Aurone Analogues Research Articles

Pyrazole-based and N,N-diethylcarbamate functionalized some novel aurone analogs: Design, synthesis, cytotoxic evaluation, docking and SAR studies, against AGS cancer cell line

The present study involves the design, synthesis, and biological evaluation of a series of thirty-three, pyrazole-based and N,N-diethylcarbamate functionalized, novel aurone analogs, against AGS cancer cell line. These novel aurone analogs are obtained from the reaction of pyrazole-based 6-hydroxyaurones with diethyl carbamoyl chloride using mild basic reagent. The cytotoxic activities of these compounds were evaluated against a human gastric adenocarcinoma cell line (AGS) and disclosed some potential outcomes as several analogs were found to have cytotoxicity better than the reference drugs Oxaliplatin and Leucovorin. The structure-activity relationship (SAR) study further unveiled the critical role of replacing the hydroxyl group in ring A with a carbamoyl group for cytotoxic activity. Among these aurone analogs, 8e and 8f, with IC50 values of 6.5 ± 0.024 μM and 6.6 ± 0.035 μM, respectively, are identified as the most active compounds. Molecular docking studies were conducted against HER2, a human epidermal growth factor involved in gastric and ovarian cancer, to investigate the binding interactions between the compounds and the protein HER2, where7e and 8e exhibited maximum interactions.

Arylureidoaurones: Synthesis, in vitro α-glucosidase, and α-amylase inhibition activity

Because of the colossal global burden of diabetes, there is an urgent need for more effective and safer drugs. We designed and synthesized a new series of aurone derivatives possessing phenylureido or bis-phenylureido moieties as α-glucosidase and α-amylase inhibitors. Most of the synthesized phenylureidoaurones have demonstrated superior inhibition activities (IC50s of 9.6–339.9 μM) against α-glucosidase relative to acarbose (IC50 = 750.0 μM) as the reference drug. Substitution of aurone analogues with two phenylureido substituents at the 5-position of the benzofuranone moiety and the 3′ or 4′ positions of the 2-phenyl ring resulted in compounds with almost 120–180 times more potent inhibitory activities than acarbose. The aurone analogue possessing two phenylureido substitutions at 5 and 4′ positions (13) showed the highest inhibition activity with an IC50 of 4.2 ± 0.1 μM. Kinetic studies suggested their inhibition mode to be competitive. We also investigated the binding mode of the most potent compounds using the consensually docked 4D-QSAR methodology. Furthermore, these analogues showed weak-to-moderate non-competitive inhibitory activity against α-amylase. 5-Methyl substituted aurone with 4′-phenylureido moiety (6e) demonstrated the highest inhibition activity on α-amylase with an IC50 of 142.0 ± 1.6 μM relative to acarbose (IC50 = 108 ± 1.2 μM). Our computational studies suggested that these analogues interact with a hydrophilic allosteric site in α-amylase, located far from the enzyme active site at the N-terminal.

Synthesis, Nematicidal Evaluation, and the Structure-Activity Relationship Study of Aurone Derivatives.

Plant-parasitic nematodes (PPNs) are one of the major threats to modern agriculture. Chemical nematicides are still required for the management of PPNs. Based on our previous work, the structure of aurone analogues was obtained using a hybrid 3D similarity calculation method (SHAFTS, SHApe-FeaTure Similarity). Thirty-seven compounds were synthesized. The nematicidal activity of target compounds against Meloidogyne incognita (root-knot nematode, M. incognita) was evaluated, and the structure-activity relationship of synthesized compounds was analyzed. The results showed that compound 6 and some of its derivatives exhibited impressive nematicidal activity. Among these compounds, compound 32 bearing 6-F showed the best in vitro and in vivo nematicidal activity. Its lethal concentration 50% after exposure to 72 h (LC50/72h) value was 1.75 mg/L, and the inhibition rate reached 97.93% in the sand at 40 mg/L. At the same time, compound 32 also exhibited excellent inhibition on egg hatching and moderate inhibition on the motility of Caenorhabditis elegans (C. elegans).

An Expedient Synthesis of Functionalized Pyrazole‐Based Aurone Analogs

AbstractThe efficient methods for the synthesis of pyrazole‐based aurones were developed. It was shown that reaction of benzofuran‐3(2H)‐ones with 1H‐pyrazole‐3(5)/4‐carboxaldehydes or 4‐[(dimethylamino)methylene]‐2,4‐dihydro‐3H‐pyrazol‐3‐ones led to formation of the 2‐pyrazolylmethylene‐1‐benzofuran‐3(2H)‐ones or 2‐[(3(5)‐hydroxy‐1H‐pyrazol‐4‐yl)methylene]‐1‐benzofuran‐3(2H)‐ones respectively while the reaction of 2‐[(dimethylamino)methylene]‐1‐benzofuran‐3(2H)‐ones with 1‐methyl‐5‐aminopyrazoles led to formation of 2‐[(5‐amino‐1‐methyl‐1H‐pyrazol‐4‐yl)methylene]‐1‐benzofuran‐3(2H)‐ones and 1‐methyl‐1H‐[1]benzofuro[3,2‐b]pyrazolo[4,3‐e]pyridines as minor products.

Synthesis of pyrazole based novel aurone analogs and their cytotoxic activity against MCF-7 cell line

Abstract A series of pyrazole based aurone analogs 3(a-n) have been synthesized and evaluated for their cytotoxic activity against MCF-7 cell line. All the products have been obtained by solid phase reaction and organic solvent free simple work-up procedure. Structures of the synthesized aurones were confirmed by their IR, 1H NMR, 13C NMR, elemental analysis and mass spectrometry data. The cytotoxic activity of these compounds was assessed by MTT assay and the nine products were found to be potential inhibitors against human breast adenocarcinoma cell line i.e. MCF-7. Aurone analogs 3a, 3b, 3c, 3e, 3i and 3n are the most active against the MCF-7 cell line with IC50 of 13.8, 15.8, 4.3, 2.7, 12.9 and 15.5 μg/mL respectively, as compared to paclitaxel, with an IC50 value of 18.5 μg/mL. Cytotoxicity against MCF-7 cancer cells, makes these molecules attractive candidates for the potential anticancer drug.

Identification of Anti-tuberculosis Compounds From Aurone Analogs.

The emergence of multidrug-resistant Mycobacterium tuberculosis (Mtb) strains has made tuberculosis (TB) control more difficult. Aurone derivatives have demonstrated promising anti-bacterial activities, but their effects against Mtb have not been thoroughly determined. In this study, we aimed to develop anti-TB compounds from aurone analogs. We used a fluorescent protein tdTomato labeled Mtb CDC1551 strain to screen 146 synthesized aurone derivatives for effective anti-TB compounds. The 9504, 9505, 9501, 9510, AA2A, and AA8 aurones inhibited the growth of Mtb with minimal inhibitory concentrations of 6.25, 12.5, 25, 25, 25, and 50 μM, respectively. We also examined cytotoxicities of the six leads against the human liver cell line HepG2, the primate kidney cell line Vero and human monocyte THP-1 derived macrophages. Three of the aurone leads (9504, 9501, and 9510) showed low cytotoxic effects on all three cell lines and high Mtb inhibitory efficacy (selectivity index > 10). Aurone 9504, 9501, AA2A, or AA8 significantly reduced the Mtb load in the lungs of infected mice after a 12-days treatment. We determined that the aurone leads inhibit Mtb chorismate synthase, an essential enzyme for aromatic acid synthesis. Our studies demonstrate the promise of synthetic aurones as novel anti-TB therapeutics.

3D-QSAR, docking and ADMET properties of aurone analogues as antimalarial agents

The development of multi-resistant strains of plasmodium parasite has become a global problem, therefore, the discovery of new antimalarial agents is the only available solution. In order to improve and propose new compounds with antimalarial activity, the three-dimensional quantitative structure-activity relationship (3D-QSAR) and molecular docking studies were carried on aurone analogues acting as Qo site inhibitors in cytochrome b. The 3D-QSAR model was established in this study based on the Comparative Molecular Field Analysis (CoMFA) and the Comparative Molecular Similarity Indices Analysis (CoMSIA). The good predictability was obtained using the CoMFA model (Q2 = 0.5; R2 = 0.97; Rpred2 = 0.72) and the best CoMSIA model (Q2 = 0.526; R2 = 0.915; Rpred2= ​0.765). The predictive capacity of the developed model was evaluated through external validation using a test set compound and an applicability domain technique. In this study, the Steric, electrostatic and hydrogen bond acceptor fields played a key role in antimalarial activity. The results of the molecular docking revealed theoretically the importance of the residues his183 and his82 in the active site of the heme bL, this result was validated by a new assessment method. Based on the previous results, we designed several new potent Cytochrome b inhibitors and their inhibitory activities were predicted by the best model. Furthermore, these new inhibitors were analyzed for their ADMET properties and drug likeness. These results would be of great help in leading optimization for new drug discovery that can solve the problem of multiple drug resistance.

Catalytic Asymmetric [3 + 2] Cycloaddition Reaction between Aurones and Isocyanoacetates: Access to Spiropyrrolines via Silver Catalysis.

The first enantioselective formal [3 + 2] cycloaddition of aurone analogues with isocyanoacetates was developed via chiral Ag-complex catalysis. A variety of optically enriched spiro-1-pyrrolines were obtained in excellent yields, diastero- and enantioselectivities (up to 99% yield, >20:1 dr, >99% ee). This synthetic approach represents an extremely simple, efficient, and atom-economical method for spiro-1-pyrrolines synthesis.

Transition-metal-free synthesis of polysubstituted pyrrole derivatives via cyclization of methyl isocyanoacetate with aurone analogues.

Presented herein is an unprecedented transition-metal-free cyclization of methyl isocyanoacetate with aurone analogues catalyzed by NaOH. Various 2,3,4-trisubstituted pyrroles were obtained in excellent yields (up to 99%). The high efficiency of this synthetic procedure, coupled with the operational simplicity and atom economy, makes it an attractive method for the synthesis of polysubstituted pyrroles.

Design, synthesis, molecular modeling and anticholinesterase activity of benzylidene-benzofuran-3-ones containing cyclic amine side chain.

A series of 2-benzylidene-benzofuran-3-ones were designed from the structures of Ebselen analogs and aurone derivatives and synthesized in good yields. The target compounds were prepared by the condensation reaction between appropriate benzofuranones with amino alkoxy aldehydes and evaluated as cholinesterase inhibitors by Ellman's method. The in vitro anti-acetylcholinesterase (AChE)/butyrylcholinesterase activities of the synthesized compounds revealed that 7e (IC50 = 0.045 μM) is the most active compound against AChE. Furthermore, the docking study confirmed the results obtained through in vitro experiments and predicted the possible binding conformation. The anticholinesterase activities of benzylidene-benzofurane-3-ones as aurone analogs revealed that the compounds bearing piperidinylethoxy residue showed better activities against AChE, introducing these compounds for further drug discovery developments. [Formula: see text].

Antifungal activity of substituted aurones

Novel antifungals are in high demand as there is a growing resistance to antifungals currently in use. In particular, opportunistic fungal infections caused by Candida spp. are on the rise with infections by this genus accounting for the most severe fungal infections following chemotherapy, implantation procedures, and in patients with HIV/AIDS. A series of simple aurone analogs were synthesized and screened for antifungal activity versus Candida spp. Several compounds displayed activity at 100μM, with two having IC50 values below 20μM for three species of Candida. One of the compounds tested here also exhibits anti-biofilm activity for mid-maturation growth.

N-heterocyclic carbene catalyzed annulation of enals to aurone analogs: synthesis of cyclopentene-fused spirobenzofuran-3-ones.

A nucleophilic heterocyclic carbene mediated homoenolate annulation of enals to aurone analogs leading to the efficient synthesis of cyclopentene-fused spirobenzofuran-3-ones is reported.

Antimicrobial and antioxidant evaluation of new quinolone based aurone analogs

A new series of aurones 3a–x has been synthesized by aldol condensation of N-(Un)substituted quinolone-3-carbaldehydes 1a–h and (Un)substituted benzofuran-3(2H)-ones 2a–c in the presence of 10mol% NaOH in ethanol using a microwave irradiation method. All the aurone derivatives were screened for in vitro antimicrobial activity against a representative panel of bacterial and fungal pathogens using a broth microdilution method. The majority of the synthesized compounds elicited more or equipotent inhibitory action against all the tested bacterial and fungal strains. In vitro antioxidant activity was evaluated by the Ferric Reducing Antioxidant Power (FRAP) method. Compounds 3k and 3u displayed the highest antioxidant potential.

B-ring modified aurones as promising allosteric inhibitors of hepatitis C virus RNA-dependent RNA polymerase

Following our recent report showing the potential of naturally occurring aurones (2-benzylidenebenzofuran-3(2H)-ones) as anti-hepatitis C virus (HCV) agents, efforts were continued in order to refine the structural requirements for the inhibitory effect on HCV RNA-dependent RNA polymerase (RdRp). In this study, we targeted the B-ring moiety of aurones with the aim to improve structural features associated with higher inhibition of the targeted polymerase. In vitro evaluation of the RdRp inhibitory activity of the 37 newly synthesized compounds pointed out that the replacement of the B-ring with an N-substituted indole moiety induced the highest inhibitory effect. Of these, compounds 31, 40 and 41 were found to be the most active (IC50 = 2.3–2.4 μM). Docking experiments performed with the most active compounds revealed that the allosteric thumb pocket I of RdRp is the binding pocket for aurone analogues.

Design, Synthesis and Biological Evaluation of the Novel Antitumor Agent Aurone Derivatives

Aurones belong to a class of heterocyclic flavonoids which contains a benzofuran element associated with a benzylidene linked in position 2. Aurones possess a wide range of pharmacological activities and biological activities, such as antitumor, antifungal, phytoalexin and so on. A novel series of 2-ayl-yl (5-methacrylate) aurone analogues were synthesized in six steps with the overall yield of 11%-13% and characterized by 1H NMR. Among the key intermediates and target compounds, 2-(2-furan-ylmethylene)-5-methacrylate-benzofuran-3(2H)-one (7a) and 2-(2-thienyl-ylmethylene)-5-methacrylate-benzofuran-3(2H)-one (7b) have never been reported before. Primary biological activities evaluation showed that 7a exhibited good inhibitory activities against K562 with an IC50 of 2.18 μM and against HepG2 with an IC50 of 3.95μM.

ChemInform Abstract: Synthesis and Biological Evaluation of a Novel Series of 2,2‐Bisaminomethylated Aurone Analogues as Antiinflammatory and Antimicrobial Agents.

AbstractThe 2,2‐bisaminomethylated aurone analogues (IV) are obtained for the first time.

The scope of thallium nitrate oxidative cyclization of chalcones; synthesis and evaluation of isoflavone and aurone analogs for their inhibitory activity against interleukin-5

The oxidative cyclization of 2′-hydroxy-6′-cyclohexylmethoxychalcones 5 using thallium (III) nitrate (TTN) in alcoholic solvents produced isoflavones 2 and (or) aurones 3 depending on the electronic nature of p-substituents on ring B. Chalcones with strong electron donating substituents (OH, OCH 3) were exclusively converted to isoflavones 2. Chalcone with weak electron donating substituents (CH 2CH 3) was transformed into isoflavone 2 and the aurone 3 in approximate ratio 1:1. Chalcones with hydrogen or electron withdrawing substituents (Cl, CHO, COOCH 3, and NO 2) formed aurones 3. Synthesized isoflavones 2 and aurones 3 were evaluated for their inhibitory activity against interleukin-5. Among them, 5-(cyclohexylmethoxy)-3-(3,4,5-trimethoxyphenyl)-4 H-chromen-4-one ( 2h, >100% inhibition at 50 μM, IC 50 = 6.1 μM) gave most potent activity. All the aurones 3 were inactive.

Synthesis and biological evaluation of a novel series of 2,2-bisaminomethylated aurone analogues as anti-inflammatory and antimicrobial agents

This is the first report on aurones as a new class of drugs with anti-inflammatory and antimicrobial agents. A series of 2,2-bisaminomethylated aurone analogues ( 4a– j) were synthesized by Mannich reaction from 1,3,5-trimethoxybenzene in three steps. The structures of the newly synthesized compounds were confirmed by IR, 1H NMR and mass spectral analysis. All the synthesized compounds were screened against the pro-inflammatory cytokines (TNF-α, IL-6) and antimicrobial (antibacterial and antifungal) activity. Compounds 4a, 4b, 4c, 4d, and 4e showed promising results against IL-6 at 10 μM concentration (74–100%). Compounds 4a, 4b and 4c were found to be active against TNF-α (76–100%) at 10 μM. Interestingly, all compounds have shown good antimicrobial activity. Compounds 4d, 4e and 4f showed excellent antimicrobial activity as compared with standard drugs.

Design, syntheses, and antitumor activity of novel chromone and aurone derivatives

A series of new chromone analogues bearing heterocyclic thioether moiety and aurone analogues bearing cyclic tertiary amine moiety were designed and synthesized under microwave irradiation. The synthetic protocol was found to present many advantages, such as higher yields, shorter reaction time (10–20 min), mild condition, and readily isolation of the products. The synthesized compounds were assayed for their antitumor activity against four kinds of human solid tumor cell lines including HCCLM-7, Hep-2, MDA-MB-435S, and SW-480. Two compounds, ( Z)-2-((4-benzyl-piperazin-1-yl)methylene)benzofuran-3(2 H)-one 5e and ( Z)-2-((4-(bis(4-fluorophenyl)methyl)piperazin-1-yl)methylene)benzofuran-3(2 H)-one 5f, were identified as the most promising candidates with the IC 50 values in the range of 4.1–13.1 μM. Further cell cycle studies revealed that compounds 5e and 5f arrest the cell cycle in G 0/G 1 phase and displayed apoptosis-inducing effect on Hep-2 cells.