Ring Substituents Research Articles

Synthesis, Antimicrobial Evaluation, Molecular Docking, and ADME Studies of Some Novel 3‐Hydroxypyridine‐4‐one Derivatives

AbstractA new class of 3‐hydroxypyridine‐4‐one derivatives was synthesized and screened against several Gram‐positive and Gram‐negative bacteria, as well as two species of fungi. Among these synthesized compounds, the substituted derivatives with ortho‐ and para‐nitro and para‐methoxy groups showed the highest antibacterial activities against S. aureus and E. coli species with MIC value of 32 μg/mL, which were more potent compared to ampicillin as a reference drug. Furthermore, the substituted derivatives with ortho‐methoxy, ortho‐, para‐chloride, ortho‐, and para‐hydroxy groups exhibited MIC values of 64 μg/mL against S. aureus and E. coli species. In addition, the synthesized compounds were evaluated for their antifungal activities against C. albicans and A. niger strains. The best antifungal activity was observed for compounds with ortho‐methoxy, ortho‐hydroxy, and para‐methyl substitutions against A. niger species with MIC values of 64 μg/mL. The analysis of the antimicrobial results revealed that the type and position of the phenyl ring substituents greatly influence the antimicrobial activities of the synthesized compounds. Subsequently, molecular docking studies on E. coli species were performed to predict the interaction mode of these compounds in the active site of the receptor. Also, in silico ADME profile outputs showed that the compounds comply with the rule of five.

Potent MOR Agonists from 2′-Hydroxy-5,9-dimethyl-N-phenethyl Substituted-6,7-benzomorphans and from C8-Hydroxy, Methylene and Methyl Derivatives of N-Phenethylnormetazocine

(−)-5,9-Dimethyl-6,7-benzomorphan (normetazocine) derivatives with a para-OH or ortho-F substituent in the aromatic ring of the N-phenethyl moiety were synthesized and found to have subnanomolar potency at MOR, and both were fully efficacious in vitro. These new compounds, (1R,5R,9R)-6,11-dimethyl-3-(2-fluorophenethyl)-1,2,3,4,5,6-hexahydro-2,6-methanobenzo[d]azocin-8-ol and (1R,5R,9R)-6,11-dimethyl-3-(4-hydroxyphenethyl)-1,2,3,4,5,6-hexahydro-2,6-methanobenzo[d]azocin-8-ol, were more potent than the unsubstituted compound N-phenethylnormetazocine and about 30 or 40 times more potent than morphine, respectively. A variety of substituents in the ortho, meta, or para position in the aromatic ring of the N-phenethyl moiety were synthesized, 25 of these compounds, and found to have varying effects on potency and efficacy as determined by the forskolin-induced cAMP accumulation assay. The N-phenethyl moiety was also modified by increasing chain length to form a N-phenylpropyl side chain with and without a para-nitro moiety, and by an N-cinnamyl side chain. Also, an indole ethylamine normetazocine was synthesized to replace the N-phenethylamine side chain in normetazocine. The phenylpropylamine, propenylamine (cinnamyl) and the para-nitropropylamine had little or no MOR potency. The indole-ethylamine on the normetazocine nucleus, however, had moderate potency (MOR EC50 = 12 nM), and was fully efficacious (%Emax = 102%) in the cAMP assay. Retention of the N-phenethyl moiety and the addition of alkyl and alkenyl moieties on C8 in (−)-N-phenethylnormetazocine gave a C8-methylene derivative that had subnanomolar potency at MOR and a C8-methyl analog that had nanomolar potency. Five C8-substituted compounds were synthesized.

Synthesis, molecular docking, analgesic, anti-inflammatory, and ulcerogenic evaluation of thiophene-pyrazole candidates as COX, 5-LOX, and TNF-α inhibitors.

The thiophene bearing pyrazole derivatives (7a-j) were synthesized and examined for their in vitro cyclooxygenase, 5-lipoxygenase, and tumour inducing factor-α inhibitory activities followed by the in vivo analgesic, anti-inflammatory, and ulcerogenic evaluations. The synthesized series (7a-j) were characterized using 1H NMR, 13C NMR, FT-IR, and mass spectral analysis. Initially, the compounds (7a-j) were evaluated for their in vitro cyclooxygenase, 5-lipoxygenase, and tumour inducing factor-α inhibitory activities and the compound (7f) with two phenyl substituents in the pyrazole ring and chloro substituent in the thiophene ring and the compound (7g) with two phenyl substituents in the pyrazole ring and bromo substituent in the thiophene ring were observed as potent compounds among the series. The compounds (7f and 7g) with effective in vitro potentials were further analyzed for analgesic, anti-inflammatory, and ulcerogenic evaluations. Also, to ascertain the binding affinities of compounds (7a-j), docking assessments were carried out and the ligand (7f) with the highest binding affinity was docked to know the interactions of the ligand with amino acids of target proteins.

Synthesis and biochemical evaluation of 17-N-beta-aminoalkyl-4,5α-epoxynormorphinans

Opiate alkaloids and their synthetic derivatives are still widely used in pain management, drug addiction, and abuse. To avoid serious side effects, compounds with properly designed pharmacological profiles at the opioid receptor subtypes are long needed. Here a series of 17-N-substituted derivatives of normorphine and noroxymorphone analogues with five- and six-membered ring substituents have been synthesized for structure–activity study. Some compounds showed nanomolar affinity to MOR, DOR and KOR in in vitro competition binding experiments with selective agonists [3H]DAMGO, [3H]Ile5,6-deltorphin II and [3H]HS665, respectively. Pharmacological characterization of the compounds in G-protein signaling was determined by [35S]GTPγS binding assays. The normorphine analogues showed higher affinity to KOR compared to MOR and DOR, while most of the noroxymorphone derivatives did not bind to KOR. The presence of 14-OH substituent resulted in a shift in the pharmacological profiles in the agonist > partial agonist > antagonist direction compared to the parent compounds. A molecular docking-based in silico method was also applied to estimate the pharmacological profile of the compounds. Docking energies and the patterns of the interacting receptor atoms, obtained with experimentally determined active and inactive states of MOR, were used to explain the observed pharmacological features of the compounds.

Effects of the aldehyde-derived ring substituent on the properties of two new bioinspired trimethoxybenzoylhydrazones: methyl vs nitro groups.

N-Acylhydrazones are a versatile class of organic compounds with a diversity of potential applications. In this study, two new structure-related 3,4,5-trimethoxybenzoyl-containing N-acylhydrazones were synthesized and fully characterized, both in solution and in the solid state. The compounds differ with respect to the carbonyl precursors, i.e., 3-substituted salicylaldehydes with either a methyl or a nitro group. Single crystals of both compounds were isolated from the respective mother liquors and, in both cases, XRD confirmed the obtention of the (E)-isomer, in an anti-conformation. Computational calculations (gas and water phases) were performed in order to confirm some of the structural and vibrational aspects of the compounds. An important intramolecular H bond involving the phenolic hydroxy group and the azomethine nitrogen was identified in the solid state and seems to be maintained in solution. Moreover, the presence of the electron-withdrawing nitro substituent makes this interaction stronger. However, the contact should probably not subsist for the nitro compound under physiological conditions since the presence of this substituent significantly affects the pKa of the phenol: an apparent value of 5.68 ± 0.02 was obtained. This also impacts the basicity of the azomethine nitrogen and, as a consequence, increases the hydrazone's susceptibility to hydrolysis. Nevertheless, both compounds are stable at physiological-like conditions, especially the methyl-derived one, which qualifies them for further toxicological and activity studies, such as those involving trivalent metal ions sequestering in the context of neurodegenerative diseases.

Structure-property relationships in alkoxy substituted benzoates from experimental and computational thermochemistry

The energetics of formation and the phase transitions for isomeric methyl and ethyl methoxy‑benzoates were studied. The vapour pressures of methyl 2‑methoxy-benzoate and methyl 4‑methoxy-benzoate were measured by transpiration method. The high-precision combustion calorimetry was used to derive the liquid-phase enthalpy of formation of methyl 2‑methoxy-benzoate. The new results and the data available in the literature were critically evaluated using the structure-property correlations. Reliable correlations were established between the vaporisation enthalpies and the normal boiling temperatures as well as with the Kovats indices. Moreover, the validity of vaporisation enthalpies of alkyl methoxy‑benzoates was proved using structure-property relationships within families of structurally similar molecules. Mutual validation of the experimental and theoretical gas phase enthalpies of formation was performed using high-level quantum-chemical methods. The enthalpic contributions to the enthalpy of formation in the gas phase, resulting from the nearest and non-nearest neighbour interactions of the substituents in the benzene ring, were developed and used to quantify the intra-molecular hydrogen bond strength in the ortho-substituted species.

Enantioselective Regulation of Short‐Chain Dehydrogenases via Key Sites in its Loop and Adjacent Regions for the Enantiodivergent Reduction of Difficult‐To‐Reduce Ketones

AbstractShort‐chain dehydrogenases (SDRs) are powerful catalysts for the asymmetric reduction of prochiral ketones in pharmaceutical products. Herein, through gene mining and evolutionary analysis, we obtained two major types of SDRs (SDR‐1 and SDR‐2) for the enantioselective complementary reduction of N‐Boc‐piperidone, which gives the corresponding product (R)‐ or (S)‐N‐Boc‐piperidol, an intermediate of the interleukin inhibitor and lymphoma treatment drug (imbruvica), respectively. By integrating multiple sequence alignment, site‐directed mutagenesis and computational modeling, we proposed a “loop regulation” mechanism for the enantioselective control of SDRs, through which residues in the loop region could potentially fine‐tune their enantioselectivity. Further, site‐directed mutagenesis assays showed that two key residues (L201 and F205 for SDR‐1, F92 and H93 for SDR‐2) in the loop and its adjacent region played critical roles in fine‐tuning the enantioselectivity of SDRs. Understanding this mechanism of SDR stereo preference in catalyzing asymmetric reduction, we further switched the enantioselectivity of the homologous enzymes. The obtained enzymes catalyzed the enantiodivergent synthesis of chiral heterocyclic alcohols with different ring sizes and substituents (25–99% conversion and 25–99% ee (R/S)), including piperidols, 4‐hydroxy azepanes, 3‐hydroxy azepanes and pyrrolidinols. These findings could potentially guide future attempts at protein engineering of stereoselective SDRs.

Hydration of Propargyl Esters Catalyzed by Gold(I) Complexes with Phosphoramidite Calix[4]pyrrole Cavitands as Ligands.

We report the synthesis and characterization of two diastereomeric phosphoramidite calix[4]pyrrole cavitands and their corresponding gold(I) complexes, 2in•Au(I)•Cl and 2out•Au(I)•Cl, featuring the metal center directed inward and outward with respect to their aromatic cavity. We studied the catalytic activity of the complexes in the hydration of a series of propargyl esters as the benchmarking reaction. All substrates were equipped with a six-membered ring substituent either lacking or including a polar group featuring different hydrogen bond acceptor (HBA) capabilities. We designed the substrates with the polar group to form 1:1 inclusion complexes of different stabilities with the catalysts. In the case of 2in•Au(I)•OTf, the 1:1 complex placed the alkynyl group of the bound substrate close to the metal center. We compared the obtained results with those of a model phosphoramidite gold(I) complex lacking a calix[4]pyrrole cavity. We found that for all catalysts, the presence of an increasingly polar HBA group in the substrate provoked a decrease in the hydration rate constants. We attributed this result to the competing coordination of the HBA group of the substrate for the Au(I) metal center of the catalysts.

Electron ionization fragmentation studies for a series of 4-methoxymethylene benzoate esters.

Product ion studies and stable isotope deuterium labeling experiments provide useful data for understanding the electron ionization (EI)-mass spectroscopy (MS) fragmentation of methoxymethylene substituted benzoate esters. The methoxymethylene ether is regioisomeric with the ethoxy group and represents the two possible ether substituents of a benzene ring of C2 H5 O. Structural confirmation of these synthetic precursor materials via gas chromatography (GC)-EI-MS revealed unexpected fragment ions. The synthesis and EI-MS evaluation of some homologs and deuterated derivatives allowed for the characterization of these unique ions and their fragmentation pathways. The relative effects of the position of the oxygen of the ether side chain are the subject of this investigation. The desired compounds were prepared from 4-chloromethylbenzoyl chloride by alkoxide displacement followed by transesterifications and the deuterated analogs were prepared similarly. The compounds were separated by capillary GC and their MS fragmentation evaluated in EI, MS/MS and chemical ionization experiments. The methoxymethylene-substituted benzoate esters yield major fragment ions from the loss of the alkyl group from the ether as well as alkoxy group loss from the ester or ether portion of the molecule. The loss of the alkyl group from the ether followed by loss of the ester alkoxy group as the corresponding alcohol yielded the unique cation at m/z 133 for all compounds. The identity of the major ions was confirmed by product ion and deuterium labeling studies and possible mechanisms of fragment ion formation are described. The aliphatic oxygen of the alkoxymethylene group plays a much more active role in the EI-MS fragment formation profile than the direct aromatic ring linked oxygen of the ethoxy group. Thus, yielding a greater variety of characteristic fragments. The m/z 133 ion is unique to this class of compounds and does not have an equivalent pathway for the regioisomeric ethoxy series.

Reactions of Alkyl β‐Nitroacrylates with Arenes in Triflic Acid: Synthesis of Oximes of Alkyl 2,3‐Diaryl‐3‐oxopropanoates

AbstractMethyl or ethyl 3‐nitropropenoates (β‐nitroacrylates) AlkO(O)C1−C2H=C3H−NO2 in reaction with arenes ArH in triflic acid CF3SO3H (TfOH) at room temperature in 1 h give rise to oximes of alkyl 2,3‐diaryl‐3‐oxopropanoates AlkO(O)C−CH(Ar)−C(Ar)=NOH in yields of 42–92 %. The obtained oximes bearing ortho‐methyl substituents in the aryl ring exist as atropoisomers in solutions. The study of protonated forms of β‐nitroacrylates by NMR and DFT calculations has revealed that the reactive electrophiles are species AlkO(HO+)C1−C2H=C3H−N+(O)(OH) protosolvated on the acceptor groups NO2 and CO2R. Plausible reaction mechanism is based on the primary interaction of aromatic nucleophiles with these electrophilic species onto their carbon C2.

Influencing ionic conductivity and mechanical properties of ionic liquid polymer electrolytes by designing the chemical monomer structure

ABSTRACTPolymeric single chloride-ion conductor networks based on acrylic imidazolium chloride ionic liquid monomers AACXImCYCl as reported previously are prepared. The chemical structure of the polymers is varied with respect to the acrylic substituents (alkyl spacer and alkyl substituent in the imidazolium ring). The networks are examined in detail with respect to the influence of the chemical structure on the resulting properties including thermal behavior, rheological behavior, swelling behavior, and ionic conductivity. The ionic conductivities increase (by two orders of magnitude from 10−6 to 10−4 S·cm−1 with increasing temperature), while the complex viscosities of the polymer networks decrease simultaneously. After swelling in water for 1 week the ionic conductivity reaches values of 10−2 S·cm−1. A clear influence of the spacer and the crosslinker content on the glass transition temperature was shown for the first time in these investigations. With increasing crosslinker content, the Tg values and the viscosities of the networks increase. With increasing spacer length, the Tg values decrease, but the viscosities increase with increasing temperature. The results reveal that the materials represent promising electrolytes for batteries, as proven by successful charging/discharging of a p(TEMPO-MA)/zinc battery over 350 cycles.

Activation of xanthine oxidase by 1,4-naphthoquinones: A novel potential research topic for diet management and risk assessment.

Oral intake of 1,4-naphthoquinones could be a potential risk factor for hyperuricemia and gout via activation of xanthine oxidase (XO). Herein, 1,4-naphthoquinones derived from food and food-borne pollutants were selected to investigate the structure and activity relationship (SAR) and the relative mechanism for activating XO in liver S9 fractions from humans (HLS9) and rats (RLS9). The SAR analysis showed that introduction of electron-donating substituents on the benzene ring or electron-withdrawing substituents on the quinone ring improved the XO-activating effect of 1,4-naphthoquinones. Different activation potential and kinetics behaviors were observed for activating XO by 1,4-naphthoquinones in HLS9/RLS9. Molecular docking simulation and density functional theory calculations showed a good correlation between -LogEC50 and docking free energy or HOMO-LUMO energy gap. The risk of exposure to the 1,4-naphthoquinones was evaluated and discussed. Our findings are helpful to guide diet management in clinic and avoid adverse events attributable to exposure to food-derived 1,4-naphthoquinones.

One-pot synthesis of perfluorinated benzenedithiols from perfluoroarenes and thioacetic acid

The direction of the reaction between substituted perfluorobenzenes and thioacetic acid depends on the location of the substituents in perfluoroaromatic ring. Hexafluorobenzene reacts at positions 1 and 4, perfluoro-m-xylene reacts at positions 4 and 6, while perfluoroindane reacts at positions 5 and 6 to give the corresponding dithiols with para-, meta- and ortho-location of the thiol groups, respectively. Domino-reaction of perfluoroindane-5-thiol and its acetyl thioester affords hexadecafluoro-2,12-dithia-pentacyclo[11.7.0.03,11.05,9.015,19]icosa-1(13),3,5(9),10,14,19-hexaene

Tuning material properties of covalent adaptable networks containing boronate‐TetraAzaADamantane bonds through systematic variation in electron density of ring substituents

AbstractAn outstanding challenge in modern society remains how to make crosslinked polymers (thermosets) more recyclable. A breakthrough solution to this challenge has been the introduction of dynamic covalent bonds in polymer networks, yielding covalent adaptable networks (CANs). Ongoing research is focused on finding new suitable dynamic covalent chemistries and on how to tune the material properties of CANs derived from these new chemistries. Here, we first compare two different dynamic boronic acid based covalent adaptable networks, namely, a conventional boronate‐diol and a novel boronate‐TetraAzaADamantane (TAAD) system. We show that incorporating boronate‐TAAD bonds in networks results in stiffer materials, as seen in a slower relaxation and higher shear and storage moduli. This offers access to more mechanically robust boronate‐based materials, compared to conventional boronate‐based gels. Next, we investigate the effect of molecular tuning via the electron density of meta‐positioned ring substituents on the macroscopic material properties for the boronate‐TAAD network. By comparing relaxation experiments on materials with different substituents, we show that the macroscopic network relaxation can be tuned through the Hammett parameter of the meta‐substituent and the activation energy of the boronate‐TAAD exchange. This enables subtle control over the (dynamic) material properties of these novel, robust boronate‐based networks.

Effect of Substituents on Molecular Reactivity during Lignin Oxidation by Chlorine Dioxide: A Density Functional Theory Study.

Lignin is a polymer with a complex structure. It is widely present in lignocellulosic biomass, and it has a variety of functional group substituents and linkage forms. Especially during the oxidation reaction, the positioning effect of the different substituents of the benzene ring leads to differences in lignin reactivity. The position of the benzene ring branched chain with respect to methoxy is important. The study of the effect of benzene substituents on the oxidation reaction's activity is still an unfinished task. In this study, density functional theory (DFT) and the m062x/6-311+g (d) basis set were used. Differences in the processes of phenolic oxygen intermediates formed by phenolic lignin structures (with different substituents) with chlorine dioxide during the chlorine dioxide reaction were investigated. Six phenolic lignin model species with different structures were selected. Bond energies, electrostatic potentials, atomic charges, Fukui functions and double descriptors of lignin model substances and reaction energy barriers are compared. The effects of benzene ring branched chains and methoxy on the mechanism of chlorine dioxide oxidation of lignin were revealed systematically. The results showed that the substituents with shorter branched chains and strong electron-absorbing ability were more stable. Lignin is not easily susceptible to the effects of chlorine dioxide. The substituents with longer branched chains have a significant effect on the flow of electron clouds. The results demonstrate that chlorine dioxide can affect the electron arrangement around the molecule, which directly affects the electrophilic activity of the molecule. The electron-absorbing effect of methoxy leads to a low dissociation energy of the phenolic hydroxyl group. Electrophilic reagents are more likely to attack this reaction site. In addition, the stabilizing effect of methoxy on the molecular structure of lignin was also found.

Synthesis of a BC-Dihydrodipyrrin Building Block of Bacteriochlorophyll a.

A strategy for the synthesis of bacteriochlorophyll a relies on joining AD and BC halves that contain the requisite stereochemical configurations of the target macrocycle. The BC half (1) is a dihydrodipyrrin bearing a dimethoxymethyl group at the 1-position, a β-ketoester at the 8-position, and (R)-2-methyl and (R)-3-ethyl substituents in the pyrroline ring. An established route to AD-dihydrodipyrrins (Pd-mediated coupling of a 2-halopyrrole with a chiral 4-pentynoic acid followed by Petasis methenylation, acidic hydrolysis, Paal-Knorr ring closure, and Riley oxidation) proved to be unviable for BC-dihydrodipyrrins given the presence of the β-ketoester unit. A route presented here entails Pd-mediated coupling of a 2-halopyrrole (2) with (3R,4R)-4-ethyl-1,1-dimethoxy-3-methylhex-5-yn-2-one (3), anti-Markovnikov hydration of the alkyne to give the 1,4-diketone, and Paal-Knorr ring closure. Compound 3 was prepared by Schreiber-modified Nicholas reaction beginning with (S)-4-isopropyl-3-propionyloxazolidin-2-one and the hexacarbonyldicobalt complex of (±) 3-methoxy-1-(trimethylsilyl)pentyne followed by transformation of the aldehyde derived therefrom to the 1,1-dimethoxymethylcarbonyl motif. The absolute stereochemical configuration of the Schreiber-Nicholas alkylation product was confirmed by single-crystal X-ray diffraction, whereas the BC half (1) by 1H NMR spectroscopy showed a J value of 2.9 Hz consistent with the trans-configuration. Taken together, the route provides a key chiral building block for the synthesis of photosynthetic tetrapyrroles and analogues.

Unveiling meta-Alkyloxy/-Silyloxy-Substituted N-Aryl PNP Ligands for Efficient Cr-Catalyzed Ethylene Tetramerization.

Novel N-aryl-functionalized PNP ligands (1-4) bearing m-alkyloxy/-silyloxy substituents were prepared and evaluated for chromium-catalyzed ethylene oligomerization using MMAO-3A as an activator. The selected Cr/PNP system under optimized condition exhibited high 1-octene-selective (up to 70 wt %) ethylene tetramerization at a remarkable rate (over 3000 kg gCr-1 h-1). More importantly, the undesirable polyethylene selectivity was restricted to a minimum level of ∼1-2 wt % for pre-catalysts derived with ligands 1 and 2. Employing chlorobenzene as a reaction medium yielded best productivity in conjunction to the total α-olefin (1-C6 + 1-C8) selectivity (∼88 wt %). N-aryl PNP ligands (3 and 4) incorporating m-silyloxy substituents in the phenyl ring exhibited relatively poorer tetramerization performance while yielding higher PE fraction as compared to their m-alkyloxy derivatives. A detailed molecular structure of the best-performing pre-catalyst 1-Cr was established by single-crystal X-ray diffraction analysis. The stability of 1/Cr-based catalyst system was investigated for a reaction time of up to 2 h under optimized condition.

Photoswitchable Bis(amidopyrroles): Modulating Anion Transport Activity Independent of Binding Affinity.

Toward photocontrol of anion transport across the bilayer membrane, stiff-stilbene, which has dimethyl substituents in the five-membered rings, is functionalized with amidopyrrole units. UV-vis and 1H NMR studies show high photostability and photoconversion yields. Where the photoaddressable (E)- and (Z)-isomers exhibit comparable binding affinities, as determined by 1H NMR titrations, fluorescence-based transport assays reveal significantly higher transport activity for the (Z)-isomers. Changing the binding affinity is thus not a necessity for modulating transport. Additionally, transport can be triggered in situ by light.

Structural characterisation and pH-dependent preference of pyrrole cross-link isoforms from reactions of oxoenal with cysteine and lysine side chains as model systems.

In this study, we subjected 5,5-diethoxy-4-oxopent-2-enal (DOPE), a model amino acids cross-linking reagent, to reactions with N-acetylcysteine (Ac-Cys) and Nα-acetyllysine (Ac-Lys), and identified three pyrrole cross-links. The compounds were isolated and their structures were rigorously determined by spectrometric and spectroscopic methods, including 2D NMR experiments. The use of 2D NMR spectroscopy was crucial to determine the position of the substituents in the pyrrole rings. The products were identified as 2,4-, 2,3-, and 2,5-substituted pyrroles. The data obtained from their structural characterisation can help similar studies on amino acids modifications induced by analogous bifunctional carbonyl compounds. Our results show that the study of pathways in which model electrophiles modify amino acids may be helpful for similar studies dealing with identification of structural changes in cysteine- and lysine-containing proteins associated with oxidative stress.

Fluorescent Properties of Cyanine Dyes As a Matter of the Environment.

In non-viscous aqueous solutions, the cyanine fluorescent dyes Cy3 and Cy5 have rather low fluorescence efficiency (the fluorescence quantum yields of Cy3 and Cy5 are 0.04 and 0.3, respectively [1, 2]) and short excited state lifetimes due to their structural features. In this work, we investigated the effect of solubility and rotational degrees of freedom on the fluorescence efficiency of Cy3 and Cy5 in several ways. We compared the fluorescence efficiencies of two cyanine dyes sCy3 and sCy5 with the introduction of a sulfonyl substituent in the aromatic ring as well as covalently bound to T10 oligonucleotides. The results show that because of the different lengths of the polymethine chains between the aromatic rings of the dyes, cis-trans-isomerization has a much greater effect on the Cy3 molecule than on the Cy5 molecule, while the effect of aggregation is also significant.