became apparent that the Zika virus provided a regional threat for Latin America and the Caribbean 77 , 78 .

figure 6

Inhibition of dengue virus (DEN-2) post-treatment with 4,7-dichloroquinoline.

figure 7

Post treatment reduction in DEN-2 viral yield with 4,7-dichloroquinoline at different time intervals.

It is clear from previous reports that resistance to the malaria vector continues to grow. This is increasingly limiting our ability to control malaria worldwide. Our present study demonstrated the mosquitocidal potential of 4,7-dichloroquinoline derivatives against the key mosquito vectors, An. stephensi and Ae. aegypti . This would be a promising advance in the development of clean, non-toxic, and environmentally acceptable quinoline compounds for their effect against mosquito vectors. Furthermore, 4,7-dichloroquinoline had a significant and promising anti-malarial potential to reduce the global threat malaria. Quinoline decreased virus proliferation and replication during protein synthesis at mRNA levels. No cell cytotoxicity was identified. A compound was recognized as a unique kind of structure different for additional improvement against DENV specialists. We have presented here novel quinoline subordinates that are fundamentally dynamic against dengue infection in a partially subordinate way. The discoveries presented here are significant as a starting point for additional clarification of the particular components of the antiviral action and to pick up the necessary information to additionally grow new, compelling, strong, and safe medications to lessen the risks from viral diseases.

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Acknowledgements

Financial support from the Ministry of Science and Technology of Taiwan (Grant no. MOST 108-2621-M-019-003, MOST 109-2621-M-019-002, and MOST 110-2621-M-019-001) and the Center of Excellence for Ocean Engineering (Grant no. 109J13801-51 and 110J13801-51) to J.-S. Hwang is acknowledged.

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Kadarkarai Murugan

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Kadarkarai Murugan, Jayapal Subramaniam, Manickam Paulpandi, Rajapandian Rajaganesh, Mathath Roni, Balamurugan Chandramohan & Devakumar Dinesh

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K.M., J.S., J.S.H., R.R., S.P.: Wrote the original draft, conventionalization, experimentation, writing and editing. K.M., J.S.H., L.W., R.R., S.C.M.-S., J.E.D., A.T.A.: Project administration and funding acquisition. J.S., M.P., J.M., C.P., J.E.D., S.M.S., J.P.P., S.P.: Writing, revision, editing, and data curation and results interpretation. K.M., L.W., R.R., D.D., A.T.A., M.R., D.D., C.P., J.M., S.S.S., S.M.S.: Methodology and revision. M.V., B.C., J.M., M.R., J.S.P.-P., S.P.: Instruments, experimentation and synthesis, review and editing. All authors reviewed the manuscript.

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Murugan, K., Panneerselvam, C., Subramaniam, J. et al. Synthesis of new series of quinoline derivatives with insecticidal effects on larval vectors of malaria and dengue diseases. Sci Rep 12 , 4765 (2022). https://doi.org/10.1038/s41598-022-08397-5

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quinoline synthesis research paper

Quinoline-Containing π-Conjugated Systems: Synthesis, Research, and Application of Quinophthalone Dyes

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  • Published: 28 February 2024
  • Volume 13 , pages 238–264, ( 2023 )

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quinoline synthesis research paper

  • E. V. Shklyaeva 1 ,
  • A. V. Ozhgikhina 3 &
  • G. G. Abashev 1 , 2  

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Here we present the literary review concerning methods of synthesis and application fields of substituted quinophthalones, an interesting class of heterocyclic compounds containing fragments of substituted/unsubstituted quinolines and phthalic anhydride in their structure. Such compounds have an extended π-conjugated system and are, therefore, most often used as dyes.

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Shklyaeva, E.V., Ozhgikhina, A.V. & Abashev, G.G. Quinoline-Containing π-Conjugated Systems: Synthesis, Research, and Application of Quinophthalone Dyes. rev. and adv. in chem. 13 , 238–264 (2023). https://doi.org/10.1134/S2634827623600196

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Received : 10 October 2023

Revised : 30 October 2023

Accepted : 02 November 2023

Published : 28 February 2024

Issue Date : September 2023

DOI : https://doi.org/10.1134/S2634827623600196

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    dilute HCl to prepare quinoline-4-carboxylic acid (28) in good to excellent yields.7 The authors claimed that using enaminone as a replacement for 1,3-dicarbinols improves the yield and prac-ticality of the reaction. 2.5. Skraup/Doebner-von Miller quinoline synthesis A synthesis of quinoline via aniline and glycerine in the pres-

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    Desai and co-workers reported the synthesis of quinoline derivatives 107, 108 and 109 exhibiting the most powerful antimicrobial activities ... His research topics include the study and development of new methods and synthetic approaches towards organic compounds, as well as a focus on developments in the synthesis of heterocyclic organic ...

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    Abstract. The quinoline ring system is one of the most ubiquitous heterocycles in the fields of medicinal and industrial chemistry, forming the scaffold for compounds of great significance. These include anti-inflammatory and antitumor agents, the antimalarial drugs quinine and chloroquine, and organic light-emitting diodes.

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  23. Quinoline-Containing π-Conjugated Systems: Synthesis, Research, and

    The authors of [] believe that, in the unexcited (ground) state, the most stable form is the form 1b, which is confirmed by NMR spectroscopy data and quantum-chemical calculations.In this form, the quinoline and phthalone rings of the quinophthalone system are linked by a double bond, making them essentially coplanar and leading to the formation of a more efficient π-conjugation system.

  24. An Organocatalyzed Multicomponent Reaction: A Rapid and Efficient

    ChemistrySelect is a sound science chemistry journal publishing original authoritative research in all areas of chemistry. Abstract A three-component multicomponent approach has been developed at room temperature for the synthesis of 4H-pyrano[3,2-c]quinoline-3-carbonitriles.

  25. Palladium Complexes Derived from Waste as Catalysts for C-H ...

    Palladium-mediated reactions are among the most frequently employed transformations in synthetic chemistry and are used widely for C-C, C-N and C-O bond formation [1,2,3,4,5,6].However, the extremely low natural abundance of palladium in the Earth's crust, its limited distribution and geopolitical factors threaten future supply [].This has led to a substantial palladium deficit due to the ...

  26. PDF The effects of working time on productivity and firm performance: a

    work schedules. This paper - alongside two other papers, one on working time, health and safety, and another on working time and work-life "integration" or "balance" - was used as an input into the discussion report for the meeting. This paper provides a comprehensive synthesis of previous research examining the link between