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| Analysis of Activity of Chalcones Against Plasmodium-falciparum. | |||||||||||||||||||||||||
| Paper Id :
18014 Submission Date :
2023-08-06 Acceptance Date :
2023-08-16 Publication Date :
2023-08-25
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| Abstract |
A new class of compounds comprising of chalcones were synthesized and screened for in vitro antiplasmodial activity against Plasmodium falciparum . Novel chalcones have been synthesized by conventional method. P. falciparum is the most wide spread and dangerous as it can lead to the fatal cerebral malaria. which often results in death. we designed and synthesized new chalcone derivatives and evaluated their antiplasmodial activity in-vitro against P. falciparum (NF-54) with the hope to develop potent antiparasitic agents.
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| Keywords | Antimalarial activity, Plasmodium falciparum, In vitro. | ||||||||||||||||||||||||
| Introduction | A number of medicines have been developed to treat malaria
with chloroquine and its derivatives' as the mainstay therapy. In recent years,
P. falciparum has become increasingly resistant to conventional anti-malarial
drugs, and the search for new anti¬malarial compounds by combining natural
sources and synthetic approaches is still underway(Gessler, M.C. Nkunya, M.H.H.;
Mwasumbi, L.B.; Heinrick, M.; Tanner, M. ACTA Tropica et al.,1994)( Tran, Q.L.
Tezuka, Y. ; Ueda, J.Y. ; Nguyen, N.T. ; Maruyama Y.1 ; Begum, K.; Kim, H.S.;
Wataya, Y.; Tran, Q.K.; Kabota, et al.,2003) As a part of search(Iwasa,
K.;Nishiyama, Y.; Ichimaru, M.; Moriyasu, M.; Kim. H.S. Wataya, Y.; Yamori, T.;
Takashi, T , et al.,1999)( Fujimoto, K.; Marisaki, D.; Yoshida, M.; Namba, T.;
Kim, H.S., Wataya, Y.; Kourai, H.; Kakuta, H.; Sasaki, K. Bioorg, et al.,2006)(
Kumura, N.; Izumi, M.; Nakajima, S.; Shimizu, S. ; Kim, H.S.; Wataya, Y.; Baba,
et al.,2005), for novel anti-malarial agents from plants or via chemical
synthesis, prepared derivatives of chalcones. Many natural and synthetic
possess anti-malarial activity(Kanokmedhkul, S.; Kanokmedhakul, K; Nambuddee,
K.; Kongsaeree P. J. Nat et al.,2004)( Beldjoudi, N.; Mambu, L.; Lobaieed, M.
Greelier, P. Ramanitrohasimbola, D.; Rasoanaivo, P.; Martin, M.T.; Frappier et
al.,2003)( Auffret, G.; Labaied, M.; Frappier, F.; Rasoanaivo, P.; Grellier,
P.; Lewin, G. Bioorg et al.,2007) . chalcones have a diverse array of
substituents on the two aromatic rings. Depending on the substitution pattern
on the two aromatic rings, chalcones have a wide range of biological
activities, including anti-malarial activity16-19. The potential anti-malarial
activity of chalcones has generated great interest(Chen M.; Theander T.G.;
Christchsch B.S.; Hviid L.; Zhai L; Kharazmi A et al.,1994). It is believed
that anti-malarial chalcones act against falcipain-2 a malarial cysteine protease(Li
R.; Kenyon G.L.; Cohen F.E.; Chen X. Gong B.; Dominguez, J.N. Davidson E.;
Kurzban G.; Miller R.E. Nuzum E.O. Rosenthal P.J.; Mckerrow J.H et al.,1995) In
the present study, new chalcones were synthesized and evaluated for in-vitro
anti-malarial activity against P. falciparum. |
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| Objective of study | To investigate in vitro antimalarial activity of chalcone
derivative compounds against Plasmodium falciparum . |
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| Review of Literature | All malaria
parasites are obligate intracellular protozoa of the genus Plasmodium with a
complex life cycle consisting of sexual reproduction (sporogonic phase) in
invertebrates, e.g. mosquito and asexual reproduction (schizogonic phase) in
vertebrates e.g. mammals, birds and reptiles(Chen M.; Theander T.G.; Christchsch B.S.; Hviid L.; Zhai L; Kharazmi A et al.,1994)( Chen M.; Brogger C.S.; Zhai L.; Rasmussen
M.H. Theander T.G.; Fronkjaer S.;
Steffansen S.; Davidsen J. Kharazmi A. J. Iffect et al.,1997) Malaria is
transmitted to human by the intravenous inoculation of sporozoites by the bile
of an infected female Anopheline mosquito (in Africa mainly A. gambiae), but in
rare cases transmission occurs throughexposure to infected blood products or
congenitally(Liu M.; Wilairat P.; Croft.
S.L.; Lay-Choo A, Go Mei-Lin Bioorg
Med et al.,2003) The asexual
parasites digest the host haemoglobin in their acidic food vacuoles
requirements(Charris J.E.
Dominguez J.N.; Gamboa N.; Rodrigues J.R. ; Angel J.E. Eur. J. Med et al., 2005) , but this
process is also necessary to provide room for parasite growth within the
erythrocyte24. The haemoglobion degradation results in thegeneration
of free radicals and heam, which is polymerized with the aid of liquid to form
an insoluble pigment, haemozoin. The
Intraerythrocytic Develomenttal Cycle (IDC) of P. falciparum lasts ~ 48h. Blood
schizonts, release up to 32 merozoites. The merozoite release causes the
typical febrile attacks on days 1 and 3 in falciparum malaria, hence named
“tertian malaria”. More erythrocytes are invaded by the released merozoites and
the next IDC commences. The cycle
(Fig.1.1) continues until the death of the host or death of the parasites due
to drug treatment or acquired partial immunity. A few erythrocytic parasites
differentiate into sexual forms, named gametocytes. Whaen infected blood
containing gametocytes is ingested by a female A. gambiae mosquito, the male
gametocyte exflagellates and male gametogenesis and fertilization of the female
gamete occurs in the mosquito gut. The zygote develops into an oocyst in the
gut wall of the mosquito and infective sporozoites eventually invade the insect
salivary glands to be released during the next human blood meal. Human Malaria
Species
Human have been
regarded as the natural hosts of fourspecies of malaria namely P. falciparum,
P. malariae, P. vivax, but there are more than 100 Plasmodium species. That
infect a variety of hosts such as reptiles, birds, rodents, primates and other
mammals. Each species causes a characteristic illness and has unique
morphological features in blood smears under the microscope21. P. vivax is the
most prevalent world wide and P. falciparum is the most dangerous and virulent
species that causes malignant malaria, which is associated with severe
complications such as cerebral malaria, renal failure and pulmonary affection2
1.27. P. falciparum infection is potentially lethal due to its ability to
invade erythocytes of all ages compared to P. vivax that invades only a
subpopulation, i.e., the reticulocytes28. resulting in overwhelming
parasitaemias and enhanced growth rate. Moreover, it has the capacity to adhere
(cytoadherence) to the peripheral micro-vasculature (capillaries and venules)
through sequestration. |
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| Methodology |
All chemical used in experimental work were of analytical grade and purchased from sigma-Aldrich, Merck, CDH, SRL etc. In-vitro Anti-Plasmodial Assay
The in-vitro anti-malarial assay was carried out in 96 well microlitere plates. The culture of P. falciparum NF54 strain are routinely maintained in medium RPMI-1640 supplemented with 25mm HEPES, 1% glucose, 0.23% sodium bicarbonate and 20% heat inactivated human serum. The asynchronous parasites of Pf were synchromized after 5% D-sorbital treatment to obtain only the ring stage parasitzed cells. For carrying out the assay, 10 1AL
parasites in 100 1.1L RPMEI-1640 medium was uniformly maintained in 10 wells (1 control and 2-10 test wells) of 96 microtitre plate. -100 pt test compound (1mg/mL) was added in 10th cell. Serial dilution of test compound were made from 10th well to 2nd well.
The plates were incubated at 37°C in a candle jar. After 36¬40h incubation, the blood smears from each well prepared and stained with giemsa stain. The slides were microscopically observed to record maturation of ring stage parasites intotrophozoites and schizonts in presence of different concentrations. The test concentrations which inhibited the 50% maturation into schizonts were recorded as the fifty percent inhibition concentration (IC50) chloroquine was used as the standard reference drug. |
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| Result and Discussion |
Twenty eight compounds were tested for heir ability to inhibit parasite
growth by incubating parasites in different concentrations for 48h, beginning
at the ring stage. The development of parasites was comparted with
untreated controls. Chloroquine was used as standard drug. The ISO values chloroquine was
found to be 0.030 tig/mL. Out of twenty eight compounds, only
eight compound viz., compounds 6,9,12,13,14,20,21 and 28 inhibited parasites development
at concentration lower 10 jig. However
for remaining compounds the IC50 values
were found to be greater than 101.ig show there inactivity. The effect of nature of substituted
groups on antiPlasmodial activity has been studied on anti-Plasmodial activity has been studied on para substituted chalcones.
IC50 values increase in the order
N(Me)2 < Cl < N (C2H5)2 < OMe < Br <
Me < H from compounds 1 to 7. IC50 values increase in the order N(C2H5)2 < Cl < OMe
< N (Me)2 < H < Me < Br. While IC50 values
of compounds 15 to 21 and 22 to 28 increased in the same order N (C2H5)2
< N (Me)2 < Cl < OMe < Br < H < Me Table 3.1:In-vitro Anti-Plasmodial activities of
4-(2-chloro-6- substituted-quinolin-3-y1)-3-chloro-1-1443-(4-substituted phenyl)-acrylolyll-phenyl}-azetidine-2-ones.
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| Conclusion |
The Anti-Plasmodial activities of the synthesized compounds
were tested in an In-Vitro Malaria assay against chloroquine sensitive strain
of Plasmodium-falciparum (NF-54) parasites. Introduction of different
substituents on the aromatic rings enabled investigation of the relationships
between the substitution pattern and the anti-plasmodial activity |
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