Documenti di Didattica
Documenti di Professioni
Documenti di Cultura
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
11
Chapter 2
Literature Survey
12
Chapter 2
Literature Survey
13
Chapter 2
Literature Survey
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
digested
in
presence
of
suitable
enzymes
to
give
amino
acids.
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:
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
with
14
Chapter 2
Literature Survey
Parasite Lysate (in acetate buffer pH 5)
Incubate (12-14 hrs) at 37oC with constant shaking
centrifuge
Resuspend pellet in Tris-HCl buffer containing SDS and incubate at 37oC for 30 mins
centrifuge
Resuspend pellet in alkaline bicarbonate buffer
centrifuge
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
Quantification.
Spectrophotometric,
radioisotopic,
fluorometric
and
high
performance
liquid
15
Chapter 2
Literature Survey
16