Solution-phase parallel synthesis of substituted chalcones and their antiparasitary activity against Giardia lamblia

A library of 25-membered chalcones was prepared by parallel synthesis. Substituted acetophenones and benzaldehydes were condensed using the Claisen–Schmidt base-catalyzed aldol condensation. Several chalcones showed in vitro antiparasitic activity against Giardia lamblia. The highest activity observed for the IC₅₀ values were 12.72, 15.05 and 15.31 μg/mL, respectively; these are potential leads for the development of antigiardial compounds.     

Design, synthesis, and biological evaluation of Mannich bases of heterocyclic chalcone analogs as cytotoxic agents

The chalcone skeleton (1,3-diphenyl-2-propen-1-one) is a unique template that is associated with various biological activities. We synthesized Mannich bases of heterocyclic chalcones (9-47) using a one-step Claisen-Schmidt condensation of heterocyclic aldehydes with Mannich bases of acetophenones, and tested the target compounds for cytotoxicity against three human cancer cell lines (prostate, PC-3; breast, MCF-7; nasopharynx, KB) and a multi-drug resistant subline (KB-VIN). Out of the 39 chalcones synthesized, 31 compounds showed potent activity against at least one cell line with IC(50) values ranging from 0.03 to 3.80 microg/mL. Structure-activity relationships (SAR) are also discussed.     

Synthesis and inhibitory potential towards acetylcholinesterase, butyrylcholinesterase and lipoxygenase of some variably substituted chalcones

A series of variably substituted chalcones were synthesized by condensation of substituted acetophenones with mono-, di- or trisubstituded benzaldehydes. It was observed that some of these compounds have the potential to inhibit acetylcholinesterase, whereas others show activity against butyrylcholinesterase, depending on the substitution pattern at the two aromatic rings of these chalcones. Similarly, lipoxygenase was inhibited by two of these compounds. It has been observed that inhibition of the three enzymes was concentration dependent with the IC50 values ranging from 28.2-134.5 microM against acetylcholinesterase, 16.0-23.1 microM against butyrylcholinesterase and 57.6-71.7 microM against lipoxygenase, respectively.     

Structure-activity relationships of antileishmanial and antimalarial chalcones

A series of oxygenated chalcones which have been evaluated earlier for antimalarial activity (Plasmodium falciparum K1) were tested for antileishmanial activity against Leishmania donovani amastigotes. A comparison of structure-activity relationships reveal that different physicochemical and structural requirements exist for these two activities. Antileishmanial activity is associated with less lipophilic chalcones, in particular those with 4'-hydroxyl-substituted B rings and hetero/polyaromatic A rings. In contrast, chalcones with good antimalarial activity have alkoxylated B rings and electron-deficient A rings. Visualization of the steric and electrostatic fields generated from comparative molecular field analysis (CoMFA) indicate that the ring A of chalcones make a more significant contribution to antileishmanial activity while both rings A and B are important for antimalarial activity. Despite different requirements, two alkoxylated chalcones (8, 19) were identified which combined good antimalarial and antileishmanial activities.     

Synthetic chalcones as efficient inhibitors of Mycobacterium tuberculosis protein tyrosine phosphatase PtpA

In the search for lead compounds for new drugs for tuberculosis, the activity of 38 synthetic chalcones were assayed for their potential inhibitory action towards a protein tyrosine phosphatase from Mycobacterium tuberculosis--PtpA. The compounds were obtained by aldolic condensation between aldehydes and acetophenones, under basic conditions. Five compounds presented moderate or good activity. The structure-activity analysis reveals that the predominant factor for the activity is the molecule planarity/hydrophobicity and the nature of the substituents.     

Combinatorial synthesis and antibacterial evaluation of an indexed chalcone library

A 120-membered chalcone library has been designed and prepared from six differently substituted acetophenones (A1-A6) and 20 benzaldehydes (B1-B20). The library was subjected to biological studies targeted against six bacterial strains. For the identification of the most-active member(s) of the library, the so-called indexed or positional-scanning method was applied. Six out of 26 sub-libraries, i.e., AL1-AL6, were synthesized by keeping the acetophenone moiety A fixed and using equimolar quantities of the 20 different benzaldehydes. The remaining 20 sub-libraries BL1-BL20 were prepared by keeping the benzaldehyde B component fixed and varying the six acetophenones (Table 1). The bactericidal activities of the resulting sub-libraries were tested and used as indices to the rows or columns of a two-dimensional matrix. Finally, parallel synthesis of 24 specific members with the highest-expected antibacterial activities, present in two sub-libraries, was carried out. These chalcones were screened again, and the results were exploited for establishing the structure-activity relationship (SAR) and the identification of the lead compound, which turned out to be 1,3-bis(2-hydroxyphenyl)prop-2-en-1-one (A2B2) in terms of activity towards Staphylococcus aureus and Bacillus subtilis (Tables 5-7).     

Synthesis of stilbene-fused 2′-hydroxychalcones and flavanones

Synthesis of stilbene-fused chalcones and flavanones were successfully completed. Molecules were designed in a way to mimic the structural features of both “stilbene and chalcones” or “stilbene and flavanones” at the same time, and synthesized by three steps. Heck reactions of 3-bromobenzaldehyde with styrene derivatives gave corresponding (E)-stilbenes, which were reacted with acetophenones to furnish stilbene-fused 2′-hydroxychalcones under basic conditions. Finally, intramolecular cyclization reactions were performed to produce stilbene-fused flavanones.     

Chemistry and pharmacology of oxyprenylated secondary plant metabolites

Oxyprenylated natural products (isopentenyloxy-, geranyloxy- and the less spread farnesyloxy- compounds and their biosynthetic derivatives) represent a family of secondary metabolites that have been considered for years just as biosynthetic intermediates of C-prenylated derivatives. Only in the last decade these natural products have been recognized as interesting and valuable biologically active phytochemicals. Up to now about 300 molecules have been isolated from plants mainly belonging to the families of Rutaceae and Compositae, comprising common edible vegetables and fruits. A wide variety of compounds containing a prenyloxy side chain have been isolated and these comprise alkaloids, coumarins, flavonoids, cinnamic acids, benzoic acids, phenols, alcohols, aldehydes, anthraquinones, chalcones, lignans, xanthones, aceto- and benzophenones and other more uncommon skeletons. Many of the isolated oxyprenylated natural products and their semisynthetic derivatives were shown to exert in vitro and in vivo remarkable anti-cancer, anti-inflammatory, anti-microbial and anti-fungal effects. The aim of this review is to examine in detail the different types of oxyprenylated natural compounds from a phytochemical and pharmacological point of view.     

Prenyloxyphenylpropanoids as a novel class of anticonvulsive agents

In this study, we synthesized some natural and semi-synthetic prenyloxyphenylpropanoids (e.g., acetophenones, benzoic and cinnamic acids, chalcones, and coumarins), and we assessed their in vivo neuroprotective activity, using the mouse maximal electroshock-induced seizure model (MES test). 7-Isopentenyloxycoumarin and (2E)-3-{4-[(3-methylbut-2-enyl)oxy]phenyl}prop-2-enoic acid, administered ip at a dose of 300 mg/kg, suppressed MES-induced seizures in mice in a time- and dose-dependent manner.     

Synthesis and characterization of biologically significant 5,5'-(1,4-phenylene)bis(1-N-alkoxyphthalimido-3-aryl-2-pyrazoline) derivatives

A facile synthesis of 5,5'-(1,4-phenylene)bis(3-aryl-2-pyrazolines) 4a-g has been achieved by the cyclo-addition reaction of hydrazine hydrate with bis-substituted chalcones 3a-g, which in turn were prepared by the Clasien-Schmidt condensation of p-substituted acetophenones 1a-g with terephthaldehyde. Condensation of 4a-g with omega-bromoalkoxyphthalimides 5a-b afforded the titled compounds 6a-n, some of which exhibited significant antimalarial as well as antimicrobial activity.     

Growth inhibitory activities of oxyprenylated and non-prenylated naturally occurring phenylpropanoids in cancer cell lines

A series of 25 selected oxyprenylated natural phenylpropanoids were synthesized, and their growth inhibitory activities were evaluated in vitro together with 14 other commercially available non-alkylated compounds belonging to the same chemical series. The compounds were tested on six human cancer cell lines using MTT colorimetric assays. The data reveal that of the six chemical groups (G) studied, coumarins (G1), cinnamic and benzoic acids (G2), chalcones (G3), acetophenones (G4), anthraquinones (G5), and cinnamaldehydes and cinnamyl alcohols (G6), G2-related compounds displayed the weakest growth inhibitory activities in vitro, whereas G5-related compounds displayed the highest activities. Quantitative videomicroscopy analyses were then carried out on human U373 glioblastoma cells, which are characterized by various levels of resistance to different pro-apoptotic stimuli. These analyses revealed that compounds 20 (4,2′,4′-trihydroxychalcone), and 30 and 31 (two cinnamaldehydes) were cytostatic and able to overcome the intrinsic resistance of U373 cancer cells to pro-apoptotic stimuli.     

Synthesis and characterization of biologically significant 5,5′-(1,4-phenylene)bis(1-N-alkoxyphthalimido-3-aryl-2-pyrazoline) derivatives

A facile synthesis of 5,5′-(1,4-phenylene)bis(3-aryl-2-pyrazolines) 4a-g has been achieved by the cyclo-addition reaction of hydrazine hydrate with bis-substituted chalcones 3a-g, which in turn were prepared by the Clasien-Schmidt condensation of p-substituted acetophenones 1a-g with terephthaldehyde. Condensation of 4a-g with ω-bromoalkoxyphthalimides 5a-b afforded the titled compounds 6a-n, some of which exhibited significant antimalarial as well as antimicrobial activity.     

Evaluation of chalcones as inhibitors of glutathione S‐transferase

Glutathione S‐transferases (GSTs) are the superfamily of multifunctional detoxification isoenzymes and play an important role in cellular signaling. In the present study, potential inhibition effects of chalcones were tested against human GST. For this purpose, GST was purified from human erythrocytes with 5.381 EU?mg^?1 specific activity and 51.95% yield using a GSH–agarose affinity chromatographic method. The effects of chalcones on in vitro GST activity were tested at various concentrations. K_i constants of chalcones were found in the range of 7.76–41.93 μM. According to the results, 4‐fluorochalcone showed a better inhibitory effect compared with the other compounds. The inhibition mechanisms of 2'‐hydroxy‐4‐methoxychalcone and 4‐methoxychalcone were noncompetitive, whereas the inhibition mechanisms of 4'‐ hydroxychalcone, 4‐ fluorochalcone, and 4,4'‐ diflurochalcone were competitive.     

Antibacterial activity of chalcones, hydrazones and oxadiazoles against methicillin-resistant Staphylococcus aureus

The increase in antibiotic resistance due to multiple factors has encouraged the search for new compounds which are active against multidrug-resistant pathogens. In this context, chalcones, dihydrochalcones, hydrazones and oxadiazoles were tested against Staphylococcus aureus ATCC 25923 and methicillin-resistant S. aureus (MRSA) isolates, which were obtained from clinical laboratories and were characterized as MRSA using traditional and molecular methods. Among 65 tested compounds, two chalcones, one dihydrochalcone and two hydrazones were active against MRSA. Based on the minimal inhibitory concentration and cytotoxicity, hydrazones provided a better selectivity index than chalcones. Active hydrazones are promising antibiotic-like substances and they should be the subject of further microbiological studies.     

Structure-activity relationship studies on chalcone derivatives. the potent inhibition of chemical mediators release

Some chalcones exert potent anti-inflammatory activities. 2',5'-Dialkoxychalcones and 2',5'-dihydroxy-4-chloro-dihydrochalcone inhibited nitric oxide (NO) production in lipopolysaccharide (LPS)/interferon-gamma (IFN-gamma)-activated N9 microglial cells and in LPS-activated RAW 264.7 macrophage-like cells have been demonstrated in our previous reports. These compounds also suppressed the inducible NO synthase (iNOS) expression and cyclooxygenase-2 (COX-2) activity in RAW 264.7 cells. In an effort to continually develop potent anti-inflammatory agent, a series of chalcones were prepared by Claisen-Schmidt condensation of appropriate acetophenones with appropriate aromatic aldehyde and then evaluated their inhibitory effects on the activation of mast cells, neutrophils, macrophages, and microglial cells. Most of the 2',5'-dihydroxychaclone derivatives exhibited potent inhibitory effects on the release of beta-glucuronidase and lysozyme from rat neutrophils stimulated with formyl-Met-Leu-Phe (fMLP)/cytochalasin B (CB). Some chalcones showed potent inhibitory effects on superoxide anion generation in rat neutrophils in response to fMLP/CB. Compounds 1 and 5 exhibited potent inhibitory effects on NO production in macrophages and microglial cells. Compound 11 showed inhibitory effect on NO production and iNOS protein expression in RAW 264.7 cells. The present results demonstrated that most of the 2',5'-dihydroxychaclones have anti-inflammatory effects. The potent inhibitory effect of 2',5'-dihydroxy-dihydrochaclones on NO production in LPS-activated macrophage, probably through the suppression of iNOS protein expression, is proposed to be useful for the relief of septic shock.     

Characteristic of alkylated chalcones from Angelica keiskei on influenza virus neuraminidase inhibition

As part of our ongoing effort to develop influenza virus neuraminidase (NA) inhibitors from various medicinal plants, we utilized bioassay-guided fractionation to isolated six alkylated chalcones (1-6) from Angelica keiskei. Xanthokeistal A (1) emerged as new compound containing the rare alkyl substitution, 6,6-dimethoxy-3-methylhex-2-enyl. When we tested the ability of these individual alkyl substituted chalcones to inhibit influenza virus NA hydrolysis, we found that 2-hydroxy-3-methyl-3-butenyl alkyl (HMB) substituted chalcone (3, IC(50)=12.3 μM) showed most potent inhibitory activity. The order of potency of substituted alkyl groups on for NA inhibition was HMB>6-hydroxyl-3,7-dimethyl-octa-2,7-dienyl>dimethylallyl>geranyl. All NA inhibitors screened were found to be reversible noncompetitive inhibitors.     

Structure-mutagenicity relationships of chalcones and their oxides in the Salmonella assay

31 p-monosubstituted chalcones (E-1, 3-diphenylpropene-1-one) and the corresponding oxides (E-1-benzoyl-2-phenyloxirane) were tested for mutagenic activity on two strains of Salmonella typhimurium (TA98 and TA100) with and without rat liver microsomal and cytosolic enzymes. Highest mutagenicity (3.0 revertants/nmole in either strain) was seen with the 4-nitrochalcone, especially after S9 activation. Epoxidation, in general, increased the mutagenic activity of the respective chalcone. Benzoyl (4') substituted chalcones and their oxides with an electron-withdrawing substituent (e.g., nitro, fluoro) usually had higher activity than their phenyl (4) substituted counterparts, whereas the converse was the case with electron-donating substituents (e.g., acetamido, methoxy). Further multiple factorial analysis revealed that increasing hydrophilicity as indicated by the Hansch pi parameter, and resonance electronic contributions were more important than other factors including steric terms in explaining the mutagenicity of these compounds. Mutagenic effects of some chalcone oxides, particularly the 4-methoxy derivative, were markedly decreased by S9 treatment. The consequence of the weak-to-moderate mutagenicity of these compounds to dietary intake of hydroxylated and methoxylated chalcones is discussed.     

Design,synthesis, and biological evaluation of prenylated chalcones as 5-LOX inhibitors

Ten novel mono- and di-O-prenylated chalcone derivatives were designed on the basis of a homology derived molecular model of 5-lipoxygenase (5-LOX). The compounds were docked into 5-LOX active site and the binding characteristics were quantified using LUDI. To verify our theoretical assumption, the molecules were synthesized and tested for their 5-LOX inhibitory activities. The synthesis was carried out by Claisen–Schmidt condensation reaction of mono- and di-O-prenylated acetophenones with appropriate aldehydes. 5-LOX in vitro inhibition assay showed higher potency of di-O-prenylated chalcones than their mono-O-prenylated chalcone analogs. Compound 5e exhibited good inhibition with an IC₅₀ at 4 μM. The overall trend for the binding energies calculated and LUDI score was in good qualitative agreement with the experimental data. Further, the compound 5e showed potent anti-proliferative effects (GI₅₀ at 9 μM) on breast cancer cell line, MCF-7.     

Chalcones are potent inhibitors of aromatase and 17beta-hydroxysteroid dehydrogenase activities

Chalcones were tested for estimating anti-aromatase, anti-3beta-hydroxysteroid dehydrogenase delta5/delta4 isomerase (3beta-HSD) and anti-17beta-hydroxysteroid dehydrogenase (17beta-HSD) activities in human placental microsomes. In the present study, we have demonstrated for the first time that chalcones are potent inhibitors of aromatase and 17beta-hydroxysteroid dehydrogenase activities: these enzymes being considered as important targets in the metabolic pathways of human mammary hormone-dependent cells. Our results showed that naringenin chalcone and 4-hydroxychalcone were the most effective aromatase and 17beta-hydroxysteroid dehydrogenase inhibitors with IC50 values of 2.6 and 16 microM respectively. In addition, inhibitory effects of some flavones and flavanones were compared to those of the corresponding chalcones. A structure-activity relationship was established and regions or/and substituents essential for these inhibitory activities were determined.