ORGANIC
LETTERS
2006
Vol. 8, No. 12
2591-2594
Antimalarial Activity of a New Family of
Analogues of Manzamine A
Jeffrey D. Winkler,*,† Allyn T. Londregan,† and Mark T. Hamann*,‡
Department of Chemistry, UniVersity of PennsylVania,
Philadelphia, PennsylVania 19104, and Department of Pharmacognosy,
UniVersity of Mississippi, UniVersity, Mississippi 38677
Received April 7, 2006
ABSTRACT
Manzamine A represents an important lead structure for the development of novel antimalarial chemotherapies. The synthesis and biological
evaluation of a group of simplified analogues of manzamine A, which were designed to examine the roles of the A and D rings and of both
the relative stereochemistry and the orientation of the
â-carboline heterocycle on the antimalarial activity of manzamine A, are described.
Malaria is a disease that affects 300-500 million people each
year and results annually in 1-2 million deaths, mostly
among children. Structurally and functionally novel antima-
larial agents with new mechanisms of action are needed as
monotherapeutic agents or for use in combined chemotherapy
with other presently available drugs. The urgent need for
new and effective antimalarials escalates as Plasmodium
falciparum and other human malaria parasite species have
developed resistance to most commercially available anti-
malarial agents.1
The manzamine alkaloids represent important lead struc-
tures for the development of antiinfectives. Manzamine A
and related structures represent highly potent, orally bio-
available2 antimalarial substances that are more effective than
most currently available therapeutics, i.e., chloroquine and
artemisinin. In addition, some of the manzamine classes have
also demonstrated activity against AIDS-opportunistic infec-
tious diseases including tuberculosis and toxoplasmosis.
The low isolated yield of 1 that was originally reported
from a natural source, the Okinawan sponge Haliclona sp.,3
prompted us to examine the SAR of manzamine A in an
effort to develop simpler structural analogues with compa-
rable antimalarial properties. We describe herein the synthesis
and biological evaluation of a “minilibrary” of analogues of
manzamine A that was designed to probe the roles of the A
and D rings as well as the relative stereochemistry and
â-carboline orientation on the antimalarial pharmacophore.
The retention of the â-carboline moiety was deemed critical
as the antimalarial activity of ircinol A (2, Figure 1) is ca.
400 times less than that of manzamine A.4
On the basis of the approach that was featured in our total
synthesis of manzamine A,5 we reasoned that the readily
† University of Pennsylvania.
‡ University of Mississippi.
(3) Sakai, R.; Higa, T.; Jefford, C. W.; Bernardinelli, G. J. Am. Chem.
Soc. 1986, 108, 6404-6405.
(1) (a) Marshall, E. Science 2000, 290, 428-430. (b) Marshall, E. Science
2000, 290, 437-438. (c) Bell, A. I. Drugs 2000, 3, 310-317. (d) Newton,
P.; White, N. Annu. ReV. Med. 1999, 50, 179-192. (e) Bell, A. Curr. Opin.
Anti-Infect. InVest. Drugs 2000, 21, 63-70.
(2) Sayed, El; Kelly, M.; Kara, U.; Ang, K.; Katsuyama, I.; Dunbar, D.;
Khan, A.; Hamann, M. J. Am. Chem. Soc. 2001, 123, 1804-1808.
(4) Muhammad, Y.; Sayed, K. A. E.; Rao, K. V.; Lim, C. W.; Fu, J.-F.;
Kelly, M.; Franzblau, S. G.; Zhang, F.; Peraud, O.; Hill, R. T.; Hamann,
M. T. Tetrahedron 2002, 58, 7397-7402.
(5) Winkler, J. D.; Axten, J. M. J. Am. Chem. Soc. 1998, 120, 6425-
6426.
10.1021/ol060848d CCC: $33.50
© 2006 American Chemical Society
Published on Web 05/18/2006