324
S. Manohar et al. / Bioorg. Med. Chem. Lett. 20 (2010) 322–325
Table 2
(Table 2). Among the series of conjugates, compounds 28–33 were
more cytotoxic to all three cell lines than others. In general the
cytotoxicity of the most of the conjugates appeared at much higher
concentrations than the concentrations responsible for their anti-
malarial activity. Some of the conjugates were not cytotoxic at all
In vitro antimalarial activity of 4-aminoquinoline–triazine conjugates
Entry
P. falciparum (D6 clone)
P. falciparum (W2 clone)
IC50
(l
M)
Selectivity index
IC50
(l
M)
Selectivity index
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
CQ
Art
0.56
0.42
0.25
3.17
NA
53.2
69.0
130.8
>15.1
0.58
0.56
0.22
3.53
NA
51.4
51.8
148.6
>13.6
up to the highest tested concentration of 48
safety in the mammalian system.
lM indicating their
In conclusion, series of 4-aminoquinoline–triazine conjugates
have been prepared in three steps and these conjugates have
shown promising antimalarial activity against both D6 and W2
strains of P. falciparum. Further chemical modification of selected
compounds is under progress, and results will be published in
due course of time.
0.48
2.45
1.59
0.97
1.74
0.67
1.46
1.27
0.56
0.21
2.54
0.39
0.42
0.79
0.62
1.58
0.31
>100
>19.6
>30.2
>49.5
19.7
46.9
24.2
>37.8
>85.7
49.5
11.6
75.4
59.0
33.8
36.9
30.4
>154.8
>300
>500
0.35
4.91
2.02
0.70
2.22
0.71
1.81
3.16
0.87
0.25
4.91
0.72
0.61
0.69
0.58
1.89
0.38
0.42
>137.1
>9.8
>23.8
>68.6
15.4
44.2
19.5
>15.2
>55.2
41.6
6.0
40.8
40.6
38.7
39.5
25.4
>126.3
>30
Acknowledgments
D.S.R. thanks Department of Science and Technology (SR/S1/OC-
08/2008), New Delhi, India for financial support. S.M. is thankful to
CSIR for the award of junior research fellowship. S.K. is thankful to
United States Department of Agriculture (USDA), Agricultural Re-
search Service Specific Cooperative Agreement No. 58-6408-2-
0009 for partial support of this work.
0.042
0.03
0.025
>670
References and notes
NA: no activity up to 9
lM; selectivity index (IC50 for cytotoxicity to vero cells/IC50
for antimalarial activity); CQ: chloroquine; Art: artemisinin.
1. (a) Hay, S. I.; Guerra, C. A.; Tatem, A. J.; Noor, A. M.; Snow, R. W. Lancet Infect.
Dis. 2004, 4, 327; (b) O‘Neill, P. M.; Posner, G. H. J. Med. Chem. 2004, 47, 2945;
(c) Haynes, K.; Vonwiller, S. C. Acc. Chem. Res. 1997, 30, 73; (d) Wahlgren, M.;
Bejarano, M. T. Nature 1999, 400, 506; (e) Vangapandu, S.; Jain, M.; Kaur, K.;
Patil, P.; Patel, S. R.; Jain, R. Med. Res. Rev. 2007, 27, 65; (f) Kumar, A.; Katiyar, S.
B.; Agarwal, A.; Chauhan, P. M. S. Drugs Future 2003, 28, 243; (g) Fidock, D. A.;
Rosenthal, P. J.; Croft, S. L.; Brun, R.; Nwaka, S. Nat. Rev. Drug Disc. 2004, 3, 509;
(h) Wiesner, J.; Ortmann, R.; Jomaa, H.; Schlitzer, M. Angew. Chem., Int. Ed. 2003,
42, 5274; (i) Kumar, N.; Singh, R.; Rawat, D. S. Med. Res. Rev., in press.
2. Ridley, R. G. Nature 2002, 415, 686.
3. Coatney, G. R.; Cooper, W. C.; Eddy, N. B.; Greenberg, J. Public Health Monogr.
1953, 15, 1.
4. Greenwood, D. J. Antimicrob. Chemother. 1995, 36, 857.
5. Loeb, F.; Clark, W. M.; Coateny, G. R.; Coggeshall, L. T.; Dieuaide, F. R.; Dochez,
A. R.; Hankansson, E. G.; Marshall Jr, E. K.; Marvel, C. S.; McCoy, O. R.; Sapero, J.
J.; Sebrell, W. H.; Shannon, J. A.; Carden Jr, G. A. J. Am. Med. Assoc. 1946, 130,
1069.
6. (a) Sidhu, A. B.; Verdier-Pinard, D.; Fidock, D. A. Science 2002, 298, 210; (b) Mita,
T.; Tanabe, K.; Kita, K. Parasitol. Int. 2009, 58, 201.
7. (a) Bioland, P. B.; Lackritz, E. M.; Kazembe, P. N.; Were, J. B. O.; Steketee, R.;
Campbell, C. C. J. Infect. Dis. 1993, 167, 932; (b) White, N. J.; Nosten, F.;
Looareesuwan, S.; Watkins, W. M.; Marsh, K.; Snow, R. W.; Kokwaro, G.; Ouma,
J.; Hien, T. T.; Molyneux, M. E.; Taylor, T. E.; Newbold, C. I.; Ruebush, T. K.;
Danis, M.; Greenwood, B. M.; Anderson, R. M.; Olliaro, P. Lancet 1999, 353, 1965.
8. Nosten, F.; ter Kuile, F. O.; Chongsuphajaisiddhi, T.; Luxemburger, C.; Webster,
H. K.; Edstein, M.; Phaipun, L.; Thew, K. L.; White, N. J. Lancet 1991, 337, 1140.
9. Ridley, R. G.; Dorn, A.; Vippagunta, S. R.; Vennerstrom, J. L. Ann. Trop. Med.
Parasitol. 1997, 91, 559.
Table 3
In vitro cytotoxicity of 4-aminoquinoline–triazine conjugates to mammalian cells
Entry
IC50 (lM)
LLC-PK11
HepG2
Vero
14
15
16
17
18
19
9.5
11.6
8.3
9.5
28.7
NC
29.8
8.9
25.4
38.8
NC
29.8
29.0
32.7
NC
NC
NC
NC
20
21
33.5
NC
12.9
NC
NC
NC
22
23
24
25
26
27
28
29
30
31
32
33
34
35
>48
10.5
8.4
27.0
>48
32.8
11.2
8.8
8.6
8.0
9.0
6.3
NC
8.3
9.6
10.4
14.1
30.5
3.9
9.8
9.8
9.3
8.8
14.6
12.6
2.0
NC
34.3
31.4
35.3
NC
NC
10.4
29.4
29.4
24.8
26.7
22.9
48.0
NC
10. O’Neill, P. M.; Ward, S. A.; Berry, N. G.; Jeyadevan, J. P.; Biagini, G. A.; Asadollaly,
E.; Park, B. K.; Bray, P. G. Curr. Top.-Med. Chem. 2006, 6, 479.
11. (a) Pandey, A. V.; Bisht, H.; Babbarwal, V. K.; Srivastava, J.; Pandey, K. C.;
Chauhan, V. S. Biochem. J. 2001, 355, 333; (b) Chou, A. C.; Chevli, R.; Fitch, C. D.
Biochemistry 1980, 19, 1543; (c) Egan, T. J.; Marques, H. M. Coord. Chem. Rev.
1999, 190–192, 493; (d) Dorn, A.; Stoffel, R.; Matile, H.; Bubendorf, A.; Ridley, R.
G. Nature 1995, 374, 269.
32.0
28.8
0.85
Doxorubicin
0.42
20
12. Egan, T. J. Targets 2003, 3, 115.
13. Cheruku, S. R.; Maiti, S.; Dorn, A.; Scorneaux, B.; Bhattacharjee, A. K.; Ellis, W.
Y.; Vennerstrom, J. L. J. Med. Chem. 2003, 46, 3166.
NC: No cytotoxicity up to 48
lM; LLC-PK11: pig kidney epithelial cells; HepG2:
human hepatoma cells; Vero: monkey kidney fibroblasts.
14. (a) Ridley, R. G.; Hofheinz, H.; Matile, H.; Jaquet, C.; Dorn, A.; Masciadri, R.;
Jolidon, S.; Richter, W. F.; Guenzi, A.; Girometta, M. A.; Urwyler, H.; Huber, W.;
Thaithong, S.; Peters, W. J. Antimicrob. Chemother. 1996, 40, 1846; (b) De, D.;
Krogstad, F. M.; Byers, L. D.; Krogstad, D. J. J. Med. Chem. 1998, 41, 4918.
15. Stocks, P. A.; Raynes, K. J.; Bray, P. G.; Park, B. K.; O‘Neill, P. M.; Ward, S. A. J.
Med. Chem. 2002, 45, 4975.
16. Egan, T. J.; Hunter, R.; Kaschula, C. H.; Marques, H. M.; Misplon, A.; Walden, J. J.
Med. Chem. 2000, 43, 283.
17. (a) Robert, A.; Dechy-Cabaret, O.; Cazelles, J.; Meunier, B. Acc. Chem. Res. 2002,
35, 167; (b) Meunier, B. Acc. Chem. Res. 2008, 41, 69.
18. (a) Dechy-Cabaret, O.; Benoit-Vical, F.; Robert, A.; Meunier, B. ChemBioChem
2000, 1, 281; (b) Dechy-Cabaret, O.; Benoit-Vical, F.; Loup, C.; Robert, A.; Vial,
H.; Gornitzka, H.; Bonhoure, A.; Magnaval, J. F.; Seguela, J. P.; Meunier, B.
Chemistry 2004, 10, 1625; (c) Singh, C.; Malik, H.; Puri, S. K. Bioorg. Med. Chem.
2004, 12, 1177.
0.87 lM with high selectivity index. However, upon increasing the
length of the linker to C4 the activity diminished (entry 29).
Compounds having o-toludine and aminoquinolines with differ-
ent linker (entries 30–33) exhibited antimalarial activity with IC50
values in the range of 0.31–1.58
lM against D6 clone and 0.38–
1.89 M against W2 strain of P. falciparum.
l
Among the most active compounds (16, 19, 28 and 35),
although 28 was more cytotoxic to Vero cells than others (Table 3)
but still exhibited a high selectivity index of antimalarial activity