Traveling across Life Sciences with Acetophenone-A Simple Ketone That Has Special Multipurpose Missions.

Each metabolite, regardless of its molecular simplicity or complexity, has a mission or function in the organism biosynthesizing it. In this review, the biological, allelochemical, and chemical properties of acetophenone, as a metabolite involved in multiple interactions with various (mi-cro)organisms, are discussed. Further, the details of its biogenesis and chemical synthesis are provided, and the possibility of its application in different areas of life sciences, i.e., the status quo of acetophenone and its simple substituted analogs, is examined. In particular, natural and synthetic simple acetophenone derivatives are analyzed as promising agrochemicals and useful scaffolds for drug research and development.

Natural Benzo/Acetophenones as Leads for New Synthetic Acetophenone Hybrids Containing a 1,2,3-Triazole Ring as Potential Antifouling Agents.

Marine biofouling is a natural process that represents major economic, environmental, and health concerns. Some booster biocides have been used in biofouling control, however, they were found to accumulate in environmental compartments, showing negative effects on marine organisms. Therefore, it is urgent to develop new eco-friendly alternatives. Phenyl ketones, such as benzophenones and acetophenones, have been described as modulators of several biological activities, including antifouling activity (AF). In this work, acetophenones were combined with other chemical substrates through a 1,2,3-triazole ring, a strategy commonly used in Medicinal Chemistry. In our approach, a library of 14 new acetophenone-triazole hybrids was obtained through the copper(I)-catalyzed alkyne-azide cycloaddition "click" reaction. All of the synthesized compounds were evaluated against the settlement of a representative macrofouling species, Mytilus galloprovincialis, as well as on biofilm-forming marine microorganisms, including bacteria and fungi. The growth of the microalgae Navicula sp. was also evaluated after exposure to the most promising compounds. While compounds 6a, 7a, and 9a caused significant inhibition of the settlement of mussel larvae, compounds 3b, 4b, and 7b were able to inhibit Roseobacter litoralis bacterial biofilm growth. Interestingly, acetophenone 7a displayed activity against both mussel larvae and the microalgae Navicula sp., suggesting a complementary action of this compound against macro- and microfouling species. The most potent compounds (6a, 7a, and 9a) also showed to be less toxic to the non-target species Artemia salina than the biocide Econea®. Regarding both AF potency and ecotoxicity activity evaluation, acetophenones 7a and 9a were put forward in this work as promising eco-friendly AF agents.

New Acetophenones and Chromenes from the Leaves of Melicope barbigera A. Gray.

The dichloromethane extract from leaves of Melicope barbigera (Rutaceae), endemic to the Hawaiian island of Kaua'i, yielded four new and three previously known acetophenones and 2H-chromenes, all found for the first time in M. barbigera. The structures of the new compounds obtained from the dichloromethane extract after purification by chromatographic methods were unambiguously elucidated by spectroscopic analyses including 1D/2D NMR spectroscopy and HRESIMS. The absolute configuration was determined by modified Mosher's method. Compounds 2, 4 and the mixture of 6 and 7 exhibited moderate cytotoxic activities against the human ovarian cancer cell line A2780 with IC50 values of 30.0 and 75.7 µM for 2 and 4, respectively, in a nuclear shrinkage cytotoxicity assay.

Anticancer, antimicrobial activities of quinoline based hydrazone analogues: Synthesis, characterization and molecular docking.

Based on the biologically active heterocycle quinoline, a series (18a-p) of quinoline hydrazone analogues were prepared, starting from 6-bromo/6-chloro-2-methyl-quinolin-4-yl-hydrazines. For all the newly synthesized compounds cytotoxic activities were carried out at the National Cancer Institute (NCI), USA, against full NCI 60 human cancer cell lines. Amongst all the tested compounds, nine compounds (18b, 18d, 18e, 18f, 18g, 18h, 18i, 18j, 18l) exhibited important anti-proliferative activity at 10 µM concentration and were further screened at 10-fold dilutions of five different concentrations (0.01, 0.1, 1, 10 and 100 µM) with GI50 values ranging from 0.33 to 4.87 µM and LC50 values ranging from 4.67 µM to >100j µM. Further, the mean values of GI50, TGI and LC50 of the most potent compound 18j were compared with the clinically used anticancer agents bendamustine and chlorambucil, revealed that the quinolyl hydrazones holds promise as a potential anticancer agents. Further all the newly prepared compounds were screened for their antimicrobial activity. All the quinolyl hydrazones displayed good to excellent antimicrobial activity with MIC values ranging from 6.25 to 100 µg/mL against the tested pathogenic strains. Molecular docking of the synthesized compounds into the active binding site of human DNA topoisomerase I (htopoI) was carried out to predict the binding mode to the DNA topoisomerase I inhibitors. Hopefully in future, compounds based on quinoline core could be used as a lead compounds for designing new anticancer agents.

Key sites insight on the stereoselectivity of four mined aldo-keto reductases toward α-keto esters and halogen-substituted acetophenones.

Biocatalytic reduction catalyzed by aldo-keto reductases (AKRs) is a valuable approach for asymmetric synthesis of chiral alcohols. In this study, four novel aldo-keto reductases with significant activity and stereoselectivity toward a variety of α-keto esters and halogen-substituted acetophenones were identified by genome mining. Through analysis of the crystal structure and multiple-sequence alignment of the starting AKR YvgN from Bacillus subtilis, residues F25 and W113 were proposed as the key positions that might control the stereoselectivity of YvgN. F25S and F25S/W113F variants of YvgN were able to improve its activity and stereoselectivity toward some α-keto ester compounds and halogen-substituted acetophenone derivatives. In addition, similar enhancement of catalytic activity and stereoselectivity was also found in the other three AKRs with corresponding mutations of starting YvgN.

Green asymmetric reduction of acetophenone derivatives: Saccharomyces cerevisiae and aqueous natural deep eutectic solvent.

OBJECTIVE: Chiral building blocks [(S)-1-(3-methylphenyl)ethanol, (S)-1-(3,4-dimethylphenyl)ethanol and (S)-1-(2,4,6-trimethylphenyl)ethanol] for drug synthesis were prepared using two green approaches: (1) the yeast Saccharomyces cerevisiae as the biocatalyst and (2) the natural deep eutectic solvents (NADES) as the alternative solvents. Three different NADES with different water contents were prepared and screened for the highest conversion and enantiomeric excess of reduction of 1-(3-methylphenyl)ethanone, 1-(3,4-dimethylphenyl)ethanone (DMPA) and 1-(2,4,6-trimethyphenyl)ethanone by S. cerevisiae. The results were used in the development of eco-friendly procedures on a preparative scale. RESULTS: The highest enantioselectivity of baker´s yeast was for the bioconversion of DMPA in choline chloride:glycerol with 30% (v/v) of water (ChGly30). This reaction was used for further studies. Parameters such as pre-treatment of biocatalysts and recyclation of solvent were tested for a possible scale-up of this reaction system. Conversion was improved with the ultrasound pre-treatment of the biocatalysts in ChGly30. Moreover, the biocatalytic asymmetric reduction of DMPA in ChGly30 was successfully performed on a preparative scale with the efficient recyclation of NADES in two cycles, in which the reduction of DMPA was also successfully performed. CONCLUSION: Three enantioselective reductions in NADES with baker's yeast were successfully conducted. According to the highest enantioselectivity of the biocatalyst, the asymmetric reduction of 1-(3,4-dimethylphenyl)ethanone in ChGly30 was also performed on a preparative scale with efficient recyclation and reuse of NADES as a first step towards the implementation of this method on the industrial scale.

UHPLC-MS Metabolome Fingerprinting: The Isolation of Main Compounds and Antioxidant Activity of the Andean Species Tetraglochin ameghinoi (Speg.) Speg.

The seriated extracts of petroleum ether (PE-E), dichloromethane (DCM-E) and methanol extracts (MeOH-E) from the aerial parts of the native South American plant Tetraglochin ameghinoi (Rosaceae), were evaluated regarding their antioxidant and antibacterial activities. The antioxidant properties were evaluated by free radical scavenging methods (DPPH and TEAC), ferric-reducing antioxidant power (FRAP) and lipoperoxidation in erythrocytes (LP), while the antibacterial activity was performed against Gram-positive and Gram-negative bacteria according to the Clinical and Laboratory Standards Institute (CLSI) guidelines. The chemical and biological analyses of this plant are very important since this bush is currently used in traditional medicine as a cholagogue and digestive. The polar MeOH-E showed the highest antioxidant activities (17.70 µg/mL in the DPPH assay, 381.43 ± 22.38 mM TE/g extract in the FRAP assay, 387.76 ± 91.93 mg TE/g extract in the TEAC assay and 93.23 + 6.77% in the LP assay) and it was selected for chromatographic isolation of its components. These components were found to be four acetophenones, including the new phloracetophenone glucoside: 4',6',-dihydroxy-2'-O-(6″-acetyl)-ß-d-glucopyranosylacetophenone or IUPAC name: (6-(2-acetyl-3,5-dihydroxyphenoxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-yl)methyl acetate, whose structure was elucidated by NMR and MS methods. In addition, twenty-six compounds, including five of these acetophenone derivatives, two sugars, six flavonoids, eleven phenolic acids and two triterpenes, were identified based on UHPLC-OT-MS and PDA analysis on the MeOH-E. The results support the medicinal use of the plant.

New carbazole linked 1,2,3-triazoles as highly potent non-sugar α-glucosidase inhibitors.

In the present study, a series of new carbazole linked 1H-1,2,3-triazoles (2-27) were synthesized via click reaction of N-propargyl-9H-carbazole (1) and azides of appropriate acetophenones and heterocycles. Synthesized carbazole triazoles including 7, 9, 10, 19, 20, and 23-26 (IC50=0.8±0.01-100.8±3.6µM), exhibited several folds more potent α-glucosidase inhibitory in vitro activity as compared to standard drug, acarbose. Compounds 2-5, 7-13, and 17-27 did not show any cytotoxicity against 3T3 cell lines, except triazoles 6, and 14-16. Among the series, carbazole triazoles 23 (IC50=1.0±0.057µM) and 25 (IC50=0.8±0.01µM) were found to be most active, and could serve as an attractive building block in the search of new non-sugar derivatives as anti-diabetic agents.

A New Approach to Synthesize of 4-Phenacylideneflavene Derivatives and to Evaluate Their Cytotoxic Effects on HepG2 Cell Line.

In this study, a convenient approach and green procedure for the synthesis of 4-phenacylideneflavenes has been developed from the reaction between 2,4-dihydroxybenzaldehyde and substituted acetophenones using boric acid as a catalyst in polyethylene glycol 400. Seven 4-phenacylideneflavenes were synthetized and their structures were confirmed by NMR and mass spectral analyses. Meanwhile, their possible mechanism of formation was also discussed. These products were found to have potential cytotoxic effect on HepG2 cell line with IC50 values from 12.5 to 50 µM.

Synthesis of 4-(2-substituted hydrazinyl)benzenesulfonamides and their carbonic anhydrase inhibitory effects.

In this study, 4-(2-substituted hydrazinyl)benzenesulfonamides were synthesized by microwave irradiation and their chemical structures were confirmed by (1)H NMR, (13)CNMR, and HRMS. Ketones used were: Acetophenone (S1), 4-methylacetophenone (S2), 4-chloroacetophenone (S3), 4-fluoroacetophenone (S4), 4-bromoacetophenone (S5), 4-methoxyacetophenone (S6), 4-nitroacetophenone (S7), 2-acetylthiophene (S8), 2-acetylfuran (S9), 1-indanone (S10), 2-indanone (S11). The compounds S9, S10 and S11 were reported for the first time, while S1-S8 was synthesized by different method than literature reported using microwave irradiation method instead of conventional heating in this study. The inhibitory effects of 4-(2-substituted hydrazinyl)benzenesulfonamide derivatives (S1-S11) against hCA I and II were studied. Cytosolic hCA I and II isoenzymes were potently inhibited by new synthesized sulphonamide derivatives with Kis in the range of 1.79 ± 0.22-2.73 ± 0.08 nM against hCA I and in the range of 1.72 ± 0.58-11.64 ± 5.21 nM against hCA II, respectively.

[Chemical constituents of ethnic medicine Cynanchum otophyllum].

In order to isolate and purify the reference compounds and improve the quality standard of ethnic medicine of Radix of Cynanchum otophyllum, the ethanol extracts were isolated by column chromatography onsilica gel, C18 reverse-phase silica gel, and semi-preparative HPLC. Twelve compounds were isolated and their structures were elucidated as 2,4-dihydroxy-6-methoxyphenylethanone(1), 4,6-dihydroxy-2-methoxyphenylethanone(2), p-hydroxyacetophenone(3), baishouwubenzophenone(4), 2,4-dihydroxyacetophenone(5), 2,5-dihydroxyacetophenone(6), otophylloside A(7),otophylloside B(8), caudatin-3-O-ß-D-cymaropyranosyl-(1→4)-ß-D-digitoxopyranoside(9),caudatin-3-O-ß-D-glucopyranosyl-(1→4)-ß-D-oleandropyranosyl-(1→4)-ß-D-cymaropyranosyl-(1→4)-ß-D-digitoxopyranoside(10),qingyangshengenin-3-O-ß-D-oleandropyranosyl-(1→4)-ß-D-cymaropyranoside(11),caudatin-3-O-ß-D-oleandropyranosyl-(1→4)-ß-D-cymaropyranosyl-(1→4)-ß-D-cymaropyranoside(12) on the basis of spectral analysis. Compounds 1 and 2 were isolated from the genus Cynanchum for the first time, and compounds 3-4, 9-12 were obtained from this plant for the first time.These compounds are main active components of Radix of C.otophyllum and can be used as reference substances for the quality control of this ethnic medicine.

Natural-derived acetophenones: chemistry and pharmacological activities.

Acetophenones are naturally occurring phenolic compounds which have found in over 24 plant families and also fungi strains. They are exist in both free or glycosides form in nature. The biological activities of these compounds have been assayed and reported including cytotoxicity, antimicrobial, antimalarial, antioxidant and antityrosinase activities. Herein, we review the chemistry and biological activity of natural acetophenone derivatives that have been isolated and identified until January 2024. Taken together, it was reported 252 acetophenone derivatives in which the genera Melicope (69) and Acronychia (44) were the principal species as producers of acetophenones.

Acronyrones A-C, unusual prenylated acetophenones from Acronychia pedunculata.

Two novel prenylated acetophenones with new carbon skeletons, acronyrones A and B (1 and 2), and a new analogue, acronyrone C (3), together with two known compounds (4 and 5) were isolated from the leaves of Acronychia pedunculata. Their structures with absolute configurations were identified by interpretation of spectroscopic data, single crystal X-ray diffraction, and electronic circular dichroism (ECD) calculations. Compounds 1 and 2 represent the first example of prenylated acetophenones possessed a C7 (1) and a C6 (2) side chain, forming a 4-isobutylchroman-2-one unit and a 3-(2-methylpropylidene)benzofuran-2(3H)-one moiety with the acetophenone core, respectively. In addition, compound 4 exhibited significant dose-dependent transcriptional activation effect against retinoid X receptor-α (RXRα), and could be regarded as a new type of non-classical RXR ligand.

Recent Development in the Synthesis of Thiazoles.

BACKGROUND: Thiazole-containing compounds are widely found in natural products as well as synthetic sources. Many thiazole-based compounds possess a broad spectrum of bioactivities, and some of them are well-known drugs in the markets. The use of thiazole derivatives in other fields such as organic materials, cosmetics, and organic synthesis has also been widely reported. Due to a wide range of applicability, the synthesis of thiazole-containing compounds has attracted extensive interest from chemists, and many studies in the synthesis of thiazole skeleton have been reported recently. OBJECTIVE: This review article will discuss recent studies in the synthesis of thiazoles (from2012). Besides the well-established Hantzsch thiazole synthesis, a large number of novel methods have been developed for the synthesis of thiazole derivatives. In most cases, reaction mechanisms have also been described. CONCLUSION: The synthesis of thiazole derivatives has drawn great attention from chemists, and many studies in the synthesis of these heterocycles have been reported recently. The classical method, the Hantzsch thiazole synthesis has received great research interest from chemists. Moreover, many new methods have been established to synthesize thiazole-derived compounds. Unquestionably, more and more approaches to access thiazole skeleton will appear in the literature. The application of well-established thiazole synthesis methods to the synthesis of drugs, organic materials, and natural products will almost certainly be studied.

Ten Years of Glory in the α-Functionalizations of Acetophenones: Progress Through Kornblum Oxidation and C-H Functionalization.

This review article focuses on the α-functionalization of acetophenones involving Kornblum oxidation and C-H functionalizations. Although various other strategies, such as classical approaches, enamine approaches and umpolung strategy are also known for this functionalization, here we discuss mainly the Kornblum oxidation approach and C-H functionalization strategy as they have advantages over the others. In Kornblum oxidation, the reaction uses iodine and dimethylsulfoxide and proceeds through the formation of arylglyoxal as the key intermediate. In C-H functionalization, the reaction requires metal, or metal-free catalyst, and generates radical intermediate in most cases. α-Functionalization of acetophenones is very important because of their huge applications in the synthesis of various natural products and pharmaceuticals and, therefore, a number of research articles have been published in this area. However, no review articles are available so far. In this article, we present a succinct discussion of various important and novel reactions, along with their mechanisms, published since 2012 to date. We believe that this first review article in this field will give readers one-stop information on this topic and encourage further intriguing work in this area.

Diversity-Oriented Synthesis: Amino Acetophenones as Building Blocks for the Synthesis of Natural Product Analogs.

Diversity-Oriented Synthesis (DOS) represents a strategy to obtain molecule libraries with diverse structural features starting from one common compound in limited steps of synthesis. During the last two decades, DOS has become an unmissable strategy in organic synthesis and is fully integrated in various drug discovery processes. On the other hand, natural products with multiple relevant pharmacological properties have been extensively investigated as scaffolds for ligand-based drug design. In this article, we report the amino dimethoxyacetophenones that can be easily synthesized and scaled up from the commercially available 3,5-dimethoxyaniline as valuable starting blocks for the DOS of natural product analogs. More focus is placed on the synthesis of analogs of flavones, coumarins, azocanes, chalcones, and aurones, which are frequently studied as lead compounds in drug discovery.

Potential hypoglycemic effect of acetophenones from the root bark of Cynanchum wilfordii.

Three new acetophenones, named cynwilforones A-C (1-3), together with cynandione A (4) were isolated from the root bark of Cynanchum wilfordii (Maxim.) Hemsl. Their structures were deduced based on spectroscopic analysis and chemical methods. Compounds 1 and 4 exhibited potential hypoglycemic effects through inhibition of hepatic gluconeogenesis by down-regulating the expression of phosphoenolpyruvate carboxykinase and glucose-6-phosphatase. This is the first report that acetophenones from the root bark of C. wilfordii possesses potential hypoglycemic activity in vitro.

Acetophenone derivatives from the roots of Melicope ptelefolia.

Five new prenylated acetophenones, melicoptelins A-E (1-5), along with one known congener (6) were isolated from the roots of Melicope ptelefolia. Among them, compounds 2a/2b, 3a/3b, and 4a/4b were obtained as inseparable interconverting mixtures of keto and enol tautomers. Their structures were elucidated on the basis of extensive spectroscopic methods, including 1D, 2D NMR and HRESIMS. Compouds 2a/2b, 4a/4b and 5 exhibit protein tyrosine phosphatase 1B (PTP1B) inhibitory activity with IC50 values of 34.4, 55.2 and 66.6 µM, respectively.

An Environmentally-Benign Synthesis of Spiro-benzo[1,4]diazepines Using Multi Phase Nano-titania as a Highly Efficient Catalyst via MAOS Technique.

AIM AND OBJECTIVE: Benzodiazepines and indole fused heterocycles are pharmacologically significant scaffolds. Trivial work on indole fused benzodiazepine compounds is reported in the literature. Hence, it is imperative to explore the synthesis of indole-fused benzodiazepines that may act as a template for biological studies in the future. Hence, in the present work, the synthesis of indole fused benzodiazepine derivatives was undertaken using multi-phase nano-titania as catalyst under microwave irradiation. MATERIALS AND METHODS: MAOS technique was used to carry out the synthesis of spiro-benzo [1,4]diazepine derivatives in the presence of multiphase nano-titania as a catalyst. Nano-titania was prepared by sol-gel method and characterized by XRD, FT-IR, FESEM, EDS and thermogravimetric techniques. The synthesized spiro-benzo [1,4] diazepine derivatives were identified by physical and spectral methods. RESULTS: Synthesized compounds were obtained in excellent yields in a short span of time. The synthesis was also carried out in the presence of conventional catalysts in addition to nano-titania. Among all the catalysts, the best result was obtained with nano-titania. The amount of nano-titania was optimized to be 0.05g giving 93- 95% yield of products. The study of reusability of nano-titania revealed that it could be reused up to four times with a negligible change in efficiency. CONCLUSION: The paper reports an efficient, cost-effective and environmentally benign approach for the synthesis of spiro-benzo [1,4] diazepine derivatives in the presence of multiphase nano-titania catalyst under microwave irradiation.

Spectroscopic and theoretical studies of some 2­(methoxy)­2­[(4­substituted)­phenylsulfanyl]­(4'­substituted) acetophenones.

The conformational analysis of some 2­(methoxy)­2­[(4­substituted)­phenylsulfanyl]­(4'­substituted) acetophenones was performed through infrared (IR) spectroscopic analysis of the carbonyl stretching band (νCO), supported by B3LYP/6-31+G(d,p) calculations and X-ray diffraction. Five (1-5) of the seven studied compounds (1-7) presented Fermi resonance (FR) on the νCO fundamental transition band. Deuteration of these compounds (1a-5a) precluded the occurrence of FR, revealing a νCO doublet for all compounds in all solvents used. The computational results indicated the existence of three conformers (c1, c2 and c3) for the whole series whose relative abundances varied with solvent permittivity. The higher νCO frequency c1 conformer was assigned to the higher frequency component of the carbonyl doublet, while both c2 and c3 were assigned to the lower frequency one. Anharmonic vibrational frequencies and Potential Energy Distribution (PED) calculations of compound 3 indicated that the combination band (cb) between the methyne δCH and one skeletal mode couples with the νCO mode giving rise to the FR on the c2 conformer in vacuum and on the c1 one in non-polar solvents. The experimental data indicated a progressive increase in c1 conformer stability with the increase of the solvent dielectric constant, which is in good agreement with the polarizable continuum model (PCM) calculations. The higher νCO frequency and the stronger solvation of the c1 conformer is a consequence of the repulsive field effect (RFE) originated by the alignment and closeness of the Cδ+Oδ- and Cδ+Oδ- dipoles. Finally, the balance between orbital and electrostatic interactions dictates the conformational preferences. X-ray single crystal analysis for compound 6 revealed the c1 geometry in the solid state and its stabilization by CH…O hydrogen bonds.