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Chapter 2

Literature Survey

2. Literature review
2.1 Journals
2.1.1 Antimicrobial activity of quinolines
The quinoline scaffold is prevalent in a variety of pharmacologically active synthetic and
natural compounds. The quinolines are historically among the most important antimalarial
drugs ever used. Throughout the 20th century, the immense use of chloroquine, the most
famous drug of this group, provided well- founded hopes for the eradication of malaria. The
emergence of pervasive strains of Plasmodium falciparum resistant to quinolone-based drug
has further brought into question the utility of this class of drug as solution to malaria. Thus
the desperate need of new antimalarials coupled with the historical benefits of quinolones in
term of selective activity and chemical efficacy, limited host toxicity, ease of use and
affordability have prompted a number of groups to pursue the search for novel quinolone
based antimalarials.11,12
2.1.2 Quinolines from nature
Jain et al. have recently provided an extensive review on anti-malarial quinoline alkaloids
isolated from natural sources. More recently, Valentin et al. reported antimalarial and
toxicological activities of the tetrahydroquinoline alkaloids from Galipea officinalis bark.
Galipinine yielded the best antimalarial effect (IC50 14 0.09e0.9 mg/mL). Strong activity
against CQR P. falciparum has been reported for benz[g]isoquinoline-5,10-dione 71, isolated
from Psychotria camponutans.
Hfle et al. reported antimalarial activity of aurachins, a large family of isoprenoid quinoline
alkaloids from the myxobacteria Stigmatella aurantiaca and Stigmatella erecta. Aurachin E
was the most active compound with IC50 values of 13 and 0.4 ng/mL against W2 and D6
strains, respectively, but was devoid of in vivo activity in a murine P. berghei model at a dose
of 100 mg/kg.13,14,15

Shobhaben Pratapbhai Patel School of Pharmacy & Technology Management, Mumbai


Chapter 2

Literature Survey

2.1.3 Synthesis of quinolone under solvent free condition

There have been continuous efforts to develop clean and rapid newer protocols for the
construction of quinoline-based structures. This has resulted in a few improved procedures for
the synthesis of quinolines. In one of the two protocols, the o-aminobenzaldehyde was
generated in situ and reacted immediately with an enolizable ketone to produce a quinoline.
The other protocol was based on microwave-assisted coupling condensation reactions
between acetophenones and 2-aminoacetophenones or benzophenones in the presence of
diphenylphosphate (DPP) as the acid catalyst, which was essential to enhance cyclization,
without the use of any solvent. The Friedlaender synthesis of quinolines is a classic method
that involves two steps, wherein reduction of o-nitro aryl aldehyde is first achieved followed
by the condensation of enolizable carbonyl compound in presence of a Brnsted or Lewis acid
catalyst. The relative instability of the intermediate (o-amino aldehyde), with its strong
tendency to undergo self- condensation made such reactions rather complicated.16,17
2.1.4 Synthesis of novel quinolones using TsOH/ ioninc liquid under microwave
3-haloacetyl-4-methylquinolines were synthesized from the reaction of 4-alkoxy-3-alken-2ones and 2-aminoacetophenone. The reaction was performed in inonic liquid and 4-toluene
sulfonic acid under microwave irradiation. Results showed that the catalytic method was
effective. Products were formed in a short time (10-20 min) and presented good yields (7091%). 18
2.1.5 Ring modified quinolones as antimalarials
Egan et al. proposed that chemical modification of compounds that form complexes with
Fe(III)PPIX, and block b- hematin formation to enhance accumulation in the food vacuole
through introduction of basic amino groups, can lead to new non- quinoline antimalarials that
avoid cross-resistance with CQ. Based upon this assumption, Egan et al. evaluated
antimalarial activity of platinum complexes. The self-stacking tendency of these complexes
was similar to that of porphyrins, suggesting association of these mixed-ligand Pt(II)
complexes with Fe(III)PPIX. The active complexes displayed moderate IC50 values ranging
from 488 to 666 nM (K1 strain).

Shobhaben Pratapbhai Patel School of Pharmacy & Technology Management, Mumbai


Chapter 2

Literature Survey

ONeill et al. examined antimalarial activity of artemisinin- acridine hybrids, semi-synthetic

trioxane-acridine, and synthetic trioxalane-acridine hybrids. The most active compounds
displayed IC50 values of 5.96, 14.3, and 6.7 nM, respectively. Sparatore et al. studied
quinolizidinyl and quinolizidinylalkyl derivatives of 9-amino-6-chloro-2-methoxyacridine.
The most active analogue was four times more potent than CQ against W2 strain (IC50 14
68.13 nM). 19,20
2.1.6 Isoquinoline as antimalarials
Based on the isoquinoline sulfonamide, a potent inhibitor of Pfmrk, one of the cyclin
dependent protein kinases(CDKs) from P. falciparum, Panda et al. synthesized a series of isoquinoline sulfonamides for antimalarial efficacy. Compounds containing a 4-ethylphenol or a
3-imidazol-1-yl-propyl group did not show good activity, while those containing a
dichlorobenzyl ring exhibited better potency (MIC 14 2 mg/ mL).21
2.1.7 4- aminoquinoline based antimalarial
Solomon & coauthors reported the synthesis of a new series of side-chain modified 4aminoquinolines and found active against P. falciparum in vitro and P. yoelli in vivo. These
analogs form a complex with hematin and inhibit the -hematin formation, suggesting that
this class of compounds act on a heme polymerization target.22
Madrid and coworkers synthesized a library of ring-substituted 4-aminoquinoline compounds
and evaluated their antimalarial activity against chloroquine (CQ) -sensitive strain, 3D7 and resistant strain, W2 of Plasmodium falciparum. Substituted quinoline rings other than the 7chloroquinoline ring of chloroquine were found to have significant activity against the drugresistant strain of P. falciparum.
2.1.8 Synthesis of quinolines catalyzed by chloramine-T
Chloramine-T has been proved as an efficient catalyst for the synthesis of substituted
quinolines. In this method, 2-amino aryl ketones were smoothly reacted with ketones to afford
the corresponding quinoline derivatives in very good yields. All the reactions were carried out
at acetonitrile reflux.23

Shobhaben Pratapbhai Patel School of Pharmacy & Technology Management, Mumbai


Chapter 2

Literature Survey

2.2 Hemoglobin Metabolism in Food vacuole of Plasmodium falciparum:

The malaria parasite requires amino acids for the synthesis of its proteins. The three sources
of amino acids are: de novo synthesis, import from host plasma, and digestion of
host hemoglobin. Hemoglobin is an extremely abundant protein in the erythrocyte
cytoplasm and serves as the major source of amino acids for the parasite. The food vacuole is
an acidic compartment (pH 5.0-5.4) that contains protease activities, when the hemoglobin
is released into the food vacuole it is broken down into globin and heme. Globin is further










Free heme is toxic due to its ability to destabilize and lyse membranes, as well as inhibiting
the activity of several enzymes.
The mechanisms by which heme is detoxified have been identified:

Sequestration of the free heme into hemozoin, or the malarial pigment;

Degradation facilitated by hydrogen peroxide within the food vacuole;
Glutathione-dependent degradation which occurs in the parasite's cytoplasm;
Heme oxygenase which has been found in P. berghei (rodent parasite) and P.
knowlesi (simian parasite), but not P. falciparum.

As a result of its high toxicity, disposal of free heme represents a crucial step for Pf survival,
and even small perturbations of its detoxification mechanisms could lead to Pf death due to
the generation of reactive oxygen species (Famin O et al., 1995).
2.3 Methods to screen anti-malarial activity of NCEs:

Several experimental approaches have been described for determination of formation of hematin in vitro and evaluation of different test compounds for antimalarial activity.
1) Cell based -hematin assay:
Activity evaluation is based on growth of Plasmodium falciparum in culture


antimalarials that inhibit -hematin formation.

Shobhaben Pratapbhai Patel School of Pharmacy & Technology Management, Mumbai


Chapter 2

Literature Survey
Parasite Lysate (in acetate buffer pH 5)
Incubate (12-14 hrs) at 37oC with constant shaking

Resuspend pellet in Tris-HCl buffer containing SDS and incubate at 37oC for 30 mins
Resuspend pellet in alkaline bicarbonate buffer
Resuspend pellet in distilled water
Quantification by U.V
2) Non-cell based -hematin assay:
Activity evaluation is carried out in absence of Pf culture, instead it involves use of
activators like lipids, alcohol, fatty acid, surfactants to initiate in-vitro -Hematin
formation by mimicking physiological conditions of parssite food vacuole.
Hemin chloride in DMSO
Buffer solution pH 5-5.5
Activator + Drug
Incubate at 37 oC for 2-4 hrs







chromatography (HPLC)based assays have been described for quantification of


Shobhaben Pratapbhai Patel School of Pharmacy & Technology Management, Mumbai


Chapter 2

Literature Survey

Shobhaben Pratapbhai Patel School of Pharmacy & Technology Management, Mumbai