J . Med. Chem. 2004, 47, 285-287
285
Discover y of a Bu lk y 2-ter t-Bu tyl Gr ou p
Con ta in in g P r im a qu in e An a logu e Th a t
Exh ibits P oten t Blood -Sch izon tocid a l
An tim a la r ia l Activities a n d Com p lete
Elim in a tion of Meth em oglobin Toxicity
Meenakshi J ain, Suryanarayana Vangapandu,†
Sandeep Sachdeva, Savita Singh, Prati P. Singh,
Gopa B. J ena, Kulbhushan Tikoo, Poduri Ramarao,
Chaman L. Kaul, and Rahul J ain*
F igu r e 1.
Although toxic, it is known that primaquine is active
against more of the life cycle stages of plasmodia than
any other class of antimalarial drugs. Research efforts
over the years are directed toward finding analogues,
which retains the tissue-schizontocidal activity of 1 with
improved blood-schizontocidal activity and/or reduced
methemoglobin (MetHb) toxicity, and few derivatives
with improved therapeutic profiles were synthesized.3-5
However, scientific endeavors to eliminate MetHb toxic
effects of 1 proved to be unsuccessful after 40 years of
research.6
National Institute of Pharmaceutical Education and
Research, Sector 67, S.A.S. Nagar, Punjab 160 062, India
Received September 16, 2003
Abstr a ct: To eliminate an unwarranted metabolic pathway
of the quinoline ring, a set of two compounds, where C-2
position of the antimalarial drug primaquine is blocked by
metabolically stable bulky alkyl group are synthesized. Com-
pound 2 [R ) C(CH3)3] of the series has produced excellent
antimalarial efficacy against P. berghei and highly virulent
multidrug-resistant P. yoelii nigeriensis strain in vivo. Com-
pound 2 was also evaluated for methemoglobin (MetHb)
toxicity. This study describes the discovery of a highly potent
blood-schizontocidal antimalarial analogue 2, completely de-
void of MetHb toxicity.
One of the main metabolic degradation pathways
known for the quinoline moiety results in oxidative
biotransformation at the C-2 position and converts it
to 1H-2-oxoquinoline.7 This pathway is supported by the
recent studies conducted by Mirghani and co-workers
that identified 2-quininone (known to display phototoxic
side-effects) as one of the major metabolite of quinine.8
Furthermore, high antimalarial activity associated with
mefloquine and related compounds is known to be
derived by the placement of a trifluoromethyl group at
the C-2 position of the quinoline ring, which prevents
the biotransformation to inactive and phototoxic 1H-2-
oxoquinolines.9 To our surprise, no such metabolic
pathway is known for primaquine; though, introduction
of 2-alkoxy (OCH3, OCH2C6H5)5 and 2-alkyl (CH3, C2H5,
CF3),10 substituents in the primaquine led to an overall
increase in therapeutic efficacy. Whether these com-
pounds show improved efficacy by blocking the proposed
metabolic pathway is yet uncertain. Upon the basis of
these observations, we hypothesize that the placement
of a metabolically stable bulky alkyl group at the C-2
position of the quinoline ring in 1 may produce ana-
logues with improved therapeutic efficacies due to their
inability to undergo C-2 position metabolic pathway
described for the quinoline ring. Thus, our research
efforts were focused toward developing a direct synthetic
route for the previously inaccessible bulky 2-alkyl group
containing primaquine analogues. We report herein,
synthesis, blood-schizontocidal antimalarial activities,
and MetHb toxicity studies of primaquine derivatives
(2 and 3) containing tert-butyl and 1-adamantyl groups
at the C-2 position of the quinoline ring.
Parasitic infections are still one of the major reasons
of mortality in the third world countries. Parasitic
protozoan belonging to genus Plasmodium causes ma-
laria, one of the most severe tropical diseases. The
infections caused by Plasmodium falciparum are highly
pathogenic and accounts for almost all deaths attributed
to malaria. Malaria is reemerging as the biggest infec-
tious killer and currently is first priority tropical disease
of the World Health Organization. The severity of the
disease is illustrated by the fact that malaria kills
approximately one child every 30 s, and 3000 per day
under the age of 5 years.1 Unfortunately, no vaccine is
available for the effective protection against malaria,
and treatment is increasingly becoming difficult due to
the widespread resistance of the P. falciparum malaria
parasite to mainstay antimalarial drug chloroquine.
This resistance problem has prompted search for new
classes of antimalarial agents, and a reexamination of
the existing antimalarial drugs that may be effective
against resistant strains.
Primaquine (PQ, 1, Figure 1) over the years is the
clinical drug of choice for the radical cure of relapsing
P. vivax and P. ovale malaria.2 The drug is effective in
clearing tissue parasites (erythrocytic stages of malaria
parasite life cycle), but has minimal suppressive activ-
ity, i.e., is ineffective as blood-schizontocide, and there-
fore is hazardous for the treatment of infections caused
by P. falciparum. The usefulness of 1 is also restricted
by toxic side effects including hemolytic lesions (caused
by methemoglobin production), pronounced in the pa-
tients deficient in glucose-6-phosphate dehydrogenase.
Commercially available 6-methoxy-8-nitroquinoline
(4) upon direct ring-alkylation via a silver-catalyzed
radical oxidative decarboxylation of appropriate alkyl-
carboxylic acid by ammonium persulfate in CH3CN and
10% H2SO4 efficiently produced 2-alkyl-6-methoxy-8-
nitroquinolines (5 and 6) in good yield (Scheme 1).11 The
reaction is highly regiospecific in nature, with no
apparent alkylation observed at other positions on the
quinoline ring. The latter compounds (5 and 6) were
* To whom correspondence should be addressed. Tel: 91-172-
2214682. Fax: 91-172-2214692. E-mail: rahuljain@niper.ac.in.
† Present address: Research Institute of Pharmaceutical Sciences,
University of Mississippi, University, MS 38677.
10.1021/jm0304562 CCC: $27.50 © 2004 American Chemical Society
Published on Web 12/19/2003
Jain, Meenakshi
