Monatshefte fu¨r Chemie 139, 179–181 (2008)
DOI 10.1007/s00706-007-0772-5
Printed in The Netherlands
Synthesis of Quinoline Analogs: Search for Antimalarial Agents
Konda Ramesh Babu1, Begari Eeshwaraiah2, Dachepally Aravind2, Harshadas M. Meshram2,
Rallabaldi Madhusudan Raju3, Apurba Bhattacharya1, and Rakeshwar Bandichhor1;ꢀ
1
Center of Excellence, IPDO, Dr. Reddy’s Laboratories Ltd., Bollaram, India
2
Division of Organic Chemistry, Indian Institute of Chemical Technology, Hyderabad, India
3
Department of Chemistry, Osmania University, Hyderabad, India
Received June 14, 2007; accepted July 23, 2007; published online December 24, 2007
# Springer-Verlag 2007
˚
It is known that the distance (approximately 3A)
Summary. Novel synthesis routes for the promising antimala-
rial agents 4(3-hydroxypyrrolidin-1-yl) and 4(3-hydroxy-
piperidine-1-yl)-2,8-bis(trifluoromethyl)quinoline have been
developed.
between the secondary alcohol and nonaromatic
secondary or tertiary amine functionalities in the
quinoline based antimalarial agents is crucial [3].
Based on this concept, we are actively involved
in the search of potential leads as antimalarial
agents. Our approach is to install all pharmacopho-
ric elements without changing significantly the qui-
noline framework. Here, we wish to report the
strategy involved in the racemic synthesis of struc-
tural type 1.
Keywords. Quinoline analogs; Antimalarial agents.
Background
Mefloquine, was an effective antimalarial agent first
introduced in 1971, that acts on the asexual intraery-
throcytic phase, one of the developmental stages of
malaria causing parasite [1]. More than a decade
before, a resistance of Plasmodium sp. emerged as
a potential threat to malaria therapy and this, togeth-
er with unavoidable side effects, e.g., CNS (central
nervous system) toxicity, have enforced physicians
not to prefer it for prescriptions that resulted in a
seldom use of this medicine [2]. Discovery of a cin-
chona alkaloid as an antimalarial agent played a piv-
otal role in the identification of lead structures that
incorporate a quinoline methanol unit. It is percepti-
ble that an emergence of mefloquine was a result of
SAR (structure activity relationship) studies based
on structural motif, as a pharmacophore, present in
the cinchona alkaloid.
Results and Discussion
The present work deals with the condensation of
substituted 4-haloquinolines 5 with cyclic amines that
led to a synthesis of novel quinoline derivatives 1.
The synthesis commences with the PPA mediated
condensation of substituted aniline with ethyl tri-
fluoroacetoacetate [4] that afforded corresponding 4-
hydroxyquinoline derivatives 3 [5]. Halogenation of
3 employing phosphorus oxyhalide or phosphorus
pentachloride yielded corresponding halo derivatives
5 [6]. Alternatively, haloquinones have been pre-
pared via tosyl derivatives [7].
Recently, it has been found that mefloquine enantio-
mers, (8R, 9S) and (8S, 9R), differ in their antimalarial
potentials. In vitro studies revealed that (þ)-(8S, 9R)-
has higher activity than (ꢁ)-(8R, 9S)-mefloquine [2].
To avoid the hazardous nature of transformation
of 3 to 5 employing phosphorus oxyhalide or phos-
phorus pentachloride, we opted to activate the phe-
nolic oxygen with a tosyl moiety to afford 4 and
substitute the ꢁOTs in it with an appropriate halide
nucleophile as presented in Scheme 1.
ꢀ
Corresponding author. E-mail: rakeshwarb@drreddys.com