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The aim of this study was to investigate the in vivo toxicities of some novel synthetic chalcones. Chalcone and four chalcone analogues 1a-d were evaluated using zebrafish embryos following antibody staining to visualize their morphological changes and muscle fiber alignment. Results showed that embryos treated with 3'-hydroxychalcone (compound 1b)...
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... this study, we synthesized four chalcones 1a-d ( Figure 1A). These aldol compounds were obtained using a procedure similar to one described previously [16][17][18][19]. ...
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... Among the studied molecules, derivatives of chalcones and chromones were the most promising. Although no apparent toxicity was observed with chalcones, the potential toxicity of these molecules is regularly pointed out, due to the presence of a Michael acceptor represented by the propenone moiety [23]. Despite their potential as very effective BCRP inhibitors, chromone derivatives mainly suffer from their poor pharmacokinetic properties [24]. ...
Aim: BCRP plays a major role in the efflux of cytotoxic molecules, limiting their antiproliferative activity. We aimed to design and synthesize new BCRP inhibitors to render cancerous tumors more sensitive toward anticancer agents. Materials & methods: Based on our previous work, we conceived potential BCRP inhibitors derived from 1,3,4-oxadiazoles bearing two substituted phenyl rings. Results: Evaluating 19 derivatives, we found that 2,5-diaryl-1,3,4-oxadiazoles possessing methoxy groups were the most active. The highest activity was recorded with derivatives bearing three methoxy groups. The most active compound (3j) was selective in inhibiting BCRP and nontoxic as evidenced by cellular tests. Conclusion: 3j is a promising BCRP inhibitor thanks to its synthetic accessibility and biological profile.
... In addition, their toxicity dose range is also predicted in silico with rat oral LD50 from 0.64 g/kg to 7.94 g/kg [22]. Meanwhile, chalcones and chalcone analogues in the study by Lee et al. (2014) showed embryotoxicity of zebrafish resulting in muscle defects [38]. ...
... In addition, their toxicity dose range is also predicted in silico with rat oral LD50 from 0.64 g/kg to 7.94 g/kg [22]. Meanwhile, chalcones and chalcone analogues in the study by Lee et al. (2014) showed embryotoxicity of zebrafish resulting in muscle defects [38]. ...
Diabetes mellitus is a chronic metabolic disease relating to steady hyperglycemia resulting from the impairment of the endocrine and non-endocrine systems. Many new drugs having varied targets were discovered to treat this disease, especially type 2 diabetes. Among those, α-glucosidase inhibitors showed their effects by preventing the digestion of carbohydrates through their inhibition against α-amylase and α-glucosidase. Recently, chalcones have attracted considerable attention as they have a simple structure, are easily synthesized as well as have a variety of derivatives. Some reports suggested that chalcone and its derivates could inhibit α-amylase and α-glucosidase. This narrative review provides a comprehensive evaluation of the inhibition of chalcone and its derivatives against α-amylase and α-glucosidase that were reviewed and reported in published scientific articles. Twenty-eight articles were reviewed after screening 207 articles found in four databases, including PubMed, Google Scholar, VHL (Virtual Health Library), and GHL (Global Health Library). This review presented the inhibitory effects of varied chalcones, including chalcones with a basic structural framework, azachalcones, bis-chalcones, chalcone oximes, coumarin-chalcones, cyclohexane chalcones, dihydrochalcones, and flavanone-coupled chalcones. Many of these chalcones had significant inhibition against α-amylase as well as α-glucosidase that were comparable to or even stronger than standard inhibitors. This suggested that such compounds could be potential candidates for the discovery of new anti-diabetic remedies in the years to come.
... The presence of melanin pigments on surface of zebrafish larvae allow ready observation in testing percutaneous effect of depigmenting agents [31]. Moreover, screening of embryotoxicity of drugs or small molecules involves rapid and simple procedure whereby compounds diluted in embryo media is readily absorbed through skin and gills during early stage of embryo [32,33]. ...
Excessive production of melanin implicates hyperpigmentation disorders. Flavokawain A (FLA) and flavokawain B (FLB) have been reported with anti-melanogenic activity, but their melanogenic inhibition and toxicity effects on the vertebrate model of zebrafish are still unknown. In the present study, cytotoxic as well as melanogenic effects of FLA and FLB on cellular melanin content and tyrosinase activity were evaluated in α-MSH-induced B16/F10 cells. Master regulator of microphthalmia-associated transcription factor (Mitf) and the other downstream melanogenic-related genes were verified via quantitative real time PCR (qPCR). Toxicity assessment and melanogenesis inhibition on zebrafish model was further observed. FLA and FLB significantly reduced the specific cellular melanin content by 4.3-fold and 9.6-fold decrement, respectively in α-MSH-induced B16/F10 cells. Concomitantly, FLA significantly reduced the specific cellular tyrosinase activity by 7-fold whilst FLB by 9-fold. The decrement of melanin production and tyrosinase activity were correlated with the mRNA suppression of Mitf which in turn down-regulate Tyr, Trp-1 and Trp-2. FLA and FLB exhibited non-toxic effects on the zebrafish model at 25 and 6.25 µM, respectively. Further experiments on the zebrafish model demonstrated successful phenotype-based depigmenting activity of FLA and FLB under induced melanogenesis. To sum up, our findings provide an important first key step for both of the chalcone derivatives to be further studied and developed as potent depigmenting agents.
... Some compounds led by Lichochalcone A have been proposed as antimalarial drug candidates [8]. However, the establishment of a drug cannot be done without the exploration of its toxic or cytotoxic profile [9]. ...
Malaria continues to kill thousands of people worldwide. People South of the Sahara are paying the heaviest price for this epidemic. In addition, the resistance of Plasmodium falciparum which spreads to artemisinin derivatives becomes worrying. To respond to this emergency, the search for new molecules effective against the parasite is essential. Otherwise, chalcones have shown their potential as an effective pharmaceutical agent in numerous studies. However, despite their mainly antiparasitic efficacy, several compounds have been shown to be cytotoxic. This study aimed to assess the cytotoxic profile of chalcone derivatives. Cytotoxicity tests were carried out according to the method described by Taylor and collaborators on Vero cells. The 96-well plates were used in carrying out this study, 100 µl of the compounds were added with concentrations ranging from 7.5 to 1000 µg/ml in DMEM. The results obtained report three compounds derivatives (Chal_B14, Chal_B17 & Chal_SCA03) no-cytotoxic with LDH product values between 129 - 132.5 U/L and ATP ranging from 8.55 to 13.6 RLU. The IC50s for no-cytotoxic compounds ranged from 102 to 236 µM. On the other hand, the cytotoxic compounds had IC50s of less than 30 µM. The results of this study show that the derivatives Chal_B14, Chal_B17 & Chal_SCA03 are candidate compounds with a view to finding new molecules.
... Similar results were reported for the chalcone, PAAPFBA [8]. Other studies also assessed the toxicity of chalcones in zebrafish, however, the authors had performed the studies using zebrafishes in the embryonic phase [23]. ...
... No other previous report was found with the evaluation of hydroxychalcone 3c in VERO cells, although two research articles performed toxicity assessments of molecules with the same structures of 3b and 3c. Lee et al. (2014) investigated the in vivo toxicities of some synthetic chalcones in zebrafish embryos, in which compounds equal to 3b and 3c (original codes: 1a and 1d, respectively) did not show significant differences from the untreated control in concentrations of up to 5 ppm (≈ 20 μM). At a concentration of 3 ppm of 3c (≈ 12.5 μM considering its molar weight of 240.25), the survival rate was kept near 100% for 60 h postfertilization. ...
... vaginalis screening as they indicate that the additional meta-hydroxyl substituent of chalcone 3c is an important binding site for TvMGL and TvLDH. As discussed before, carbonyl molecules containing a hydroxyl group at theortho position of the ring may form intramolecular bonding, which would prevent these groups from forming the hydrogen bonds (Da Silva et al. 2018a, b;Lee et al. 2014). Therefore, for hydroxychalcone 3c, even if that happened, the meta-hydroxy group would still be available for interaction with the evaluated enzymes, which would not be possible for chalcones 3a and 3b. ...
The treatment for trichomoniasis, based on 5′-nitroimidazol agents, has been presenting failures related to allergic reactions, side effects, and the emergence of resistant isolates. There are no alternative drugs approved for the treatment of these cases; thus, the search for new active molecules is necessary. In this scenario, chalcones have been extensively studied for their promising biological activities. Here, we presented the synthesis of three hydroxychalcones (3a, b, and c), in vitro and in silico analyses against Trichomonas vaginalis. The in vitro biological evaluation showed that hydroxychalcone 3c presented anti-T. vaginalis activity, with complete death in 12 h of incubation at minimum inhibitory concentration (MIC) of 100 μM. 3c showed a dose-dependent cytotoxicity against mammalian VERO cell line, but the association of 3c at 12.5 μM and metronidazole (MTZ) at 40 μM showed 95.31% activity against T. vaginalis trophozoites after 24 h of exposure and did not affect the VERO cell growth, appearing to be a good alternative. In silico analysis by molecular docking showed that 3c could inhibit the activity of TvMGL (methionine gamma-lyase), TvLDH (lactate dehydrogenase), and TvPNP (purine nucleoside phosphorylase) affecting the T. vaginalis survival and also suggesting a different mechanism of action from MTZ. Therefore, these results propose that hydroxychalcones are promising anti-T. vaginalis agents and must be considered for further investigations regarding trichomoniasis treatment.
... Chalcones are very reactive upon UV irradiation and are commonly used in the formulation of photoresists such as SU-8 27,28 . Despite their anti-inflammatory, anti-oxidant, anti-nociceptive, anti-parasites, and anti-proliferative pharmaceutical effects, chalcones have also been found to have a myotoxic effect in zebrafish 29 , and to stimulate apoptosis in human colorectal carcinoma cells 30 . 2-Chloro-ethanesulfonyl chloride, which is also part of photoresist solvents, is known to be corrosive and cause acute toxicity 31 . ...
The introduction of poly(dimethylsiloxane) (PDMS) and soft lithography in the 90’s has revolutionized the field of microfluidics by almost eliminating the need for a clean-room environment for device fabrication. More recently, 3D printing has been introduced to fabricate molds for soft lithography, the only step for which a clean-room environment is still often necessary, to further support the rapid prototyping of PDMS microfluidic devices. However, toxicity of most of the commercial 3D printing resins has been established, and little is known regarding the potential for 3D printed molds to leak components into the PDMS that would, in turn, hamper cells and/or tissues cultured in the devices. In the present study, we investigated if 3D printed molds produced by stereolithography can leach components into PDMS, and compared 3D printed molds to their more conventional SU-8 counterparts. Different leachates were detected in aqueous solutions incubated in the resulting PDMS devices prepared from widely used PDMS pre-polymer:curing agent ratios (10:1, 15:1 and 20:1), and these leachates were identified as originating from resins and catalyst substances. Next, we explored the possibility to culture cells and tissues in these PDMS devices produced from 3D printed molds and after proper device washing and conditioning. Importantly, we demonstrated that the resulting PDMS devices supported physiological cultures of HeLa cells and ovarian tissues in vitro, with superior outcomes than static conventional cultures.
... For this study, we synthesized 20 chalcones 1a-t ( Figure 1). These Aldol intermediates were obtained using a procedure similar to the one described previously in References [23][24][25][26][27]. Intramolecular hydrogen bonding such as that observed in 1a-g is known to prevent Aldol reactions. ...
... (E)-1-(2-hydroxy-phenyl)-3-phenyl-propenone (1a) [24]. 1 ...
Atherosclerosis is a process of imbalanced lipid metabolism in the vascular walls. The underlying pathology mainly involves the deposition of oxidized lipids in the endothelium and the accumulation of cholesterol in macrophages. Macrophages export excessive cholesterol (cholesterol efflux) through ATP-binding cassette transporter A1 (ABCA1) to counter the progression of atherosclerosis. We synthesized novel chalcone derivatives and assessed their effects and the underlying mechanisms on ABCA1 expression in macrophages. Human THP-1 macrophages were treated with synthetic chalcone derivatives for 24 h. In Western blot and flow cytometry analyses, a chalcone derivative, (E)-1-(3,4-diisopropoxyphenyl)-3-(4-isopropoxy-3-methoxyphenyl)prop- 2-en-1-one (1m), was observed to significantly enhance ABCA1 protein expression in THP-1 cells (10 µM, 24 h). Levels of mRNA of ABCA1 and liver X receptor alpha (LXRα) were quantified using a real-time quantitative polymerase chain reaction technique and were found to be significantly increased after treatment with the novel chalcone derivative 1m. Several microRNAs, including miR155, miR758, miR10b, miR145, miR33, and miR106b, which functionally inhibit ABCA1 expression were suppressed after treatment with 1m. Collectively, 1m increases ABCA1 expression in human THP-1 macrophages. The mechanisms involve the activation of the LXRα-ABCA1 pathway and suppression of certain microRNAs that regulate ABCA1 expression.
... In contrast to the several pharmacological proprieties attributed to chalcones derivatives, it was also discovered that many of them have a strong cytotoxic potential and might cause severe adverse effects [42]. Synthetic and natural chalcones are known by their myotoxicity, generally associated with the breakage and collapse of myofibrils, reduction of cell numbers, and disorganization of thick (myosin) and thin (actin) filaments [43], as well as by their mitotoxicity, related with the ability of chalcones in inhibit tubulin assembly and actuate on other components of cell cycle [42]. Thus, chalcones derivatives showed high toxicity on eukaryotic cells. ...
Vulvovaginal candidiasis (VVC) affects millions of women around the world every year. Candida albicans is the most frequently isolated pathogen in women and its rapid ability to develop resistance to first and second line therapies has boosted the search for new and effective antifungal agents. In this study, we show the in vitro anti-Candida activity of fifteen synthetic chalcone analogs and their antifungal potential in an in vivo model of VVC. Chalcone 12 showed potent antifungal effects, being able to inhibit the growth of Candida spp. at a concentration of 15.6 µg mL−1. In addition, mechanism of action studies have indicated the ergosterol fungal membrane as the target of this compound. Despite a considerable antifungal activity, the chalcone 12 showed high cytotoxicity in kidney cells lineages. Moreover, this compound was able to reduce Candida-associated virulence, impairing yeast–hyphal transition in C. albicans. An in vivo model of VVC showed that chalcone 12 significantly reduces the fungal load. Taken together, these findings showed that the chalcone 12 is a potent anti-Candida agent in vitro beyond of contribute to improve the fungal infection in a model of CVV. However, it showed low selectivity and high toxicity, suggesting molecular modifications to minimize these proprieties.
... As mentioned, many of the chalcone oxime compounds showed potent biological activities and low toxicities. 19 Some of the chalcone oxime compounds have been used as clinical medical agents, thus, it was considered worthwhile to synthesize and evaluate a new series of chalcone oximes for their biological activity. The present study is devoted to the synthesis new hydroxy/methoxy substituted chalcone oximes (2a-2k) by the condensation of chalcones (1a-1k) with hydroxylamine hydrochloride in the pyridine and to test their α-glucosidase inhibition activity and to find out the most stable geometric isomers of compounds 2a-2k by theoretical calculation. ...
A series of eleven hydroxy and methoxy substituted new chalcone oximes (2a-2k) were synthesized by the condensation of chalcone (1a-1k) with hydroxylamine hydrochloride in pyridine. Structures of the synthesized compounds were characterized using NMR (1D; ¹H, ¹³C/APT and 2D ¹H-¹H COSY, NOESY and ROESY), FT-IR, UV, LC-MS spectral data and elemental analysis. These synthetic compounds (2a-k) were screened for their α-glucosidase inhibition. The most α-glucosidase inhibitory activity were observe on compounds 2a and 2b with in the range of 1.61-3.36 μM (IC50 values) which were more active then acarbose (IC50, 13,34 μM). IC50 values of other synthesized compounds 2c-2h are within the range of 7,25-25,55 μM which were more or as active as acarbose, but, IC50 values for compounds 2j-2k were not observed. The geometric isomers of compounds 2a-2k were calculated theoretically. Experimental and theoretical calculations showed that cisoid 1E,2E is the most stable geometrical isomer of all.
