Hydroxychalcone Derivatives Research Articles

Synthesis and biological evaluation of 2′-hydroxychalcone derivatives as AMPK activators

A series of 2′-hydroxychalcone derivatives with various substituents on B-ring were synthesized and evaluated for AMP-activated protein kinase (AMPK) activation activity in podocyte cells. The results displayed that hydroxy, methoxy and methylenedioxy groups on B-ring could enhance the activitiy better than O-saturated alkyl, O-unsaturated alkyl or other alkoxy groups. Compounds 27 and 29 possess the highest fold change of 2.48 and 2.73, respectively, which were higher than those of reference compound (8) (1.28) and metformin (1.88). Compounds 27 and 29 were then subjected to a concentration–response study to obtain the EC50 values of 2.0 and 4.8 µM, respectively and MTT assays also showed that cell viability was not influenced by the exposure of podocytes to compounds 27 and 29 at concentrations up to 50 μM. In addition, compound 27 was proved to activate AMPK via calcium/calmodulin-dependent protein kinase kinase β (CaMKKβ)-dependent pathway without affecting intracellular calcium levels. The computational study showed that the potent compounds exhibited stronger ligand-binding strength to CaMKKβ, particularly compounds 27 (−8.4 kcal/mol) and 29 (−8.0 kcal/mol), compared to compound 8 (-7.5 kcal/mol). Fragment molecular orbital (FMO) calculation demonstrated that compound 27 was superior to compound 29 due to the presence of methyl group, which amplified the binding by hydrophobic interactions. Therefore, compound 27 would represent a promising AMPK activator for further investigation of the treatment of diabetes and diabetic nephropathy.

Targeting outer membrane protein A (OmpA) – inhibitory effect of 2′-hydroxychalcone derivatives on Acinetobacter baumannii and Candida albicans dual-species biofilm formation

Biofilm production facilitates microbial colonization of wounds and catheters. Acinetobacter baumannii produces high levels of biofilm and causes difficult-to-treat nosocomial infections. Candida albicans is another strong biofilm producer which may facilitate A. baumannii adhesion by providing hyphae-mediated OmpA-binding sites. Here we tested the potential of 2′-hydroxychalcones to inhibit dual-species biofilm production of A. baumannii and Candida spp., and further predicted the mechanism of structure-related difference in activity. The results suggest that 2′-hydroxychalcones exhibit potent activity against Candida spp./A. baumannii dual-species biofilm production. Particularly active was trifluoromethyl-substituted derivative (p-CF3), which decreased C. albicans/A. baumannii biomass produced on vein-indwelling parts of the central venous catheterization set by up to 99%. Further, higher OmpA-binding affinity was also calculated for p-CF3, which together with demonstrated significant ompA-downregulating activity, suggests that superior antibiofilm activity of this chalcone against the tested dual-species community of A. baumannii is mediated through the OmpA.

Effect of electron-donating groups on the excited state spectroscopy and dynamics of 2′-hydroxychalcone derivatives

We investigated the effect of different electron-donating groups on the intramolecular charge transfer (ICT) process in three hydroxychalcone derivatives. More efficient ICT was observed when replacing N(Me)2 by pyrrolidine due to less hydrogen bonding with solvent. Adding NH2 to the structure caused more planarity that was detected as a larger fluorescence quantum yield and narrower fluorescence peak. This was confirmed by femtosecond transient absorption in which the intramolecular twisting process, observed in the other derivatives, was absent in the presence of NH2. This work should be a useful step toward understanding and tailoring the excited state spectroscopy of chalcone derivatives.

HPLC and HPLC-MS Analysis of Intestinal Elimination and Phase 2 Metabolism of 4'-hydroxy-4-Methoxychalcone and its Bis-Mannich Analog In The Rat

Aims: The aim was to study the elimination and Phase 2 biotransformation of 4'-hydroxy-4-methoxychalcone (1) and its bis-Mannich analog (2) in the small intestine of the rat. Background: Earlier studies indicated that chalcones are promising starting points for drug design. Aminomethylation of drugs is considered to improve their delivery into the human body. Objectives: To set up validated HPLC-UV methods to quantitate the investigated chalcones in the rat intestinal perfusates. Comparison of intestinal disappearance and Phase 2 metabolic profile of the 4’-hydroxychalcone (1) and a bis-Mannich analog (2). Methods: Chalcones 1 and 2 were luminally perfused in the small intestine of rats at a concentration of 240 μM and 280 μM, respectively. Analysis of the collected intestinal perfusate samples was performed by a validated HPLC-UV method. Using HPLC-MS, the samples were analyzed for Phase 2 metabolites as well. Results: Elimination kinetics of the two 4’-hydroxychalcones displayed characteristic differences having the nonpolar chalcone 1 higher elimination rate over the 90-minute ex vivo experiments. HPLC-MS analysis of the perfusates indicated the presence of glucuronide, sulfate, and glutathione conjugates in the parent molecules. Intestinal disappearance and sulfation of the bis-Mannich derivative 2 showed characteristic differences compared to 1 Conclusion: The results demonstrate, to the best of our knowledge, for the first time, how the title structural modification of phenolic chalcones affects intestinal elimination and Phase 2 metabolism of the compounds Highlights: Study on ex vivo intestinal elimination of a 4'-hydroxy-4-methoxychalcone and its bis-Mannich analog. Development of validated HPLC-UV methods for quantitation of 4’-hydroxychalcone derivatives in rat intestinal perfusates. HPLC-MS identification of Phase 2 metabolites of 4’-hydroxychalcones in rat intestinal perfusates.

Room temperature imidazolium linked chalcone based ionic LCs: Role of terminal position on mesomorphism

A newly imidazolium linked chalcone ionic LCs (5a-5e, series-1) & (8a-8e, series-2) based on two phenyl rings have been synthesized by the quaternization of 1-methylimidazole and ortho & para-substituted hydroxy chalcone derivatives. The mesogenic behavior of synthesized ionic mesogens was perceived by POM, DSC and XRD measurements. The structure-property relationship of new class of chalcone linked imidazolium ILCs has been studied. All materials exhibited enantiotropical type mesogenic properties. Few selected ionic derivatives showed LC properties at room temperature with higher temperature range. Smectic C and nematic properties were detected in synthesized ionic compounds. Series-2 showed higher thermal stability of smectic and nematic phase as compared to series-1. The X-ray configurations revealed the coexistence of bilayer smectic C pattern over a well-defined temperature range. The molecular structures of target ILCs were identified by using IR and 1H NMR spectroscopy.

Structure-Property Relationship of Three 2-Chloro-4-fluoro Chalcone Derivatives: A Comprehensive Study on Linear and Non-linear Optical Properties, Structural Characterizations and Density Functional Theory

This work focused on the relationship between molecular structure and non-linear optical (NLO) property of the chalcone derivatives. The NLO property is well known increased by push-pull effect, therefore we have explored donor-acceptor substitutions on both rings to develop excellent NLO materials. Three new crystals of 2-chloro-4-fluorochalcone derivatives bearing various donor end groups were synthesized in order to evaluate the donor dependence of their second-order hyperpolarizability γ. The grown crystals were spectroscopically confirmed and crystallographically analysed. Their intermolecular interactions were visualized by Hirshfeld surface analysis. The electronic absorption spectrums were investigated by experimental and theoretical methods, to discuss the intramolecular charge transfer and energy gap of solution sample, which defined significantly affected NLO properties. Theoretical electronic properties have been simulated with density functional theory (DFT) at B3LYP/6-311++G (d,p) level and compared with experimental results. Thermally-induced NLO parameters such as non-linear absorption (NLA) coefficient (α2∼10−5 cmW−1), non-linear refractive (NLR) index (n2 ∼10−9cm2W−1), third-order susceptibility [χ(3)(-ω;ω,ω,-ω) ∼10−8 esu] and γ(-ω;ω,ω,-ω)∼ 10−27 esu] were measured by Z-scan technique under continuous-wave laser excitation (532 nm). The solution samples exhibit two-photon assisted reverse saturable absorption and self-defocusing non-linear refraction, optical limiting and all-optical switching behaviours. We have determined that γ depends on the strength of donor/acceptor substituents, which is the result of the two contributions: the energy gap and the transition dipole moment between the ground and first excited states. A large value of γ was found for compound I which bearing strong donor hydroxy substituent, thus the hydroxychalcone derivatives as a potential material with excellent NLO performance.

Synthesis and Investigation of Flavanone Derivatives as Potential New Anti-Inflammatory Agents.

Flavonoids are polyphenols with broad known pharmacological properties. A series of 2,3-dihydroflavanone derivatives were thus synthesized and investigated for their anti-inflammatory activities. The target flavanones were prepared through cyclization of 2′-hydroxychalcone derivatives, the later obtained by Claisen–Schmidt condensation. Since nitric oxide (NO) represents an important inflammatory mediator, the effects of various flavanones on the NO production in the LPS-induced RAW 264.7 macrophage were assessed in vitro using the Griess test. The most active compounds were flavanone (4G), 2′-carboxy-5,7-dimethoxy-flavanone (4F), 4′-bromo-5,7-dimethoxy-flavanone (4D), and 2′-carboxyflavanone (4J), with IC50 values of 0.603, 0.906, 1.030, and 1.830 µg/mL, respectively. In comparison, pinocembrin achieved an IC50 value of 203.60 µg/mL. Thus, the derivatives synthesized in this work had a higher NO inhibition capacity compared to pinocembrin, demonstrating the importance of pharmacomodulation to improve the biological potential of natural molecules. SARs suggested that the use of a carboxyl-group in the meta-position of the B-ring increases biological activity, whereas compounds carrying halogen substituents in the para-position were less active. The addition of methoxy-groups in the meta-position of the A-ring somewhat decreased the activity. This study successfully identified new bioactive flavanones as promising candidates for the development of new anti-inflammatory agents.

Characterization, molecular modeling and pharmacology of some 2́-hydroxychalcone derivatives as SARS-CoV-2 inhibitor

This work presented the microwave assisted synthesis of six new 2́-hydroxychalcones and their characterization based on FTIR, UV–Vis, 1H NMR, and mass spectral analysis. Quantum chemical studies confirmed the structures of prepared chalcones. Antioxidant, in vitro antimicrobial and in silico antiviral studies have been performed to evaluate their biological performance. Results of molecular docking of prepared 2́-hydroxychalcones against SARS-CoV-2 (7BQY) main protease disclosed their inhibition which is comparable to standard, remdesivir and better than hydroxychloroquine (HCQ). ADMET prediction revealed them to be non-carcinogenic and relatively safe.

Synthesis, cytotoxicity assay, and molecular docking study of hydroxychalcone derivatives as potential tyrosinase inhibitors

Synthesis, cytotoxicity assay, and molecular docking study of hydroxychalcone derivatives as potential tyrosinase inhibitors

Regioselective and chemoselective biotransformation of 2′-hydroxychalcone derivatives by marine-derived fungi

Eight fungal strains (Penicillium raistrickii CBMAI 931, Cladosporium sp. CBMAI 1237, Aspergillus sydowii CBMAI 935, Penicillium oxalicum CBMAI 1996, Penicillium citrinum CBMAI 1186, Mucor racemosus CBMAI 847, Westerdykella sp. CBMAI 1679, and Aspergillus sclerotiorum CBMAI 849) mediated the biotransformation of the 2′-hydroxychalcone 1a. The main products obtained were from hydrogenation, hydroxylation, and cyclization reactions. Penicillium raistrickii CBMAI 931 catalyzed the chemoselective reduction of 1a to produce 2′-hydroxydihydrochalcone 2a (72%) in 7 days of incubation in phosphate buffer (pH 7). Aspergillus sydowii CBMAI 935 promoted the hydroxylation of 1a to yield 2′,4-dihydroxy-dihydrochalcone 5a (c = 42%) in 7 days of incubation in phosphate buffer (pH 8). The reaction using P. citrinum CBMAI 1186 and M. racemosus CBMAI 847 presented main cyclization products in phosphate buffer (pH 8), but the reactions with these fungi did not present enantioselectivity. Marine-derived fungi were effective and versatile biocatalysts for biotransformation of the 2′-hydroxychalcones yielding different products according to the conditions and microorganism used.

A TD-DFT molecular screening for fluorescence probe based on excited-state intramolecular proton transfer of 2’-hydroxychalcone derivatives

A systematic screening of fluorescence probe based on excited-state intramolecular proton transfer (ESIPT) of 2’-hydroxychalcone (2HC) derivatives with different electron donating (EDG) and electron withdrawing (EWG) groups at para position of phenol moiety (R1) and para position of the connected benzene ring to carbonyl (R2) of 2HC has been carried out by the best method of choice at ωB97XD/6-311++G(d,p) level. Seven selected 2HC derivatives with OH donor having mono-substitution with –NMe2 at R1 position or di-substitution with –NMe2 at R1 position and EDG (Me, OMe, NMe2) or EWG (Br, Cl, F) at R2 position have passed all required parameters (photophysical parameters, kinetic and thermodynamic parameters). Whereas, seven selected 2HC derivatives with NH donor having the same substituents as the 2HC derivatives with OH donor have passed photophysical parameters but failed kinetic and thermodynamic parameters due to high PT barrier and endothermic reaction. To ensure the effective ESIPT occurrence, a hydrogen atom on the amine group of NH donor derivatives is replaced with a tosyl (Ts) group, providing the Ts-substituted NH donor derivatives. The Ts substituent helps strengthening the intramolecular hydrogen bond, leading to low PT barrier with exothermic reaction thus facilitating ESIPT process. The systematically screening procedure from this theoretical calculation is beneficial for the design of fluorescent molecular probes utilizing the ESIPT process.

Sonochemical Synthesis of 2'-Hydroxy-Chalcone Derivatives with Potential Anti-Oomycete Activity.

This work reports on the synthesis of eight new 2′-hydroxy-chalcones with potential anti-phytopathogenic applications in agroindustry, AMONG others, via Claisen–Schmidt condensation and ultrasound assisted reaction. Assays showed three chalcones with allyl moieties strongly inhibited growth of phytopathogenic oomycete Phytophthora infestans; moreover, compound 8a had a half maximal effective concentration (EC50) value (32.5 µg/mL) similar to that of metalaxyl (28.6 µg/mL). A software-aided quantitative structure–activity relationship (QSAR) analysis of the whole series suggests that the structural features of these new chalcones—namely, the fluoride, hydroxyl, and amine groups over the carbon 3′ of the chalcone skeleton—increase anti-oomycete activity.

Revealing and comparing different excited‐state intramolecular proton transfer processes for 3‐(4‐dimethylamino‐phenyl)‐1‐(4‐fluoro‐2‐hydroxy‐phenyl)‐propenone and 3‐(4‐dimethylamino‐phenyl)‐1‐(4‐fluoro‐2‐hydroxy‐phenyl)‐3‐hydroxy‐propenon

AbstractTwo novel 2′‐hydroxychalcone derivatives (i.e., M1 and M2) are explored in this work. We mainly focus on investigating the effects of photoexcitation on hydrogen bonds and on the excited‐state intramolecular proton transfer (ESIPT) process. On the basis of calculations of electrostatic potential surface and intramolecular interactions, we verify the formation of hydrogen bond O1H2···O3 in both S0 and S1 states. Exploring the ultraviolet–visible spectra in the liquid phase, our simulated results reappear in the experimental phenomenon. Analyzing molecular geometry and infrared stretching vibrational spectra, we confirm O1H2···O3 is strengthened for both M1 and M2 in the S1 state. We further confirm that charge redistribution facilitates ESIPT tendency. Constructing potential energy curves, we find the ultrafast ESIPT behavior for M1, which is because of the deficiency of side hydroxyl moiety comparing with M2. This work makes a reasonable affiliation of the ESIPT mechanism for M1 and M2. We wish this paper could facilitate understanding these two novel systems and promote their applications.

Microwave assisted synthesis, characterization, molecular docking and pharmacological activities of some new 2′-hydroxychalcone derivatives

Synthesis of six new α, β-unsaturated carbonyl compounds (2′-hydroxychalcones) from 2′-hydroxyacethophenone and aromatic aldehyde derivatives under microwave condition has been described due to their pharmaceutical interest. They were characterized by FTIR, 1H NMR, Mass spectra, micro-analytical data and other physic-chemical properties. Density functional theory (DFT) with B3LYP/6-311 + G (d,p) has been employed for the optimization of all synthesized chalcones which helps to confirm the structures of the compounds proposed based on experimental evidences. The synthesized compounds were proved to inhibit microbial activity and showed good antioxidant property. Molecular docking was performed against prostaglandin H2 (PGH2) synthase protein 5F19. The binding affinity and binding mode of 2′-hydroxychalcones with this protein was searched considering paracetamol (PCT) as standard.

Chalcones and Flavanones Bearing Hydroxyl and/or Methoxyl Groups: Synthesis and Biological Assessments

Chalcones and flavanones are isomeric structures and also classes of natural products, belonging to the flavonoid family. Moreover, their wide range of biological activities makes them key scaffolds for the synthesis of new and more efficient drugs. In this work, the synthesis of hydroxy and/or methoxychalcones was studied using less common bases, such as sodium hydride (NaH) and lithium bis(trimethylsilyl)amide (LiHMDS), in the aldol condensation. The results show that the use of NaH was more effective for the synthesis of 2′-hydroxychalcone derivatives, while LiHMDS led to the synthesis of polyhydroxylated chalcones in a one-pot process. During this study, it was also possible to establish the conditions that favor their isomerization into flavanones, allowing at the same time the synthesis of hydroxy and/or methoxyflavanones. The chalcones and flavanones obtained were evaluated to disclose their antioxidant, anticholinesterasic, antibacterial and antitumor activities. 2′,4′,4-Trihydroxychalcone was the most active compound in terms of antioxidant, anti-butyrylcholinesterase (IC50 26.55 ± 0.55 μg/mL, similar to control drug donepezil, IC50 28.94 ± 1.76 μg/mL) and antimicrobial activity. 4′,7-Dihydroxyflavanone presented dual inhibition, that is, the ability to inhibit both cholinesterases. 4′-Hydroxy-5,7-dimethoxyflavanone and 2′-hydroxy-4-methoxychalcone were the compounds with the best antitumor activity. The substitution pattern and the biological assay results allowed the establishment of some structure/activity relationships.

Determinant of ESIPT Mechanism by the Structure Designed for Symmetrical and Unsymmetrical Molecules.

In this work, we present that different structures lead to different excited state properties based on the investigations of the systems with symmetrical and unsymmetrical properties. Our work shows that the symmetrical and unsymmetrical compounds with a modified structure play key roles in regulating the excited state intramolecular proton transfer (PT) (ESIPT) process. For N,N'-bis(salicylidene)-p-phenyle-nediamine (BSP) and N,N'-disalicylidene-1,6-pyrenediamine (BSD), when they are excited, the torsion angels result in the rematch of the spectra. By analyzing the potential energy surfaces (PESs) of the torsion angle and PT process, we conclude that the size of the π stack largely affects the molecular properties in the excited states. For 2'-hydroxychalcone derivatives, which have important applications in biotransformation reactions, investigating the molecules of M1 and M2 could promote innovation in bioengineering. The results of molecular electrostatic potential (MEP) and the real space intramolecular interactions show the state and position of the hydrogen bond (HB) in both S0 and S1 states. The corresponding PT PESs show that the ESIPT reaction is much easier for the M1 system due to the lack of the side chain hydroxyl compared with the M2 system. This work is not only consistent with experimental results and explains its mechanism but also presents that symmetric and nonsymmetric structures modify their own potential regulation and controlling effects for ESIPT behaviors.

Synthesis and Kinetic Investigations for the Isomerization Process of 2–Hydroxy Chalcone Derivatives

The wide biological activities of flavanones are mainly depends on their physical and chemical properties, thus a number of substituted 2-Hydroxy chalcones have been synthesized, and their isomerization to their corresponding flavanones was studied. In order to determine the rate constant, kinetic experiments were performed using HPLC technique in (9:1) (CH3CN:H2O) medium at different temperature (298-318) K. The obtained results were interpreted by four steps mechanism, which considered the existence of phenoxide ion as the key intermediate. This study performed with a pseudo first order ( reaction in which the rate for the studied compounds follow the sequence 5 andgt; 2 andgt; 1 andgt; 4 andgt; 3, the activation energy have the same sequence for these compounds .The effect of substituents on the rate showed that electronic and steric factors play reasonable role on the stability of the product .

Synthesis of Functionalized Chromene and Chroman Derivatives via Cesium Carbonate Promoted Formal [4 + 2] Annulation of 2'-Hydroxychalcones with Allenoates.

A new strategy has been established for the synthesis of functionalized chromene and chroman derivatives via a Cs2CO3-catalyzed domino addition of 2'-hydroxychalcone derivatives with allenoates, which can serve as a general avenue for the construction of multireplaced chromene derivatives. Chemoselectivity of this synthesis was found to depend on substituents on substrates. Good to excellent yields were achieved under simple and mild conditions at room temperature.

Positions and numbers of hydroxyl groups in hydroxychalcone derivatives are involved in cytotoxicity against human monoblastic U937 cells

Positions and numbers of hydroxyl groups in hydroxychalcone derivatives are involved in cytotoxicity against human monoblastic U937 cells

Solvent Polarity Dependent Excited State Dynamics of 2′-Hydroxychalcone Derivatives

The excited-state properties of 4-(dimethylamino)methoxychalcones (DEAMC) and its derivative 4-(dimethylamino)hydroxychalcones (DEAHC) were investigated in various solvents with different polarities by using steady-state and femtosecond transient absorption spectroscopy combined with quantum chemical calculations. It is found that their photophysical parameters such as fluorescence quantum yields, lifetimes, and excited-state relaxation paths strongly depend on the solvent polarity. Quantum-chemical calculations elucidate that the geometry of DEAMC in the ground state is slightly torsional whereas DEAHC adopts a near planar conformation stabilized by O–H···O chelated hydrogen bonds. Steady state spectra show that DEAHC is weak fluorescent in all solvents due to nonradiative relaxation in the excited enol and keto states, whereas the fluorescence quantum yield of DEAMC increases with the increasing of solvent polarities, and the emission yield is as large as 0.16 in acetonitrile. Femtosecond and nanosecond...