M. Nivsarkar et al. / Bioorg. Med. Chem. Lett. 15 (2005) 1371–1373
1373
Table 2. Antimalarial activity of compounds by schizont maturation
assay against chloroquine sensitive (CS) and chloroquine resistant
(CR) strains of P. falciparum (lM)
2. Greewood, B.; Mutabingwa, T. Nature 2002, 415, 670–
672.
3. White, N. J. Br. Med. Bull. 1998, 54, 703–715.
4. Ridley, R. G. Science 1999, 285, 1502–1503.
5. Peters, W. Chemotherapy and Drug Resistance in Malaria,
2nd ed.; Academic: London, 1987.
Compound
IC50
IC90
IC99
CS
5.4
CR
CS
CR
CS
CR
6. Georg, G. I.; Ravikumar, V. T. In The Organic Chemistry
of b-Lactams; Georg, G. I., Ed.; VCH: NewYork, 1992.
7. Bose, A. K.; Manhas, M. S.; Banik, B. K.; Sriranjan, V. b-
Lactams: Cyclic Amides of Distinction. In The Amide
Linkage: Selected structural Aspects in Chemistry, Bio-
chemistry, and Material Science; Greenberg, A., Bren-
eman, C. M., Liebman, J. F., Eds.; Wiley Interscience:
New York, 2000; pp 157–214.
8. (a) Manhas, M. S.; Banik, B. K.; Mathur, A.; Vincent, J.
E.; Bose, A. K. Tetrahedron Symp. 2000, 56, 5587–5601;
(b) Banik, B. K.; Manhas, M. S.; Bose, A. K. J. Org.
Chem. 1993, 58, 307–309; (c) Banik, B. K.; Manhas, M. S.;
Bose, A. K. J. Org. Chem. 1994, 59, 4714–4716; (d)
Burnett, D. A.; Capten, M. A.; Darris, H. R.; Burrier, R.
E., Jr.; Clader, J. W. J. Med. Chem. 1994, 37, 1733–
1736.
MNR00
MNR0
MNR1
MNR2
MNR3
MNR4
MNR5
MNR6
MNR7
MNR11
Chloroquine
5.8
7.3
8.4
7.9
8.7
1.6
1.8
4.6
12.4
7.4
10.7
25.4
33.7
18.8
19.3
5.6
11.4
26.1
33.9
19.4
21.2
6.1
13.3
43.4
51.2
25.2
23.2
6.1
14.5
48.7
54.8
27.4
25.3
6.4
6.8
8.1
8.1
9.1
1.5
1.8
5.9
13.5
6.5
2.8
2.9
3.2
3.3
14.5
31.9
11.2
15.4
34.5
12.4
0.5
20.1
42.2
12.3
24.8
48.7
14.5
0.02
0.03
0.05
both these compounds are active against the chloro-
quine sensitive as well as the resistant strains of P. falci-
parum this class of compounds has the potential as
antimalarial. The normal human RBCÕs used for the cul-
ture when exposed at all the concentrations showed no
cell lysis which suggests that the test compounds have
no lytic activity on the normal human cells. Compounds
MNR4 and MNR5 that showed maximum activity in
the schizont maturation assay were also highly active
in the total growth inhibition assay indicates that the
possible mode of action of these compounds is on the to-
tal growth inhibition rather than slowing down the cell
division cycle. Its also noteworthy to mention that
although these compounds are active against the chloro-
quine resistant strain P. falciparum at much higher con-
centrations than chloroquine (which is six times more
potent than the lactams) or other natural products like
artemesinin, the potency of these compounds can be en-
hanced by further structural modifications. From the re-
sults it has been clearly indicated that the introduction
of benzyl group on the 2-azetidine ring has some effect
towards the antimalarial activity. In conclusion, the re-
sult obtained established that N-benzylated lactam (Ta-
ble 1 S. no 1–10) has in vitro antimalarial activities
against both chloroquine resistant and choloroquine
sensitive malarial strains (Table 2).
9. (a) Edward, P. D.; Bernstein, P. R. Med. Res. Rev. 1994,
14, 127–194; (b) Buynak, J. D.; Rao, A. S.; Fod, G. P.;
Carver, C.; Larver, C.; Adam, G.; Geng, B.; Bachmann,
B.; Shobassy, S.; Lackey, S. J. Med. Chem. 1997, 40, 3423–
3433.
10. Parsons, P. J.; Camp, N. P.; Underhood, J. M.; Harvey,
M. D. Tetrahedron 1996, 52, 35, 1637–11642.
11. Compounds (1–10) were fully characterized by IR, MS, 1H
NMR and 13C NMR.
For example compound number 3 code MNR1. Mp 105–
106 ꢁC (dec) IR 3214 cmÀ1, 1731 cmÀ1. 1H NMR (CDCl3,
400 MHz) d 2.99 (td, 1H, 9 Hz, 4 Hz), 1.30 (m, 2H), 1.50
(m, 2H), 3.07 (m, 1H), 6.1 (br, NH, 1H). 13C (CDCl3,
100 MHz) NMR d 24.9, 26.8, 29.8, 30.01, 31.09, 36.1, 45.5,
48.7, 171.30. ESI-MS 154 (M+H).
Compound number 4 code MNR2. Mp 62–63 ꢁC (dec). IR
1767, 1730, 1656, 3011, 1485, 1440 cmÀ1 1H NMR
.
(CDCl3, 400 MHz) d 1.25 (m, 2H), 1.29 (m, 8H), 1.51
(m, 2H), 1.53 (m, 2H), 2.85 (m, 1H), 3.03 (td, 1H,
9 Hz, 4 Hz), 3.98, 4.46 (dd, 2H) AB Coupling JAB 16 Hz,
7.06 (m, 2H), 7.33 (m, 2H), 7.07 (m, 1H). 13C NMR
(CDCl3, 100 MHz) d 25.2, 26.8, 29.6, 30.0, 31.12, 33.9,
43.3, 52.5, 53.3, 128.3, 126.8, 137.2, 176.7. ESI-MS 244
(M+H).
Compound number 5 code MNR3. Mp 98–99 ꢁC (dec). IR
3210, 1729 cmÀ1 1H NMR (CDCl3, 400 MHz) d 2.18 (m,
2H), 2.20 (m, 2H), 3.10 (m, 1H), 5.59–5.74 (td, 2H, J = 8.0,
2.8 Hz), 6.20 (br, NH, 1H). 13C NMR (CDCl3, 100 MHz)
d 29.3, 35.0, 35.3, 47.7, 131.7, 172.54 ESI-MS 124
(M+H).
Acknowledgements
Compound number 6 code MNR4.Mp 58–63 ꢁC (dec). IR
We thank Shri K. Sekhar, Director DRDE. Gwalior for
his keen interest and encouragement in the present study.
1760, 1732, 1650, 3017, 1495, 1440 cmÀ1 1H NMR
.
(CDCl3, 400 MHz) d 2.18 (m, 2H), 2.20 (m, 2H), 3.07
(m, 1H), 2.89 (m, 1H), 4.07 (d, J = 5.4 Hz, 1H), 4.55 (d,
J = 15.4 Hz, 1H), 5.66–5.72 (m, 2H), 7.06 (m, 3H), 7.14
(m, 2H). 13C NMR (CDCl3, 100 MHz) d 29.6, 33.1, 45.5,
53.4, 54.9, 131.7, 128.1–128.45, 137.2, 174.1 ESI-MS 244
(M+H).
References and notes
1. TDR News (News from the WHO Division of control of
Tropical Diseases) 1994, 46, 5.
12. Trager, W.; Jensen, J. B. Science 1976, 193, 673–675.