Hydroxyl Substituents Research Articles

Synthesis, Structure-Activity Relationship and Antibacterial Activity of Some Simple (E)-Chalcones

In present work, 14 simple (E)-chalcones (1-14), synthesized via the Claisen-Schmidt condensation between arylmethyl ketone and aromatic aldehyde in the presence of either in NaOH or H3BO3, were tested for in vitro antibacterial activity against two Gram-positive (Staphylococcus aureus and Bacillus subtilis) and three Gram-negative (Escherichia coli, Enterobacter cloacae and Klebsiella pneumoniae) bacterial strains. Among them, (E)-3-(4-hydroxy-3-methoxyphenyl)-1-(3-nitrophenyl)prop-2-en-1-one (8) was found most efficient, while (E)-3-(4-(dimethylamino)phenyl)-1-phenylprop-2-en-1-one (4) and (E)-1-(2,4-dihydroxyphenyl)-3-(4-(dimethylamino)-phenyl)prop-2-en-1-one (14) were completely ineffective. The rest of the (E)-chalcones have displayed moderate to good antibacterial activity, particularly against Gram-positive bacteria, while E. coli was found resistant. From the structure-activity relationship (SAR) analysis, it is revealed that the presence of a strong electron-withdrawing group (NO2) in ring A and the presence of electron-donating group in ring B of (E)-chalcones could enhance the antibacterial activity. The presence of hydroxyl and/or alkoxyl substituents in both 3 and 4 positions of ring B proved beneficial.

Synthesis and Antibacterial Activity of Hydroxy and Chloro-Substituted Chalcone Derivatives

Chalcones are a class of natural products reported with a wide range of biological activities. Among them antibacterial is much promising and many potent chalcones have been emerged as useful antibacterial agents. In view of this, we synthesized 15 chalcones (3a-3o) containing both hydroxyl and chlorine substituents and studied them by using spectroscopic methods. The compounds were tested for antibacterial efficacy against Staphylococcus aureus, Bacillus subtilis, Escherichia coli, and Proteus vulgaris, among other harmful microorganisms. The compounds have moderate to high antibacterial activity, among them heteroaromatic ring containing compounds (3m, 3n, and 3o) elicited higher activity than the standard drug benzyl penicillin. The compound 3m having the pyridinyl compound displayed the maximum activity against Staphylococcus aureus, Bacillus subtilis, Escherichia coli, and Proteus vulgaris, with zone of inhibition (in mm) values of 27.52±0.16, 28.85±0.11, 22.05±0.16, and 23.18±0.17, respectively. The synthesized compounds could be used as lead molecules in the development of novel antibacterial medicines.

Molecular Docking Studies on Phenolic Constituents of Anethum graveolens L. Seed Extracts

Background: There are studies indicating that aqueous or hydroalcoholic dill extracts showed higher antioxidant activity compared to other fractions. Molecular docking studies would be relevant to get information on the mechanism of action of the phenolic constituents of Anethum graveolens seed extracts as bioactive compounds.
 Methodology: In order to perform the docking studies of antioxidant activity of phenolic constituents of Anethum graveolens seed extracts, BIOVIA Discovery Studio and AutoDock Vina software were used.
 Results: The orientation of flavonoids within Hck and CYP2C9 binding sites has been shown to be the main reason for their inhibitory potency.
 Conclusion: Molecular docking studies indicate that the compounds identified interact with the target enzymes Hck and CYP2C9 at molecular level through their condensed ring systems and hydroxyl substituents and therefore support the antioxidant capacity of the studied phenolic compounds.

Antibacterial and phytotoxic activity of the Schiff’s bases of 5-phenyl-4-amino-3-mercapto-4H-1,2,4-triazole with the donor substituents in the 4th position on heterosystem

Background. Triazoles and Schiff’s bases have a high biological activity. For the practical use of the derivatives, their low toxicity is important. The purpose of this work was to investigate the antibacterial and phytotoxic properties of Schiff’s bases of 5-phenyl-4-amino-3-mercapto-4H-1,2,4-triazole with donor substituents in the 4th position of heterosystem. Materials and methods. In the study of antibacterial activity of the derivatives, corrosion-active 4-day association cultures of ammonifying and sulfate-reducing bacteria were used as a test culture of microorganisms. Sensitivity of bacteria to derivatives was determined by diffusion method in agar using sterile paper disks according to the standard method. In the investigation of phytotoxic activity of the derivatives, Lepidium sativum of the “Ajour” cultivar was used as a test plant. Seed germination and biometric indices (length, weight of the aboveground part and roots) of 5-day sprouts were determined, the phytotoxic effect of the derivatives was calculated. Experimental data were processed using methods of mathematical statistics. Results. The introduction of substituents does not provide for an increase in antibacterial properties of the studied compounds in relation to some corrosion active ammonifying and sulfate-reducing bacteria. Low activity was observed regarding the association culture of ammonifying bacteria to the compound without substituents in the phenyl fragment and the compound with fluor as a substituent in the phenyl fragment at a concentration of 2.0%. Derivatives with the methoxyl substituent in the phenyl fragment and with the hydroxyl substituent in the phenyl fragment did not show any antibacterial activity against the association culture of ammonifying bacteria isolated from ferrosphere in meat-peptone broth. Antibacterial action against the association of sulfate-reducing bacteria Desulfovibrio orizae with organic acid-producing bacteria Anaerotignum propionicum for derivatives were not detected. Phytotoxic properties were observed for the compound with the hydroxyl substituent that influenced the processes of growth in the test plant. Conclusion. The introduction of electron-donor substituents into the basic structure did not provide for an increase in antibacterial properties against corrosive bacteria. Phytotoxic properties were observed for the compound with the hydroxyl substituent in the phenyl fragment, which influenced the L. sativum growth processes by inhibiting growth of the above-ground part and roots. Other compounds either did not show any action, or demonstrated a weak stimulating effect on the growth and development of the test plant.

Synthesis and Evaluation of Trypanocidal Activity of Chromane-Type Compounds and Acetophenones.

American trypanosomiasis (Chagas disease) caused by the Trypanosoma cruzi parasite, is a severe health problem in different regions of Latin America and is currently reported to be spreading to Europe, North America, Japan, and Australia, due to the migration of populations from South and Central America. At present, there is no vaccine available and chemotherapeutic options are reduced to nifurtimox and benznidazole. Therefore, the discovery of new molecules is urgently needed to initiate the drug development process. Some acetophenones and chalcones, as well as chromane-type substances, such as chromones and flavones, are natural products that have been studied as trypanocides, but the relationships between structure and activity are not yet fully understood. In this work, 26 compounds were synthesized to determine the effect of hydroxyl and isoprenyl substituents on trypanocide activity. One of the compounds showed interesting activity against a resistant strain of T. cruzi, with a half effective concentration of 18.3 µM ± 1.1 and an index of selectivity > 10.9.

Preparation of biosensor based on triarylmethane loaded cellulose acetate xerogel for the detection of urea

Urea released by kidney into blood and urine is a major reason for the gradual loss of kidney function. Therefore, it is of great importance to construct a real-time detection method for Urea. On the other side, a sponge-like microporous cellulose acetate (CA) xerogel has been introduced as a low-density biomaterial with various promising applications. In this study, a facile, portable, fast, and highly sensitive microporous CA biopolymer test dipstick, comprising triarylmethane (TAM) as a spectroscopic chromophore and urease (U) enzyme as a catalytic agent, is constructed for colorimetric detection of urea. Identification of urea occurs via proton transfer from the hydroxyl substituent of TAM to ammonia released in an aqueous environment from the hydrolysis of urea/urease reaction. Importantly, TAM probe was in-situ integrated within the generated sponge-like CA dipstick sensor assay (CA-U-TAM). This resulted in ratiometric changes of 131 nm red-shift in the absorption spectra, from 439 nm to 580 nm, as a function of the urea total content in the aqueous medium. Additionally, composition/morphology of the prepared CA-TAM dipstick was explored and revealed the presence of large surface area and high porous scaffolds with a pore size of ∼7.5 μm.

Sodium storage in triazine-based molecular organic electrodes: The importance of hydroxyl substituents

Rational design and synthesis of novel organic electrodes have captured growing attention for the development of sustainable sodium ion batteries (SIBs), but the battery performance has been significantly limited by poor reversible specific capacity and cycling ability. Here, we report a simple structural modulation approach for creating a new type of triazine compounds as anode materials displaying superior SIB performance. We find that trihydroxyphenyl functionalities conjugated with the triazine ring enhance electrochemical affinities for Na-ion trapping, thereby promoting reversible Na-ion insertion/deinsertion. The resultant trihydroxyl-modulated triazine-based anode exhibits an exceptional battery capacity, reaching as high as 650 mAh g−1 at a current density of 0.1 A g−1 and ranks at the top among all reported molecular SIB electrodes. The simple modulation approach not only enables us to achieve exceptional sodium storage but simultaneously provides a means to extends our understanding of structure–property relationship and facilitate new possibilities for organic SIBs.

A Novel Statin Compound from Monacolin J Produced Using CYP102A1-Catalyzed Regioselective C-Hydroxylation.

Statins inhibit the 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase (HMG-CoA reductase), which is the rate-limiting enzyme in cholesterol biosynthesis. Statin therapy reduces morbidity and mortality in those who are at high risk of cardiovascular disease. Monacolin J is a statin compound, which is an intermediate in the lovastatin biosynthesis pathway, in the fungus Aspergillus terreus. It is also found in red yeast rice, which is made by culturing rice with the yeast Monascus purpureus. Monacolin J has a hydroxyl substituent at position C’-8 of monacolin L. Here, a new statin derivative from monacolin J was made through the catalysis of CYP102A1 from Bacillus megaterium. A set of CYP102A1 mutants of monacolin J hydroxylation with high catalytic activity was screened. The major hydroxylated product was C-6′a-hydroxymethyl monacolin J, whose structure was confirmed using LC–MS and NMR analysis. The C-6′a-hydroxymethyl monacolin J has never been reported before. It showed a greater ability to inhibit HMG-CoA reductase than the monacolin J substrate itself. Human liver microsomes and human CYP3A4 also showed the ability to catalyze monacolin J in producing the same product of the CYP102A1-catalyzed reaction. This result motivates a new strategy for the development of a lead for the enzymatic and chemical processes to develop statin drug candidates.

Selectivity in the Formation of Straight-Chain Versus Cyclised products on Knoevenagel Condensation between Thiobarbituric acid and Naphthaldehydes

The prevalence of Clostridium difficile (CD) infection has grown rapidly due to resistance and the emergence of new, highly virulent strains of the organism that have become less sensitive to many antibiotics. Vancomycin and metronidazole are front-line treatments of CD infection that still show good efficacy, but their effectiveness has declined for the treatment of recurrent infection and less sensitive strains of CD. More recently, the macrolide antibiotic fidaxomicin been introduced in the treatment of CD infection. Its high cost and limited usefulness against recurrent infection has prompted the search for new, narrow spectrum agents. We identified the CD dihydroorotate dehydrogenase (DHODase) as a potential enzyme target for the design of Knoevenagel products formed from reaction of 2-thiobarbituric acid and naphthaldehyde substrates. The presence of a hydroxyl substituent at position C2 in the naphthaldehyde ring offers the possibility to form the Knoevenagel product and to cyclize to give the tetracyclic, oxadeazaflavine with benzo-homologation. In this work, the selectivity for straight-chain formation over competing cyclisation on Knoevenagel condensation between thiobarbituric acid and naphthaldehyde substrates was examined. The outcomes of uncatalyzed condensations in refluxing ethanol were investigated by various methods including high field 1H and 13C NMR. Unsubstituted naphthaldehyde and its 2-methoxyl derivative favored straight-chain product formation whereas use of 2-hydroxynaphthaldehyde favored cyclisation and concomitant Michael addition of a second molecule of the corresponding acid to the newly formed exocyclic C=C bond. The pattern of reactivity was mirrored in the benzaldehyde series where the presence of the 2-hydroxyl function led to cyclized products with concomitant formation of the Michael adducts. The Knoevenagel products and the benzo-homologated oxadeazaflavine derivatives are candidates for evaluation as potential growth inhibitors of CD.

Analog Kalkon (E)-1,3-bis(4-hydroxyphenyl)prop-2-en-1-one: Sintesis dan Uji Aktivitas Antimicrobia terhadap Bakteri Kontaminan Produk Darah

Bacterial infection remains a leading cause of death in the world. It caused by incorrect antimicrobial used in the hospital, bacterial resistance caused by prolonged use of antimicrobial, minimum controlling of antimicrobial utilization, and late development of new antimicrobial drugs. Chalcone compounds with particular structure are believed to have the capability as an antimicrobial agent. The objective of this study is to synthesize and examine the activity of chalcone analogue compound with two hydroxyl substituents groups in ring A and B as a characteristics. Chalcone analogue (E)-1,3-bis(4-hydroxyphenyl)prop-2-en-1-one was successfully synthesized by Claisen-Schmidt condensation method and produced a pale-yellow crystalline powder with 89.40% yield as reaction powder. The elucidation of reaction product structure using FTIR and GC-MS. Furthermore, the GC-MS test was obtained one-peak chromatogram with 100% of relative purity and m/z 240 as molecular ions detected according to the target compound of (E)-1,3-bis(4-hydroxyphenyl)-prop-2-en-1-one molecular weight. Antimicrobial activity examination was performed by paper disk diffusion method and the result showed that chalcone analog compound (E)-1,3-bis(4-hydroxyphenyl)prop-2-en-1-one has medium inhibition activity to Staphylococcus aureus as positive gram bacteria, with the clear zone diameter was 9,2 mm in the 25,00 ppm of concentration. This compound were indicated to work selectively into Staphylococcus aureus, because it was not actively inhibit the growth of another bacterial test such as Bacillus sp., Escherichia coli and Acinetobacter

Pyridine Scaffolds, Phenols and Derivatives of Azo Moiety: Current Therapeutic Perspectives

Synthetic heterocyclic compounds have incredible potential against different diseases; pyridines, phenolic compounds and the derivatives of azo moiety have shown excellent antimicrobial, antiviral, antidiabetic, anti-melanogenic, anti-ulcer, anticancer, anti-mycobacterial, anti-inflammatory, DNA binding and chemosensing activities. In the present review, the above-mentioned activities of the nitrogen-containing heterocyclic compounds (pyridines), hydroxyl (phenols) and azo derivatives are discussed with reference to the minimum inhibitory concentration and structure–activity relationship, which clearly indicate that the presence of nitrogen in the phenyl ring; in addition, the hydroxyl substituent and the incorporation of a diazo group is crucial for the improved efficacies of the compounds in probing different diseases. The comparison was made with the reported drugs and new synthetic derivatives that showed recent therapeutic perspectives made in the last five years.

1-Ethyluracil, a New Scaffold for Preparing Multicomponent Forms: Synthesis, Characterization, and Computational Studies

In this work, we describe the successful preparation of a series of cocrystals of the modified nucleobase 1-ethyluracil with different coformers in a 1:1 or 2:1 (nucleobase:coformer) ratio including urea (URE) or some compounds containing carboxylic and hydroxyl groups such as l-malic acid (MAL), l-tartaric acid (TAR), 2-hydroxybenzoic acid (SAL), 4-hydroxybenzoic acid (4HB), and 2,4-dihydroxybenzoic acid (DHB). The influence of the hydroxyl substituent on the alkyl chain for 1·TAR and 1·SAL cocrystals or the phenyl ring for 1·SAL, 1·4HB, and 1·DHB multicomponent solids was studied. All of the compounds were characterized by powder X-ray diffraction, FT-IR, and thermal methods. Moreover, for those whose single-crystal structures could be determined, computational studies were also performed to investigate the factors that may affect the cocrystal formation, the recurrent motifs, and the energies associated with the H-bonding interactions using DFT calculations and a combination of the quantum theory of atoms in molecules (QTAIM) and the noncovalent interaction index (NCIplot) computational tools.

Small Molecules of Natural Origin as Potential Anti-HIV Agents: A Computational Approach.

The human immunodeficiency virus type 1 (HIV-1), one of the leading causes of infectious death globally, generates severe damages to people’s immune systems and makes them susceptible to serious diseases. To date, there are no drugs that completely remove HIV from the body. This paper focuses on screening 224,205 natural compounds of ZINC15 NPs subset to identify those with bioactivity similar to non-nucleoside reverse transcriptase inhibitors (NNRTIs) as promising candidates to treat HIV-1. To reach the goal, an in silico approach involving 3D-similarity search, ADMETox, HIV protein-inhibitor prediction, docking, and MM-GBSA free-binding energies was trained. The FDA-approved HIV drugs, efavirenz, etravirine, rilpivirine, and doravirine, were used as queries. The prioritized compounds were subjected to ADMETox, docking, and MM-GBSA studies against HIV-1 reverse transcriptase (RT). Lys101, Tyr181, Tyr188, Trp229, and Tyr318 residues and free-binding energies have proved that ligands can stably bind to HIV-1 RT. Three natural products (ZINC37538901, ZINC38321654, and ZINC67912677) containing oxan and oxolan rings with hydroxyl substituents and one (ZINC2103242) having 3,6,7,8-tetrahydro-2H-pyrido[1,2-a]pyrazine-1,4-dione core exhibited comparable profiles to etravirine and doravirine, with ZINC2103242 being the most promising anti-HIV candidate in terms of drug metabolism and safety profile. These findings may open new avenues to guide the rational design of novel HIV-1 NNRTIs.

Pyrrolizidine alkaloids and unusual millingtojanine A-B from Jacobaea vulgaris (syn. Senecio jacobaea L.)

Four undescribed pyrrolizidine alkaloids (seneciojanine A-D), two enantiomeric pairs of unusual alkaloids (millingtojanine A-B) with a unique tricyclic core, and nine known pyrrolizidine alkaloids were isolated from whole plant extracts of Jacobaea vulgaris Gaertn. The structures of the undescribed compounds were established by extensive spectroscopic and spectrometric analyses and comparison of theoretical and experimental ECD data. Several of the structures were also confirmed by X-ray diffraction analysis. Seneciojanine A-D possess a rare natural necine moiety with an α,β-unsaturated carbonyl group located at C-3 and a hydroxyl substituent at C-8.

An effect of positional isomerism of benzoic acid derivatives on antibacterial activity against Escherichia coli.

This study demonstrated the effect of positional isomerism of benzoic acid derivatives against E. coli ATCC 700728 with the serotype O157. The addition of hydroxyl and methoxyl substituents weakened the effect of acids against E. coli with respect to benzoic acid (except 2-hydroxybenzoic). The connection of the hydroxyl group at the second carbon atom in the benzoic ring reduced the time needed to kill bacterial cells. Phenolic acids with methoxyl substitutes limited the biofilm formation by E. coli to a greater extent than hydroxyl derivatives. The most significant influence on the antibacterial activity of phenolic acids has the type of substituent attached to the benzoic ring, their number, and finally the number of carbon atoms at which the functional group is located.

New Paradigm in NKT Cell Antigens: MCS-0208 (2-(Hydroxymethyl)phenylthio-phytoceramide) - an Aryl-Phytoceramide Compound with a Single Hydroxyl Group Stimulates NKT Cells.

Natural Killer T (NKT) cells play an important role in the immune response and can be activated by glycolipids presented by CD1d protein. We present MCS‐0208, an unprecedented arylthioether‐phytoceramide able to induce potent invariant NKT (iNKT) cell activation, notably when tested in human iNKT cells. This arylsphingolipid analog has a simple phenyl group containing a single hydroxyl substituent as a surrogate of the sugar ring. The phenylthioether structure contrasts with α‐galactosylceramide (1), the prototypical glycolipid used to induce iNKT cell stimulation, where the galactose 2’‐OH and 3’‐OH substituents are accepted as the minimal footprint and considered critical for NKT T cell receptor (TCR) recognition. A computational study supports the recognition of aromatic compound by the CD1d and TCR proteins as radically new structures for NKT cell stimulation.

The Identification of New Triterpenoids in Eucalyptus globulus Wood.

Eight polyhydroxy triterpenoid acids, hederagenin, (4α)-23-hydroxybetulinic acid, maslinic acid, corosolic acid, arjunolic acid, asiatic acid, caulophyllogenin, and madecassic acid, with 2, 3, and 4 hydroxyl substituents, were identified and quantified in the dichloromethane extract of Eucalyptus globulus wood by comparing their GC-retention time and mass spectra with standards. Two other triterpenoid acids were tentatively identified by analyzing their mass spectra, as (2α)-2-hydroxybetulinic acid and (2α,4α)-2,23-dihydroxybetulinic acid, with 2 and 3 hydroxyl substituents. Two MS detectors were used, a quadrupole ion trap (QIT) and a quadrupole mass filter (QMF). The EI fragmentation pattern of the trimethylsilylated polyhydroxy structures of these triterpenoid acids is characterized by the sequential loss of the trimethylsilylated hydroxyl groups, most of them by the retro-Diels-Alder (rDA) opening of the C ring with a π-bond at C12-C13. The rDA C-ring opening produces ions at m/z 320 (or 318) and m/z 278 (or 277, 276, 366). Sequential losses of the hydroxyl groups produce ions with m/z from [M - 90] to [M - 90*y], where y is the number of hydroxyl substituents present (from 2 to 4). Moreover, specific cleavage in ring E was observed, passing from m/z 203 to m/z 133 and conducting other major fragments such as m/z 189.

Green synthesis of silver nanoparticles from Stachys byzantina K. Koch: characterization, antioxidant, antibacterial, and cytotoxic activity

In the present study, silver nanoparticles were synthesized by aqueous extract of Stachys byzantina K. Koch and characterized by various analytical methods. The formation of AgNPs was confirmed by UV–Visible spectroscopy at 441.75 nm. The XRD study affirmed the crystalline structure of AgNPs. The value of zeta potential was −43.9 mV that showed the stability of nanoparticles. The TEM images revealed well-distributed nanoparticles with spherical shapes and an average size of 17 nm. FT-IR spectra depicted the presence of different functional groups such as hydroxyl and carbonyl substituents of biomolecules. These groups acted as reducing and capping agents which led to the stability and dispersion of AgNPs. The quantitative phytochemical investigations revealed the presence of phenolic compounds and flavonoids in the aqueous extract and on the surface of AgNPs. Also, they indicated strong antioxidant activity (IC50=48.29 µg.ml−1) in the DPPH assay. The AgNPs had the best antibacterial effects against Escherichia coli and Pseudomonas aeruginosa (MIC = 12.5 µg.ml−1). The AgNPs showed remarkable cytotoxic activities against A431, B-CPAP, and HepG2 (IC50=8.16 ± 0.99, 11.39 ± 3.24, and 11.85 ± 0.33 µg.ml−1, respectively). Also, these three cell lines revealed the best selectivity index (≥3) which demonstrated that they are significantly more toxic to cancerous cell lines than the healthy one.

CF3SOCl-promoted intramolecular cyclization of β-diketones: An efficient synthesis of flavones

An efficient intramolecular cyclization reaction of β-diketones containing a phenyl group with an ortho-hydroxyl substituent was achieved. Using CF 3 SOCl as an additive, the reaction took place under transition-metal-free and mild conditions. A series of flavones were synthesized in moderate to excellent yields. An efficient intramolecular cyclization of β-diketones containing a phenyl group with an ortho -hydroxyl substituent was achieved in the presence of trifluoromethanesulfinyl chloride. A series of flavones were obtained in moderate to excellent yields under transition-metal-free and mild conditions.

Exploring the 2'-Hydroxy-Chalcone Framework for the Development of Dual Antioxidant and Soybean Lipoxygenase Inhibitory Agents.

2′-hydroxy-chalcones are naturally occurring compounds with a wide array of bioactivity. In an effort to delineate the structural features that favor antioxidant and lipoxygenase (LOX) inhibitory activity, the design, synthesis, and bioactivity profile of a series of 2′-hydroxy-chalcones bearing diverse substituents on rings A and B, are presented. Among all the synthesized derivatives, chalcone 4b, bearing two hydroxyl substituents on ring B, was found to possess the best combined activity (82.4% DPPH radical scavenging ability, 82.3% inhibition of lipid peroxidation, and satisfactory LOX inhibition value (IC50 = 70 μM). Chalcone 3c, possessing a methoxymethylene substituent on ring A, and three methoxy groups on ring B, exhibited the most promising LOX inhibitory activity (IC50 = 45 μM). A combination of in silico techniques were utilized in an effort to explore the crucial binding characteristics of the most active compound 3c and its analogue 3b, to LOX. A common H-bond interaction pattern, orienting the hydroxyl and carbonyl groups of the aromatic ring A towards Asp768 and Asn128, respectively, was observed. Regarding the analogue 3c, the bulky (-OMOM) group does not seem to participate in a direct binding, but it induces an orientation capable to form H-bonds between the methoxy groups of the aromatic ring B with Trp130 and Gly247.