You are hereA Review on Pharmacological Diversity of Chalcone Derivatives

A Review on Pharmacological Diversity of Chalcone Derivatives


3. Antibacterial properties
The antibacterial activity of chalcones is being increasingly documented. Many research groups either isolated and identified the structure of chalcones that possess antibacterial activity. The bactericidal effects have been related to the ability of α, β unsaturated ketone to undergo a conjugated addition to a nucleophilic group like a thiol group in an essential protein.7

Liquorice (root and rhizome of Glycyrrhiza spp.) is currently used in the tobacco, confectionery, and pharmaceutical industries. Among the retrochalcones (chalcones which do not have an oxygen-function at the 2-position) isolated from Glycyrrhiza inflata licochalcone A and licochalcone C showed potent antibacterial activity especially to Bacillus subtilis,Staphylococcus aureus and Micrococcus luteus. Licochalcone A inhibited the growth of Legionella pneumophila, Legionella longbeacheae, Legionellawadsworthii, Legionella bozemanii, Legionella runoffs and Legionella feelei.  Licochalcone A, inhibitory activity was detected against the growth of Helicobacter pyroli in vitro.  Licochalcone A was tested against S. aureus and showed that the free hydroxyl group in 4-position of ring B was necessary for the antibacterial activity. On the other hand, no change in its activity is observed when the hydroxyl group in the 4-position of ring A is removed, blocked by a methyl, or replaced by a chlorine. Removal of both hydroxyl groups or blockage of both hydroxyl groups by methylation eliminates the activity completely.8-9

Biological screening of dihydrochalcones showedthat these compounds demonstrated relatively goodactivity against the Gram-positive bacteria S. aureus and B.subtilis, and the Gram-negative bacterium Pseudomonas aeruginosa.10

4. Antileismanial properties
Leishmaniasis is a group of prevalent diseases caused by protozoan parasites belonging to the genus Leishmania. Recently a series of synthetic and naturally occurring chalcone derivatives have been reported to be potential agents against Leishmania in a number of in vitro and in vivo assays.

Chalcones are structurally simple compounds of the flavonoid family and are present in a variety of plant species with a vast spectrum of pharmacological activities including antibacterial, antifungal, immunosuppressive, and antinociceptive properties.11-13 One of the most studied antileishmanial chalcones is licochalcone A isolated from the Glycyrrhiza spp. Chinese plant, which inhibits the parasite enzyme fumarate reductase.14 However, licochalcone A and some synthetic derivatives have also been shown to affect human cell functioning by inhibiting lymphocyte proliferation and cytokine production.15

The selective activity of the 20, 60-dihydroxy-40-methoxychalcone (DMC) isolated from the inflorescences of Piper aduncum against intracellular amastigotes of Leishmania amazonensis and the improvement of its therapeutic activity in mice by encapsulation in biodegradable nanospheres.16-17

Licochalcone A inhibited the activities of both nicotinamide adenine dinucleotide reduced-fumarate reductase (NADH-FRD) and succinate dehydrogenase (SDH) in the permeabilized promastigotes in a concentration-dependent manner. This compound also inhibited the activities of SDH, NADH dehydrogenase (NDH), succinate-cytochrome c reductase (SCC), and NADH-cytochrome c reductase (NCC). The IC50s of licochalcone A for SDH (593 µM), NDH (460 µM), SCC (1,519 µM), and NCC (1,985 µM) after 60 min of incubation were at least 33 times higher than the IC50 for fumarate reductase (FRD) (14 µM). The IC50s of licochalcone A for SDH and NDH in the crude mitochondria of mammalian cells of human peripheral blood mononuclear cells (PBMC) were very high: both were 1.4 µM after 60 min of incubation. The IC50s of licochalcone A for SDH in mammalian cells were more than 67 times higher than the IC50 for FRD in the parasite. Licochalcone A clearly exhibited concentration- and time-dependent inhibitory effects on soluble FRD in the parasite. The IC50 of licochalcone A after 60 min of incubation was 32 µM. Licochalcone A probably first inhibits FRD of the parasite, then influences the parasite respiratory chain and affects the function and ultra structure of the parasite mitochondria, and finally kills the parasite. Licochalcone C inhibited the growth of the L. major parasite to the same extent as licochalcone A.18

5. Antimalarial properties
Malaria continues to be one of the major public health problems in many tropical countries causing extensive morbidity and loss of life. Annual malaria mortality due to Plasmodium falciparum costs 1-2.7 million lives in Africa alone, comprising of mainly young children. Artemisinin contained in the decoction prepared from the aerial parts of a plant Artemisia annua, used for over thousand years for fever resolution has been re-discovered as the most potent antimalarial drug. Resistance to this drug has not been clinically encountered so far. Chloroquine the only synthetic antimalarial drug which cured malaria for decades, rather than centuries, has fallen to resistance.19 One of the strategies adopted by malariologist to delay the emergence of resistance to artemisinin and its derivatives is to use them in combination with other novel antimalarial(s). Artemisinin based combination therapies (ACTs) instead of artemisinin monotherapy are being advocated and supported by WHO. Currently used ACTs are in demand and by no means the ideal combinations. There is scarcity of artemisinin globally. Thus there is a need to search for novel, inexpensive antiplasmodials as suitable synergistic partners for artemisinin to reduce dependence on artemisinin for malarial treatment.20-22

Chalcone, a biosynthetic product of shikimate pathway, is a class of privileged structure that has a wide range of biological properties. Chalcones are precursors of various flavones and key intermediates for combinatorial assembly of different heterocyclic scaffolds. Chalcone (1, 3-diaryl propenone or 1, 3-diphenyl- 2-propen-1-one) constitutes an important group of natural products, and some of them possess a wide range of biological activities, such as anti-bacterial, anti-fungal, antiviral, anti-inflammatory , anti-tumor, antioxidant, insect anti-feedent, and act as tyrosinase inhibitors. Interest in chalcones as antimalarials was initiated by the discovery of antiplasmodial activity of licochalcone A an oxygenated chalcone isolated from the roots of the Chinese licorice during routine screening. Computational structural analysis also identified chalcones as potential plasmodial cysteine protease inhibitors.23-24

Plasmodium falciparum and Plasmodium vivax are the two major human malaria parasites. P. falciparum is responsible for most deaths, and it has developed resistance to nearly all available drugs. Chalcone derivatives exhibit antimalarial activity by inhibiting plasmodial cysteine protease enzyme. In vitro antiplasmodial results of 4-chloro, 4-methoxy and 3, 4, 5-trimethoxy series suggested that small or medium sized but highly lipophilic groups containing multiple nitrogen or amine in acetophenone moiety impart antiplasmodial potential. Such compounds may provide additional hydrogen bonding with histidine residue present at the active site of the enzyme, cysteine protease. This is the first report in which chalcones containing small highly polar, lipophilic cyclic amines are showing antimalarial potential.25-26 The mechanism of chalcone derivative binding to histidine in the site S2 of enzyme are given in figure 2.

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