ABOUT AUTHORS:
Sarthak B. Dave*, Dr. Dipen K. Sureja.
Department of Pharmaceutical Chemistry,
Shree H. N. Shukla Institute of Pharmaceutical Education & Research,
Rajkot, Gujarat, India
*davesarthak@ymail.com
ABSTRACT:
Chalcones are 1, 3-diphenyl-2-propene-1-one, consist of two aromatic rings linked by a three carbon a, ß-unsaturated carbonyl system. Mainly chalcone are synthesized by Claisen-schmidt condensation reaction (Cross-aldol reaction). Chalcones are well known intermediates for synthesizing various heterocyclic compounds. Chalcones, precursors of open chain flavonoids and isoflavonoids present in edible plants, and their derivatives have attracted increasing attention due to numerous potential pharmacological applications. They have displayed a broad spectrum of pharmacological activities. Changes in their structure have offered a high degree of diversity that has proven useful for the development of new medicinal agents having improved potency and lesser toxicity. The present review highlights the recently synthesized Chalcones and their derivatives possessing important pharmacological activities.
Reference ID: PHARMATUTOR-ART-1958
INTRODUCTION:
Chalcones - one of the major classes of natural product with widespread distribution in fruits, vegetables, spices, tea and soy based foodstuff have been recently subjects of great interest for their interesting pharmacological activities.1Chalcones are 1,3-diphenyl-2-propene1-one,
In which two aromatic rings are linked by a three carbon a, β unsaturated carbonyl system as,
These are abundant in edible plants and are considered to be precursors of flavonoids and isoflavonoids. Chalcones possess conjugated double bonds and a completely delocalized Π-electron system on both benzene rings. Molecules possessing such system have relatively low redox potentials and have a greater probability of Undergoing electron transfer reactions. Chalcones are synthesized by Claisen-schmidt condensation of aldehyde and ketone by base catalyzed or acid catalyzed followed by dehydration to yield Chalcones.2 Chalcones are well known intermediates for synthesizing various heterocyclic compounds. The compounds with the backbone of Chalcones have been reported to possess various biological activities such as antimicrobial, anti-inflammatory, analgesic, ant platelet, ant ulcerative, ant malarial, anticancer, antiviral, antileishmanial, Antioxidant, Ant tubercular, antihyperglycemic, activities. The presence of a reactive & unsaturated keto function in Chalcone is found to be responsible for their antimicrobial activity.
In present review include the reaction of various acetophenone derivatives with different aromatic aldehyde derivatives to form Chalcones. The structures of the various synthesized compounds were assigned on the basis of IR, 1H-NMR spectral data and Elemental analysis and also show different Biological activities.
REACTION:
PRINCIPAL BEHIND THIS REACTION:
* It is based on Claisen-Schmidt Condensation Reaction (Cross-Aldol reaction) Aromatic Aldehyde Condense with aliphatic or mixed aryl alkyl ketone in presence of aqueous alkali to form α, β unsaturated ketone, which is well known as Claisen-Schmidt condensation reaction.
* When an ethanolic solution containing both Acetophenone and Benzaldehyde are reacted in presence of alkaline medium like NaOH solution, rapid condensation occurs with the formation of benzyldideneacetophenone (Chalcone).
* One may note that the C-C bond forming step in aldol condensations is facilitated by groups with –I effect (e- withdrawing group) and retarded by + I effect (e- releasing group) on the carbonyl component of ketone.3
General Procedure:-
* Dissolve 2.7 g of NaOH in about 25 ml water and add this solution to 250 ml iodine flask containing 15.2ml ethanol provided with mechanical stirrer.
* Immerse flask in a bath of crushed ice, add 6.4 ml of freshly distilled Acetophenone drop wise with continuous stirring the reaction mixture and then add 5.5 ml of pure Benzaldehyde drop by drop. Keep the temperature of mixture at about 200C and stir vigorously until the mixture becomes as thick so that stirring is no longer effective (generally 2 hrs).
* Remove the stirrer and leave the reaction mixture at room temp overnight. Filter the product with Buchner funnel and wash it thoroughly with ice – cold water until the washings are neutral to litmus and finally wash with 5 ml cold ethanol. Dry the obtained crude chalcone.
* Recrystallize the crude chalcone from rectified spirit by warming to 500C. (for 1 g crude chalcone 6 ml rectified spirit is required).3
Microwave assisted synthesis of Chalcones:-
* The Claisen–Schmidt condensation stays the most common method in homogeneous phase or in interfacial solid-liquid conditions using barium hydroxide catalyst (C-200). Unfortunately 2’-hydroxychalcones alwayscyclised to flavanones. One synthetic pathway to avoid this undesirable reaction is using protective group or the Friedel–Crafts reaction of phenols with acyl halides.
* This method request long reaction time and anhydrous conditions which limits the scope of its application. Convenient reaction procedure for the synthesis of 2’-hydroxychalcones with very good yields without formation of by-products. By applying successful microwave irradiation for the preparation of target molecules. The reaction took place in well closed pressure tube for 2 min with high yields. It is noteworthy to mention that to carry out the reaction in an open vessel failed.
* A mixture of twoproducts and starting compounds was obtained in this case. Obviously, the well closed tube affords to reach temperatures much higher than boiling point of ethanol. The measured temperature in the reaction tube immediately after the irradiation was 1320C.4
Physical Properties of Chalcone: -The physical propertiesof chalcone are as follows:
1) Molecular formula: C5H12O
2) Molar mass: 208.26 g mol-1
3) Exact mass: 208.088815
4) Density: 1.071g/cm3
5) Melting point: 55-57oC
6) Boiling point: 345-348oC
Pharmacological Activities:
1) Anti microbial activity:
Compounds with electron releasing groups such as methoxy and hydroxyl showed better antibacterial activity than the others not having such groups. Compounds having pharmacophores such as chloro, dichloro and fluoro groups have exhibited more antifungal activity on all the three fungi than the others. Chalcone derivatives with these substituent’s showing greater antimicrobial activity.5
Yayli et al6 synthesized N-alkyl derivatives and photochemical dimmers of 3 o-, m-, and p-nitro substituted 4azachalcones. The monomeric compounds showed good antimicrobial activity against test micro-organisms E.coli,K. pneumonia, Yesinia pseudo tuberculosis, P. aeruginosa, Enterococcus faecalis, S. aureus, Bacillus cereus, andCandida tropicalis. The most sensitive micro-organisms were Gram +ve bacteria. The compounds (A)‘ 1-decyl-4-(3-(3nitrophenyl)-3-oxoprop-1-enyl) pyridiniumbromide’ and (B) ‘1-decyl-4-(3-(4-nitrophenyl)-3-oxoprop-1enyl) pyridiniumbromide’ exhibited broad-spectrum antimicrobial activity. The MIC values (MBC) for the testmicro-organisms were between <0.35 and 25 µg/ml. The synthesized compounds were also tested for their antioxidantactivity based on their ability to scavenge the stable radical DPPH (2, 2-diphenyl-1-picrylhydrazine). Themonomers showed high anti-oxidant activity, while the dimerization products were less active. The monomericcompounds exhibited higher radical scavenging potential in general, with low IC values. The compound ‘1-decyl4-(3-(4-nitrophenyl)-3-oxoprop-1-enyl) pyridinium bromide’ was found to have similar or even higher activity when compared to the standard anti-oxidants Trolox and vitamin C, respectively.
2) Anti-inflammatory Activity:
Chalcone derivatives contain a, β-unsaturated carbonyl moiety which is responsible for anti-inflammatory activity. Activated macrophages play a key role in inflammatory responses and release a variety of mediators, including nitric oxide (NO). NO is a potent vasodilator that facilitates leukocyte migration and formation of edema as well as leukocyte activity and cytokine production. NO can also react with superoxide anion to form cell lines (PC-3, MCF-7, KB and KB-VIN). Mannich base of chalcone with morpholine substitution at C3 or C5 and pyridyl or phenyl at C substitution are found to possess good cytotoxic activity.7
Yadav et al8 synthesized a series of five chalcone derivatives and were subjected to anti-inflammatory screening using the carrageen an-induced rat hind paw edema model. Chalcone derivatives at dose 25 mg/kg by oral route inhibited significantly the formation of edema. The P value was found to be <0.05 showing significant anti-inflammatory activity. The compound ‘4-fluoro/4-chloro chalcone’ (C) showed more activity comparable to standard drug indomethacin due to -F/-Cl groups present in the compound. Hence, the anti inflammatory activity of chalcone derivatives was increased when electron withdrawing groups (EWG) were present on the chalcone moiety.
Zhang et al9 through in vivo inhibition assay monitoring of their ability to inhibit xylene-induced ear edema in mice. Some of the tested compounds exhibited significant activity, and the compound ‘3-(4-chlorophenyl)-1-(2,4-dihydroxyphenyl)prop-2-en-1-one’ (D) showed the highest anti-inflammatory activity (68% inhibition) comparable with or even slightly more potent than the reference drug ibuprofen (53%). Furthermore, the structure-activity relationship of these substituted chalcone derivatives demonstrated that the substituted 2’,4’-dihydroxychalcone derivatives was stronger than that of 4’hydroxychalcone. The position of the substituted group on the phenyl ring greatly influenced the anti-inflammatory activity. These results indicated that the character of the substitution on the ring A had a significant influence on the anti-inflammatory activity.
3) Antimalerial activity:
Antimalarial property10,11,12 of some chalcone derivatives is derived from their ability to inhibit the parasitic enzyme, cysteine protease. The enzyme catabolizes globin into small peptides within the acidic food vacuole of the intra-erythrocytic malaria parasite. Without cysteine protease action osmotic swelling occurs, food vacuolar functions are impaired, and parasite death ensues. Malaria blood stage cysteine protease as the most likely target enzyme of chalcones. The chalcones are conjugates of a, ß-unsaturated ketones that assume linear or near planar structure. This structure is stable in acidic food vacuolar environment where malarial cysteine protease acts, and structural conformation may fit well into the long cleft of the active site of the enzyme. The chloro-series compounds showed marked antiplasmodial activity. Compound , a triazole substituted chalcone was found to be the most effective against the parasites, and pyrrole and benzotriazole showed comparable activities. The morpholine substituents in chloroseries was found to be the least active. Compound , containing triazole and chloro substituents, was found to be the most potent antiplasmodial derivative evaluated, suggesting that small lipophilic groups containing single or multiple nitrogen can enhance antimalarial activity in vitro. In vitro antiplasmodial results of 4chloro, 4-methoxy and 3,4,5trimethoxy series suggested that small or medium sized but highly lipophilic groups containing multiple nitrogen or amine in Acetophenone moiety impartanti plasmodial 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.
Motta et al13 studied chalcone derivatives. He performed quantitative structure-activity relationships of a series of chalcone derivatives (1,3-Diphenyl-2-propen-1-one) as anti-Plasmodium falciparum agents (antimalarial agents). The study investigated the factors that may be important in the inhibitory activity of chalcone derivatives on P. falciparum cysteine protease. The obtained models presented good capacity to explain the observed values of biological activity, high adjustment level, statistical significance and good predictive capacity. Hydrophobic and steric properties seemed to play an important role in the explanation of the activity of the dataset. The results indicated that the activity on W2 and D6 strains was favored if ring A had a width-limited chemical substituent on it. The limited molecular width of these derivatives can be related with the activity against the D6 strain. The molecular weight, which is related to molecular volume, appeared to influence only the activity of D6 strain. The results also indicated that molar refractivity and molecular length have positive contributions to the activity against chloroquine-resistant (W2) Plasmodium falciparum strains, while molecular weight against mefloquine-resistant (D6) strains. The main conclusions of this work were: (i) The C2–C3 double bond is essential for high inhibitory activity. It is not only a conjugated linker between A and B aromatic substituents, but it keeps extended the molecular conformation. In this way, the drug molecule seems to bind much better to the active site, which resembles a cleft on the surface of falcipain; (ii) Substitutions on the bridge portion of the chalcone series caused a pronounced decrease in the inhibitory activity, probably due to steric interactions; (iii) Chloro or fluoro substitution on the ring B and electron-donating substitution on the ring A increased the antimalarial activity; (iv) Quinolinyl group in the ring B resulted in increased activity.
Awasthi et al 14 synthesized several new chalcone analogues and evaluated as inhibitors of malaria parasite. Inhibitory activity was determined in vitro against a chloroquine-sensitive P. falciparum strain of parasites. The chalcone ‘3-(4-methoxyphenyl)-1-(4-pyrrol-1-yl-phenyl)prop-2-en-1-one’ (E) was found to be the most active with 50% inhibition concentration (IC50) of 1.61 µg/ml. This inhibitory concentration was comparable to a prototype phytochemical chalcone, licochalcone, with an IC of 1.43 µg/ml. The study suggested that small lipophilic nitrogen heterocyclic at ring B together with small hydrophobic functionality at ring A can enhance antimalarial activity. These results suggested that chalcones are a class of compounds that provides an option of developing inexpensive, synthetic therapeutic antimalarial agents in the future.
Cheng et al 15 had developed a methodology for the solid phase synthesis of chalcone analogues in reasonably high yields. On the basis of their structure activity relationship (SAR) and computer modelling data, they expected that the chalcone derivatives with hydroxyl functionality on one of the aromatic rings and with some other appropriate substitutions on the other ring will be even more potent as Antimalerial. They found that the chalcone ‘1-(2-chloroquinolin-3-yl)-3-(3-hydroxyphenyl) prop-2-en-1-one’ (F) was synthesized in the highest percentage yield, 97%.
Lim et al 16 prepared twenty derivatives of flavonoids and Chalcones, four derivatives for each of flavones, flavanones, Chalcones, dihydrochalcones, and 3'-chlorochalcones, and evaluated for in vitro Antimalerial activity against P. falciparum strain FCR-3 and cytotoxicity against FM3A cells (a mouse mammary tumour cell). The aim was to derive predictive structure activity relationships to guide lead compound design. Among the Chalcones tested, the most active compound was 3-(3,4-dimethoxyphenyl)-1-(2-hydroxy-4-methoxy-phenyl)propan-1-one (G) showing 100% inhibition against P. falciparum at the final concentration of 5.4 µg/ml (EC50 = 1.0 µg/ml). The compound also showed strong cytotoxicity against FM3A cells, a model of the host, with relatively low EC50 values (>3.3 µg/ml) and low selectivity index (>3.3) indicating that the compound have non-selective Antimalerial activity.
4) Anticancer Activity:-
Achanta et al17 evaluated a series of boronic Chalcones for their anticancer activity and mechanisms of action. Among the eight chalcone derivatives tested, the chalcone ‘3, 5-bis-(4-boronic acid-benzylidene)-1-methyl- piperidin-4-one’ (H) exhibited most potent growth inhibitory activity with IC50 values of 1.5 and 0.6 µM in the 3(4, 5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay and colony formation assay respectively. The cytotoxic activity of AM114 was shown to be associated with the accumulation of p53 and p21 proteins and induction of apoptosis. Mechanistic studies showed that AM114 treatment inhibited the chymotrypsin like activity of the 20S proteasome in vitro, leading to a significant accumulation of ubiquitinated p53 and other cellular proteins in whole cells. In vitro studies showed that AM114 did not significantly disrupt the interaction of p53 and murine double minute 2 protein. It was noteworthy that AM114 as a single agent was preferentially toxic to cells with wild type p53 expression, whereas combination of this compound with ionizing radiation significantly enhanced the cell killing activity of ionizing radiation in both wild type p53 and p53 null cells. Together, these results indicated that the boronic chalcone derivative AM114 induced significant cytotoxic effect in cancer cells through the inhibition of the cellular proteasome and provided a rationale for the further development of this class of compounds as novel cancer chemotherapeutic agents.
Romagnoli et al18 for ant proliferative activity and inhibition of tubulin assembly and colchicine binding to tubulin. The replacement of the double bond with a thiophene maintained ant proliferative activity and therefore must not significantly alter the relative conformation of the two aryl rings. The synthesized compounds were found to inhibit the growth of several cancer cell lines at nanomolar to low micromolar concentrations. In general, all compounds having significant antiproliferative activity inhibited tubulin polymerization with an IC < 2 µM. Several of these compounds caused K562 cells to arrest in the G2/M phase of the cell cycle. Turning to the effects of an electron-releasing group (ERG) on the phenyl moiety, they found that a p-methyl group caused only minor changes in antiproliferative activity. Reduced activity occurred when the methyl substituent was moved from the para to ortho position. The more active compounds were evaluated for their in vitro inhibition of tubulin polymerization and for their inhibitory effects on the binding of colchicines to tubulin (in the latter assay, the compounds and tubulin were examined at a concentration of 1 µM with the colchicine at 5 µM). For comparison, the antitubulin agent CA-4 was examined in contemporaneous experiments as a reference compound. Compounds ‘3,4,5-trimethoxyphenyl-(5-(thiophen-2-yl)thiophen-2-yl)methanone’ (I) and‘3,4,5trimethoxyphenyl-(5-p-tolylthiophen-2-yl)-methadone (J) were the most active (IC50, 0.8 µM), having twice the potency of CA-4 (IC50, 1.4 µM).
Llango et al 19 synthesized a series of chalcones and evaluated them for their in vitro cytotoxic activity by microculture Tetrazolium Test Assay method using two breast cancer cell lines MCF-7 and T47D. The IC value was calculated at the 0.1-100 µM concentration range. The assay was dependent on the activity of mitochondrial dehydrogenase enzymes that reduce yellow MTT to a blue formazan product and the activity of enzyme that is directly proportional to cell viability. The result showed significant cytotoxicity against both of the cell lines and value lied between 52-89 µM. All the compounds showed good cytotoxic activity and the compound ‘N-(4- hydroxy-3-(3-(2/3/ nitrophenyl)acryloyl)phenyl)acetamide’ (K) showed better activity than other compounds, this may be due to presence of nitro group in the compound.
Echeverria et al 20 studied relationships between the structural characteristic of synthetic chalcones and their antitumoral activity. Treatment of HepG2 hepatocellular carcinoma cells for 24 h with synthetic 2’hydroxychalcones resulted in apoptosis induction and dose-dependent inhibition of cell proliferation. The calculated reactivity indexes and the adiabatic electron affinities using the DFT method including solvent effects, suggested a structure-activity relationship between the chalcone structure and the apoptosis in HepG2 cells. The absence of methoxy substituents in the ring A of synthetic 2’-hydroxychalcones, showed the major structureactivity pattern along the series and because of this, the chalcone ‘1-(2-hydroxyphenyl)-3-phenylprop-2-en-1-one’ (L) was found to be the most active.
5) Hypoglycemic activity:-
Non-insulin dependent diabetes mellitus21 (NIDDM, type-II diabetes) is a chronic metabolic disease characterized by insulin resistance, hyperglycemia and hyperinsulinaemia. The disease is often associated with obesity, dyslipidemia and hypertension leading to cardiovascular risks. ß 3 -adrenergic receptors (ß -AR) are
found on the cell surface of both white adipose (WAT) and brown adipose tissue (BAT) where their stimulation promotes lipolysis and thermogenesis respectively. BAT also plays an important role in the maintenance of glucose homeostasis; hence ß3 -AR agonists are useful for treating diabetes as well as obesity. The aryloxypropanolamines were first described as ß3-AR agonists. Chalcones with proper substitution have recently been isolated from Broussonetia papyrifera known to selectively inhibit enzymes like protein tyrosine phosphatase 1B (PTP1B) and aldose reductase. Their antioxidant property attracted to explore hybrid structures as antihyperglycemic agents, because oxidative stress also plays an important role in diabetic patients leading to vascular complications. 3, 4-Dimethoxy compound displayed significant anti hyperglycemic effect. Mono methoxy series showed blood glucose lowering activity. Compounds vicinally deoxygenated as dimethoxy and methylenedioxy substitution showed the best antihyperglycemic activity when compared to the corresponding monomethoxy compounds. Compounds containing propanolamine chain at para position showed significant activity as compared to meta and ortho substituted compounds.
6) Antioxidant Activity:
Free radicals, including22 the superoxide radical (O2-), hydroxyl radical (OH), hydrogen peroxide (H2O2) , and lipid peroxide radicals have been implicated in a number of disease processes, including asthma, cancer, cardiovascular disease, cataracts, diabetes, gastrointestinal inflammatory diseases, liver disease, macular degeneration, periodontal disease and other inflammatory processes. These radical oxygen species (ROS) are produced as a normal consequence of biochemical processes in the body and as a result of increased exposure to environmental and/or dietary xenobiotics. Antioxidants are the agents, which can inhibit or delay the oxidation of an ox disable substrate in a chain reaction. Chalcones belongs to the largest class of plant secondary metabolites. Which, in many cases, serve in plant defence mechanisms to counteract reactive oxygen species (ROS) in order to survive and prevent molecular damage and damage by microorganisms, insects, and herbivores. They are known to possess antioxidant character at various extents. The antioxidant activity of natural compounds like chalconoids is related to a number of different mechanisms such as free radical scavenging, hydrogen donation singlet oxygen quenching, metal ion chelation and acting as a substrate for free radicals such as superoxide and hydroxide.
Vasil’ev et al 23 studied six anti-oxidants from the class of Chalcones (ArOH), compounds from which flavonoids are obtained in nature. The antiradical activity of Chalcones and a number of related compounds was determined by a chemiluminescence method using the scavenging of peroxide radicals ROO• + ArOH → ROOH + OAr• (with the rate constant k) in a model reaction of diphenylmethane (RH) oxidation. The structures and energies of the reagents and intermediates were determined by semi-empirical quantum chemical (PM3, PM6) calculations. 3(3, 4-Dihydroxyphenyl)-1-phenylprop-2-en-1-one (M) and caffeic acid, which have catechol structure.
Sivakumar et al 24 synthesized 25 of chalcone derivatives and evaluated their antioxidant activity, and (QSAR). Antioxidant activity was evaluated through four different methods namely, superoxide radical-scavenging, hydrogen peroxide-scavenging, reducing power, and DPPH radical-scavenging assays at 50 µg/ml in vitro. The antioxidant potential of the compound was related to its (i) hydrogen or electron donation capacity, (ii) its ability to stabilize and delocalize the unpaired electron, and (iii) potential to chelate transition metal ions. These actions were achieved either by the hydrogen atom or single electron transfer. In the case of ferric reducing anti-oxidant power (FRAP), it was due to the single electron transfer and in the cases of superoxide radical-scavenging, hydrogen peroxide-scavenging, and DPPH radical-scavenging activities, it was due to the transfer of hydrogen atom. The antioxidant activity of the flavonoids was due to the inhibition of the enzyme responsible for the superoxide radical production, chelation of the metal ions and scavenging of ROS. Generally, compounds with – SCH3 and –OCH3 in the Para position of the ring A and –OH in the ring B were most active than others. The chalcone ‘1-(4-hydroxyphenyl)-3-(4-(methylthio) phenyl) prop-2-en-1-one’ (N) was showing the highest superoxide radical-scavenging activity (>50%), reducing power activity (>46%), DPPH scavenging activity (>20%). In few cases, some of the compounds were more active than ascorbic acid or butylated hydroxytoluene.
Vogel et al25 established a general strategy for the synthesis of 3’-prenylated chalcones and synthesized a series of prenylated hydroxychalcones, including the hop (Humulus lupulus L.) secondary metabolites xanthohumol, desmethyl xanthohumol, xanthogalenol, and 4-methylxanthohumol. They investigated the influence of the ring A hydroxylation pattern on the cytotoxic activity of the prenylated chalcones in a HeLa cell line and revealed that non-natural prenylated chalcones, like 2’,3,4’,5-tetrahydroxy-6’-methoxy-3’-prenylchalcone (O).
7) Antihepatotoxic activity:
Silymarin26 isolated from seeds of silybum marianum commonly known as Milk Thistle has been used as a potent Antihepatotoxic agent against a variety of toxicants. It is a mixture of three isomers namely, silybin (1), silydianin (2) and silychristin (3). Silybin is the most active component containing 1,4-dioxane ring system, whereas other isomers do not possess 1,4-dioxane ring, and thus do not display significant activity. Chalcone derivatives possessing 1,4dioxane ring system exhibiting antihepatotoxic activity. The potent compounds possess 2-hydroxy methyl group at position 2 of the dioxane ring of chalcone derivatives, which has also indicated that the presence of hydroxyl methyl group at position 2 in dioxane ring possesses a significant role in exhibiting the antihepatotoxic activity. This is in accordance with the view that silybin too possess the same group at the same position. The substitution in the aromatic ring of chalcones have no significant role in exhibiting antihepatotoxic activity.
8) Mammalian Alpha-Amylase Inhibitory Activity:
Trans-chalcone, a biphenolic core structure of flavonoids precursor was tested for inhibitory activity toward alpha-amylase (1, 4-a-D-glucan glucanohydrolase) using Bernfeld method by Najafian et al 27. Porcine pancreatic alpha-amylase was observed to be effectively inhibited by this compound, which showed competitive behaviour with a K of 48 µM and an IC 50 of 96.44 µM as compared to flavonoids possessing IC50 values ranging typically from about 10 to about 30 µM for mammalian alpha-amylase. Soluble starch (the natural substrate of the enzyme) was used in this study in order to obtain more realistic results. The possible binding mode of the compound was assessed in silico, and the two residues Trp 59, and Tyr 62 were proposed as main interacting residues with transchalcone. In conclusion, this compound could be used to design effective inhibitors of alpha-amylase. The core chalcone structure that could be detected in the flavone structure (scutellarein) has been highlighted by circles in the figure and putative mode of interaction between trans-chalcone (represented as sticks) within porcine pancreatic alpha-amylase structure in the figure , Residues of the active site are represented in the line mode and labeled. Elements of secondary structure of the enzyme, as well as a transparent surface of the interaction site are also visible. Two p-p interactions of trans-chalcone with Trp59 and Tyr62 are highlighted with the use of circles in the center of aromatic components.
9) Monoamine Oxidases (MAOs) Inhibitory Activity:
Chimenti et al28 synthesized a large series of substituted chalcones tested in vitro for their ability to inhibit human monoamine oxidases A and B (hMAO-A and hMAO-B). The potential effects of the test drugs on hMAO activity were investigated by measuring their effects on the production of hydrogen peroxide (H) from ptyramine usingthe Amplex Red MAO assay kit and microsomal MAO isoforms prepared from insect cells infected with recombinant baculovirus containing cDNA inserts for hMAO-A or hMAO-B. While all the compounds showed hMAO-B selective activity in the micro- and nano-molar ranges, the best results were obtained in the presence of chlorine and hydroxyl or methoxyl substituents. The most active compounds, ‘3-(4-chlorophenyl)-1-(2-hydroxy-4methoxyphenyl)prop-2-en-1-one’ (P) and ‘3-(4-chlorophenyl)-1-(2,4-dihydroxyphenyl)prop-2-en-1-one’ (Q) (IC50 =0.0044+0.00027 µM and 0.0051+0.00019 µM, respectively), are disubstituted in the 2- and 4-position of the B aromatic moiety with two hydroxyls or hydroxyl and methoxy groups and in 4’-position of the A aromatic moiety with a chlorine atom. To better understand the enzyme-inhibitor interaction and to explain the selectivity of the most active compounds toward hMAO-B, molecular modeling studies were carried out on new, high resolution, hMAO-B crystallographic structures. For the only compound that also showed activity against hMAO-A as well as low selectivity, the molecular modeling study was also performed on the hMAO-A crystallographic structure. The docking technique provided new insight on the inhibition mechanism and the rational drug design of more potent/selective hMAO inhibitors based on the chalcone scaffold. In the reversibility and irreversibility tests, hMAO-B inhibition was found to be irreversible in presence of the compounds ‘3-(4-chlorophenyl)-1-(2-hydroxy-4methoxyphenyl)prop-2-en-1-one’ and ‘3-(4-chlorophenyl)-1-(2,4 dihydroxyphenyl)prop-2-en-1-one’ (chosen for docking experiments).
10) Tyrosinase inhibitors:
Tyrosinase 29,30 (monophenol monooxygenase, E: C: 1.14. 18.1), also known as polyphenol oxidase), is a copper-containing enzyme widely distributed in nature. It catalyzes two reactions involving molecular oxygen in the melanin biosynthesis pathway: the hydroxylation of monophenols to o-phenols (monophenolase activity), and the oxidation of the o-phenols to o-quinones (diphenolase activity). These quinones are highly reactive and tend to polymerize spontaneously to form brown pigments of high molecular weight (melanins), which determine the color of mammalian skin and hair. Quinones can also react with amino acids and proteins and thus enhance the development of brown color. The inhibitory activity of a series of chalcones was set against their structure and their antioxidant potency (which can contribute to prevent pigmentation resulting from nonenzymatic oxidation). The position of the hydroxyl groups attached to the A and B aromatic rings is of major importance, while hydroxylation on ring B contributes markedly more to inhibition than when it is on ring A. Butein, an effective Tyrosinase inhibitor, was also able to delay linoleic acid auto-oxidation, as shown by conjugated diene (CD) formation. The OH in position 4 (ring B) was the major factor affecting potency.
11) Anticonvulsant Activity:-
Some new phenoxy chalcones were prepared and screened for their anticonvulsant activity using Maximal Electroshock Method (MES) by Kaushik et al 31. Neurotoxicity study was performed using rotarod method. It was found that substitution of 4-methoxy and 3,4-dimethoxy group in the substituted ring A of phenoxy chalcone showed significant anticonvulsant activity without neurotoxicity while hydrogen and chloro substitution does not showed the significant anticonvulsant activity. It was also found that the compounds ‘3-(4-methoxyphenyl)-1-(4phenoxyphenyl) prop-2-en-1-one’ (R) and ‘3-(3,4-dimethoxyphenyl)-1-(4-phenoxyphenyl)prop-2-en-1-one’ (S) showed the most potent anticonvulsant activity without neurotoxicity.
12) Antifungal Activity:-
With the aim of developing potential antifungals, Bag et al 32 synthesized a series of chalcones incorporating sulfur either as part of a hetero-aromatic ring (thiophene) or as a side chain (thiomethyl group) and tested for their in vitro activity. Some of the compounds showed appreciable activity against a fluconazole-sensitive and fluconazole-resistant strain with the chalcone ‘3-(4-(methylthio)phenyl)-1-(thiophen-2-yl)prop-2-en-1-one’(T) exhibiting the highest activity. Maximum activity was obtained with p-fluoro substitution on ring A. Activity was decreased with increasing halogen size. Presence of p-methoxy or hydroxy groups at the o-, m- or, p- position also resulted in good activity while the p-nitro group as well as the bulky p-phenyl substitution decreased activity as compared with the unsubstituted compound. The m- and p- disubstitution with methoxy led to increased activity while again the p-phenyl-substituted compounds exhibited considerably decreased activity. All compounds with the bromo thiophene ring in place of ring B exhibited less activity compared with those with the unsubstituted thiophene ring. Bromine substitution on the thiophene ring B decreased antifungal activity. Compounds with unsubstituted thiophene ring B and thiomethyl substitution at the p- position of ring A, exhibited good antifungal activity. Highest activity was found when both thiophene ring B and thiomethyl substitution at ring A were present together in the chalcone ‘3-(4-(methylthio)phenyl)-1-(thiophen-2-yl)prop-2-en-1-one’.
Lahtchev et al 33 reported the synthesis, antifungal evaluation and study on substituent effects of several chalcones. A lot of genetically defined strains belonging to different yeast genera and species, namely Saccharomyces cerevisiae, Hansenula polymorphaand Kluyveromyces lactis, were used as test organisms. Concerning the mode of the antifungal action of chalcones it was shown that DNA was probably not the main target for the chalcones. It was revealed that the yeast’s intracellular glutathione and cysteine molecules play significant role as defence barrier against the chalcone action. It was also shown that chalcones may react with some proteins involved in cell separation. The antifungal effects of the substituted chalcones were compared with those of the parent chalcone.
13) Mosquito Larvicidal Activity:-
A series of chalcone analogues and some of their derivatives were synthesized and subjected to the mosquito larvicidal study (larvae of Culex quinquefasciatus), SAR and QSAR by Begum et al 34. The chalcones showed % mortality ranging from a very low value (10%) to a very high value (90%). Chalcones having EDG(s) on either ring A or ring B showed high toxicity to larva of the mosquito. EWG(s), especially at ring A, reduced the activity of chalcones. The activity was abruptly decreased due to replacement of ring B by CH, extension of conjugation or blocking of a,ß-unsaturated ketone part of chalcones by derivation. QSAR studies of these compounds were performed using various spatial, electronic and physicochemical parameters.
Genetic function approximation with linear and spline options was used as the chemometric tool for developing the QSAR models. The investigation had clearly shown that certain chalcone analogues had potent mosquito larvicidal activity. Most of the hydroxyl chalcones showed toxicity against the third instar larvae of C. quinquefasciatus. The favorable chemical structures were found to be a hydroxyl substituent in ring B at 2’-position which may be hydrogen bonded with the electron pair on a,ß-unsaturated ketone moiety, thereby decreasing the electrophilicity of this part of the molecule. Presence of hydroxyl group at 2’-position of ring B and replacement of ring A (phenyl) by a furan ring also increased the larvicidal activity. Besides that 3-chlorine substitution in ring A was also another feature of favourable activity. Presence of methylenedioxy group at 3,4 positions of ring A also enhanced the larvicidal activity of chalcone-type compound.
However, extension of conjugation and blocking of a,ß-unsaturated ketone part of chalcones had bad effects toward the activity of these compounds. The chalcone ‘3-(furan-2-yl)-1-(2hydroxyphenyl)prop-2-en-1-one’ (U) had shown 100% mortality and LC50 was very low with a value of 19 µmole/dm3. QSAR analysis also suggested that charge distribution on molecular surface and surface area are important determinants of the larvicidal activity. The derived models suggested that for the good larvicidal activity positively charged surface areas of the compounds should be limited. Moreover, there should be a balanced distribution of +ve and -ve charges on the molecular surfaces of the compounds.
14) Cyclooxygenase (COX) Inhibitory Activity:
Zarghi et al 35 synthesized chalones possessing a methanesulfonamido (MeSO2NH) or an azido (N)pharmacophore at the para-position of the C-1 phenyl ring and evaluated their biological activity as cyclooxygenase-1/-2 inhibitors. In vitro COX-1/COX-2 structure-activity relationships were determined by varying the substituents on the C-3 phenyl ring (4-H, 4-Me, 4-F, and 4-OMe). Among the chalones possessing a C-1 paraMeSO NH COX-2 pharmacophore ‘1-(4-methanesulfonamidophenyl)-3-(4-methylphenyl)prop-2-en-1-one’ (V) was identified as a selective COX-2 inhibitor (COX-2 IC2 = 1.0 µM; selectivity index >100) that was less potent than the reference drug rofecoxib (COX-2 IC = 0.50 µM; SI > 200). The corresponding chalcone analogue possessing a C-1 para-N COX-2 pharmacophore ‘1-(4-azidophenyl)-3-(4-methylphenyl)prop-2-en-1-one’ (W), exhibited potent and selective COX-2 inhibition (COX-1 IC = 22.2 µM; COX-2 IC = 0.3 µM; SI = 60). A molecular modeling study where these two chalcones were docked in the binding site of COX-2 showed that the p-MeSO2NH and N substituents on the C-1 phenyl ring are oriented in the vicinity of the COX-2 secondary pocket (His90, Arg513, Phe518, and Val523). The structure-activity data acquired indicated that the propenone moiety constitutes a suitable scaffold to design new acyclic 1,3-diphenylprop-2-en-1-ones with selective COX-1 or COX-2 inhibitory activity.
15) Antifilarial Activity:
Chalcone derivatives were evaluated by Awasthi et al 36 for their ant filarial activity on Setaria cervi using glutathione-S -transferase (GST) enzyme as a drug target. The compounds ‘1-(4-benzotriazol-1-yl-phenyl)-3-(4methoxyphenyl)prop-2-en-1-one’ (X) and ‘3-(4-methoxyphenyl)-1-(4-pyrrolidin-1-yl-phenyl)prop-2-en-1-one’ (Y) showed a significant suppression (P < 0.01) in GST activity of adult female parasite extract at 3 µM concentration in vitro.
16) Cytotoxic activity:-
Mannich bases 37 of phenolic azobenzenes demonstrated cytotoxic activity, and various mannich bases analogs of chalcones exhibited potent cytotoxicity against murine P338 and L1210 leukemia cells as well as several human tumor cell lines. Mannich bases of heterocyclic chalcones are evaluated for cytotoxic activity against four human cancer cell lines (PC-3, MCF-7, KB and KB-VIN). Mannich base of chalcone with morpholine substitution at C2 or C5 and pyridyl or phenyl at C3 substitution are found to possess good cytotoxic activity.
17) Antileishmanial activity 38:
Conventional structure activity relationships show that antileishmanial activity is favoured by chalcones with more hydrophilic character, with the most active members found among 40-hydroxychalcones. The good antileishmanial activities of the naphthalenyl and pyridinyl derivatives suggest that considerable tolerance for the size of ring A exists.
18) Hypoglycemic activity 39:
Non-insulin dependent diabetes mellitus (NIDDM, type-II diabetes) is a chronic metabolic disease characterized by insulin resistance, hyperglycemia and hyperinsulinaemia. The disease is often associated with obesity, dyslipidemia and hypertension leading to cardiovascular risks.
ß3 -adrenergic receptors (ß3-AR) are found on the cell surface of both white adipose (WAT) and brown adipose tissue (BAT) where their stimulation promotes lipolysis and thermogenesis respectively. BAT also plays an important role in the maintenance of glucose homeostasis; hence ß3-AR agonists are useful for treating diabetes as well as obesity. The aryloxypropanolamines were first described as ß3 -AR agonists.
Chalcones with proper substitution have recently been isolated from Broussonetia papyrifera known to selectively inhibit enzymes like protein tyrosine phosphatase 1B3 (PTP1B) and aldose reductase. Their antioxidant property attracted to explore hybrid structures as antihyperglycemic agents, because oxidative stress also plays an important role in diabetic patients leading to vascular complications.
3, 4-Dimethoxy compound displayed significant antihyperglycemic effect. Mono methoxy series showed blood glucose lowering activity. Compounds vicinally deoxygenated as dimethoxy and methylenedioxy substitution showed the best antihyperglycemic activity when compared to the corresponding monomethoxy compounds. Compounds containing propanolamine chain at para position showed significant activity as compared to meta and ortho substituted compounds.
19) Analgesic Activity40:
A series of diazipine, pyrimidine, fused triazolopyrimidine and imide derivatives were newly synthesized bySaid et al.,using 4-phenyl-but-3en-2-one as a starting material. Initially the acute toxicity of the compounds was assayed via the determination of their LD . All the compounds were interestingly less toxic than the reference drug. The pharmacological screening showed that many of these obtained compounds have good analgesic activity comparable to Valdecoxib, Carbamazepine and Predensilone as reference drugs.
CONCLUSION:
The literature review of chalcone heterocyclic nucleus has proved that it is a versatile nucleus having various pharmacological activities of chalcone derivatives like antimalarial, anticancer, antileishmanial, anti-inflammatory, antibacterial, anti- fungal, antimicrobial, anticonvulsant and antioxidant activities etc. The vital information given in this article can be utilized further by researchers in the design and development of novel and potent drugs in the treatment of various diseases which are mentioned in this article.
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