HYPERQUAD Program Research Articles

New naphthoquinone thiazole hybrids as carbonic anhydrase and cholinesterase inhibitors: Synthesis, crystal structure, molecular docking, and acid dissociation constant

In this study, N-[3-(3-amino-1,4-dioxo-1,4-dihydronaphthalen-2-yl)-4-R-thiazol-2(3H)-ylidene]-2,6-difluorobenzamide derivatives as new 1,4-naphthoquinone thiazole hybrids were synthesized by reacting of N-[(3-amino-1,4-dioxo-1,4-dihydronaphthalen-2-yl)carbamothioyl]-2,6-difluorobenzamide with various α-bromoketones in 76–92% yields. Their molecular structures were characterized by 1H NMR, 13C NMR, 19F NMR, FT-IR, and HRMS, and the stereochemistry of one of the hybrids was determined by single crystal x-ray diffraction study. These synthesized new compounds (3a–e) were found to be effective inhibitor molecules for cholinesterases (butyrylcholinesterase (BChE) and acetylcholinesterase (AChE)), and carbonic anhydrase I and II (hCA I and hCA II) enzymes. KI values were found to be in the range of 45.03–84.43 nM for BChE, 26.12–98.42 nM for AChE, 67.86–161.60 nM for hCA I, and 55.27–87.48 nM for hCA II. The acid dissociation constants (pKa) of 1,4-naphthoquinone thiazole hybrids were determined in 25% (v/v) DMSO:water (25.0 ± 0.1 °C, I = 0.1 M by NaCl). Three pKa values for each hybrid were calculated with the HYPERQUAD program from the data obtained as a result of potentiometric titrations. The results obtained from molecular docking studies indicate that the compounds in question favorably fit within the active sites of hCAs and ChEs. Additionally, the acceptability of these compounds, as determined by Lipinski's and Jorgensen's rules, was estimated using the ADME/T results. Based on these estimations, it can be concluded that the synthesized molecules have the potential to be developed as effective and safe inhibitors of hCAs and ChEs, thus making them suitable lead agents for glaucoma and Alzheimer's disease.

New bis- and tetrakis-1,2,3-triazole derivatives: Synthesis, DNA cleavage, molecular docking, antimicrobial, antioxidant activity and acid dissociation constants

In this study, a series of bis– and tetrakis–1,2,3–triazole derivatives were synthesized using copper-catalyzed azide-alkyne cycloaddition (CuAAC) click chemistry in 73–95% yield. The bis– and tetrakis–1,2,3–triazoles exhibited significant DNA cleavage activity while the tetrakis–1,2,3–triazole analog 6g completely degraded the plasmid DNA. Molecular docking simulations suggest that compound 6g acts as minor groove binder of DNA by binding through several noncovalent interactions with base pairs. All bis- and tetrakis–1,2,3-triazole derivatives were screened for antibacterial activity against E. coli, B. cereus, S. aureus, P. aeruginosa, E. hirae, L. pneumophila subsp. pneumophila strains and antifungal activity against microfungus C. albicans and C. tropicalis strains. Compound 4d exhibited the best antibacterial activity among bis–1,2,3–triazoles against E. coli and E. hirae, while 6c exhibited the best antibacterial activity among tetrakis–1,2,3–triazoles against E. hirae. Furthermore, the best antifungal activity against C. albicans and C. tropicalis was reported for the compound 5, while 6d displayed the best antifungal activity against C. tropicalis and C. albicans. Reasonable iron chelating activities and DPPH radical scavenging abilities were found for some of the compounds. Finally, the acid dissociation constants (pKa) of the bis–1,2,3–triazoles were also determined with the help of HYPERQUAD program using the data obtained from potentiometric titrations. The reported data here concludes that the bis- and tetrakis-1,2,3-triazoles are important cores that should be considered for further development of especially new anticancer agents acting through the DNA cleavage activity.

Synthesis, Biological Evaluation, Molecular Docking, and Acid Dissociation Constant of New Bis‐1,2,3‐triazole Compounds

AbstractIn this study, new bis‐1,2,3‐triazole derivatives, N,N′‐(1,3‐phenylene)bis(2‐(4‐R‐1H‐1,2,3‐triazol‐1‐yl)acetamide), were synthesized by copper‐catalyzed azide‐alkyne cycloaddition click chemistry in 84–96 % yield. A wide range bioactivity screening was performed to determine DNA cleavage, antioxidant, antibacterial and antifungal activities. All of the synthesized bis‐1,2,3‐triazoles showed excellent DNA cleavage activity and 4 e, bearing 2‐bromoethyl moiety as a substituent, was almost degraded all of the plasmid DNA. Molecular docking simulations suggest that the synthesized compounds act as minor groove binders of DNA. The antioxidant activities of the bis‐1,2,3‐triazoles were determined based on the radical scavenging effect of the stable 2,2‐diphenyl‐1‐picrylhydrazyl (DPPH) free radical and iron chelating activity. The compounds exhibited effective iron chelating activity at 200 mg/L while showing a moderate ability to scavenge DPPH radical. The compounds exhibited antibacterial activity against B. cereus, L. pneumophila subsp. pneumophila, S. aureus, P. aeruginosa, E. coli and E. hirae bacterial strains, and antifungal activity against C. albicans and C. tropicalis microfungus strains with a MIC value in the range of 4–128 μg/mL. 4 d, bearing cyclohexylmethyl moiety as substituent, exhibited a broad‐spectrum antimicrobial activity (both antibacterial and antifungal). Four different acid dissociation constant (pKa) values of each product were determined potentiometrically in 20 % (v/v) dimethyl sulfoxide‐water at 25±0.1 °C, at an ionic background of 0.1mol/L of NaCl using the HYPERQUAD program.

Quantitative Analysis of Surface Sites on Carbon Dots and Their Interaction with Metal Ions by a Potentiometric Titration Method.

Carbon dots (CDs) possess abundant functional groups on their surface which are related to their application in various fields such as sensing, imaging, and catalysis. Understanding the amount and properties of these functional groups and their interaction with metal ions is essential but has posed longstanding challenges because of the diverse and complex structures of CDs. In this work, potentiometric titration is demonstrated as an effective method to figure out the categories and amounts of functional groups. Surface complexation modeling with the FITEQL program was applied to the quantification of the surface sites on CDs with the titration data. Then with the obtained molar concentrations of the surface sites, the pKas of these surface sites were calculated with the Hyperquad program. Finally, titration experiments of CDs with and without Fe(III) were carried out and the stability constants of Fe(III) and ArgCDs were simulated on the Hyperquad program. By utilizing the stability constants, the distribution of Fe(III) species at different pHs and the concentrations of Fe(III) and CDs were also investigated. This potential method might be used for characterizing the surface sites on other CDs or even other soluble nanoparticles as well as for investigating the interactions of the surface sites with different metal ions.

Characterization by Potentiometric Procedures of the Stability Constants of the Binary and Ternary Complexes of Cu(II) and Duloxetine Drug with Amino Acids

Potentiometric titration method has been used to define stoichiometries and stability constants of ternary complexes of Cu(II) with duloxetine (D) and some selected amino acids (L). The protonation constants of the ligands and the stability constants of the binary and ternary complexes of Cu(II) with the ligands were calculated from the potentiometric data using the HYPERQUAD program. The formation constants of the complexes formed in aqueous solutions and their concentration distributions as a function of pH were evaluated at 25°C and ionic strength 0.10 mol·L−1NaNO3. Respective stabilities of ternary complexes have been determined compared with the corresponding binary complexes in terms ofΔlog Kand %R.S. values. A novel binary and ternary duloxetine (D) drug with glycine and its Cu(II) complexes has been synthesized and characterized by several spectroscopic methods. Electronic spectra and magnetic susceptibility measurements reveal square planar geometry for both complexes. The elemental analyses and mass spectral data have justified the [Cu(D)(Gly)] and [Cu(D)Cl(H2O)] composition of complexes, where D = duloxetine and Gly = glycine. The EPR spectra of Cu(II) complexes support the mononuclear structures. Thermal properties and decomposition kinetics of Cu(II) complexes are investigated.

Study in Aqueous Solutions of Bioactive 2-Pyridineformamide-Derived Thiosemicarbazones and Their Iron(II) and Iron(III) Complexes

The binary systems of iron(II) and iron(III) with 2-pyridineformamide thiosemicarbazone (H2Am4DH) and its N(4)-methyl (H2Am4Me), N(4)-ethyl (H2Am4Et) and N(4)-phenyl (H2Am4Ph) derivatives were studied in aqueous solution by pH-potentiometry, ultraviolet–visible spectroscopy and EPR spectra. The formation constants of the iron(II) and iron(III) complexes were calculated from potentiometric and electronic absorption data at 25 °C and ionic strength μ = 0.1 mol·L−1 using the HYPERQUAD program. The values of the formation constant of the FeL species decrease in the order Fe:H2Am4DH > Fe:H2Am4Me ≈ Fe:H2Am4Et > Fe:H2Am4Ph in the same way as the basicity of the ligands. The species distribution diagrams show that the species FeL2 predominates at physiological pH in the Fe:H2Am4DH, Fe:H2Am4Me and Fe:H2Am4Et systems. The similar EPR spectra of these iron(III) binary systems indicate the same coordination spheres around the metallic center and the EPR g values suggests that the unpaired electron is in the dxy orbital, indicating a d xz 2 d yz 2 d xy 1 ground state configuration for the complexes. For the Fe(III):H2Am4Ph system the EPR results indicated dimerization and antiferromagnetic interaction due to the presence of only one thiosemicarbazone ligand around the metallic center.

Analysis of the factors that significantly influence the stability of fluoroquinolone–metal complexes

The aim of the present study was to evaluate factors contributing to the differences between the overall stability constants (log β pqr ) of the fluoroquinolone–metal ion complexes. The experiments were performed using potentiometric titration method in wide pH range. The overall stability constants (log β pqr ) were determined using the Hyperquad program. Complexation equilibria of eight different fluoroquinolones with six divalent and trivalent metal ions were investigated in this study. The authors employed a multifactorial ANOVA analysis, fixed effect model to describe the influence of particular variables affecting the stability of the analyzed complex species. Four different variables were set at different levels labeled. The ligand number (LF) was the first factor. LF determined the number of fluorochinolone molecules in the complex structure, and could take the values 1, 2 or 3. The second factor (Me) was connected with the type of the metal ion bonded in the complex. Since six different metal cations were studied, the Me factor was described with six levels. The number of hydrogen or hydroxide groups substituted into the complex molecule was the third variable (HR) with many levels labeled: q, a, s, d, f and g. The last factor FQ described the type of the fluorochinolone used for complex formations. All variables analyzed here were statistically significant ( p value lower than 0.01), which indicates that all of them strongly affect the log β pqr value. Binary interactions (LF–Me, LF–FQ, Me–HR and Me–FQ) between variables were also stated, which suggests that the effects of these variables were higher than we could calculate based on the effect of each variable alone. The ANOVA analysis has shown that the following factors Me, LF and HR were the most important for the stability of the fluoroquinolone–metal ion complexes. It was also found that according to the FQ factor (type of ligand molecule) all analyzed fluoroquinolones formed stable complexes with metals. It was proved that the application of ANOVA for the entire complexation profile of analyzed fluoroquinolones with polyvalent metal ions was a valid technique for detecting the statistically significant differences in the complexation profiles. Such information may be very useful for better understanding and interpretation of differences in bioavailability of fluoroquinolones and their interactions with antacids and other multimineral drugs.

Speciation in the Vanadium(III)–Carnosine System

Speciation in the aqueous V(III)–carnosine system has been determined from potentiometric and spectroscopic (UV-Vis absorption and CD) data. Application of the Hyperquad program to the experimental potentiometric data indicates that under our experimental conditions (I=0.5 mol⋅L−1 NaClO4, pH=2 to 6.5, and L/M>5) only ML2H4, ML2H3, ML2H2 and ML2H form. These potentiometric results prove that stable complexes form and, with use of the spectroscopic methods, the binding sites are identified.

Spectroscopic study of mono‐ and bis(styryl) dyes of the pyridinium series containing azathiacrown ether residue

AbstractPhenylazathiacrown ether monostyryl and bis(styryl) dyes were synthesized and their complex forming ability was evaluated in acetonitrile by absorption and fluorescence spectroscopy. It was found that dyes are sensitive to the presence of H+ and Hg2+, Ag+, Cu2+ cations. The most stable complexes were formed with mercury. Stability constants and UV–Vis spectra of complexes defined stoichiometry were determined with the use of HYPERQUAD program. Evidence was given for the occurrence of two stoichiometries: LM and LM2. The pronounced optical response on complex formation was found both in absorption and emission spectra that could be used for optical detection of cations. Copyright © 2008 John Wiley & Sons, Ltd.

Speciation in the chromium(III)-glutathione system

The hydrolysis of chromium (III) cation and the complex species formed between chromium(III) and glutathione (H3L) in aqueous solution (25°C and 0.15 M in KCl ionic medium) have been studied potentiometrically. The application of the least-squares computer LETAGROP including the LETAGROP-FONDO version, indicates that under the employed experimental conditions (glutathione-chomium (III) ratios of 5.2 ≤ R ≤ 12.6; concentrations in the range 0.0052 ≤ M ≤ 0.007 and 0.027 ≤ L ≤ 0.084 mol dm-3; pH range 2.0 ≤ pH ≤ 7.09); the hydrolytic species [Cr(OH)]2+,[Cr(OH)2]+ and [Cr2(OH)2]4+ and the complex species [Cr(H2L)]2+, [Cr(HL)]+, [CrL], [Cr(OH)L)]-and [CrL2]3- (in the chromium-glutathione system) were found in significant amounts. The stability constants of the species formed were determined. The values are confirmed by HYPERQUAD program. The results are discussed.

Zinc(II), Cadmium(II), Mercury(II), and Lead(II) Complexes of N-Carboxymethyl-D,L-threonine in Aqueous Solution

The formation of complexes of Zn(II), Cd(II), Hg(II), and Pb(II) and N-carboxymethyl-D,L-threonine (H2CMT, H2L) in aqueous solutions has been studied by spectrophotometric and potentiometric methods. The complexation model for each system has been established by the HYPERQUAD program from the potentiometric data. Three different behaviors are found: ML2H, MLH, ML, MLOH, and ML2 complexes are formed by Zn(II) and Cd(II) ions, ML2H, ML, MLOH, and ML2 are formed by Hg(II) ion, and only 1/1 complexes MLH, ML, and MLOH are formed by the Pb(II) ion. The formation constants determined for all these complexes allow simulation of experimental titration curves with good agreement. The speciation of multimetal systems with H2CMT shows that this compound is a good and selective ligand at low pH for the Hg(II) ion.

The formation of mixed ligand complexes of Fe(III) with phosphoric and citric acids in 0.5 M NaNO3 aqueous solutions

Several acid–base potentiometric titrations have been carried out to estimate a model of mixed complexation among Fe (III), orthophosphate and citrate ions. The precipitation-free pH range for stable and reproducible experimental data was between 2 and 5. The HYPERQUAD program was used to fit the experimental data. As a result of the numerical treatment, a model composed of three mixed complexes of formulas: Fe(OH)(H2PO4)2(H–citrate), Fe(H2PO4)2(H–citrate)2 and Fe(OH)(H2PO4)(H2–citrate) were obtained. The formation constants of these species are log β−6,1,2,1=21.31, log β−6,1,2,2=33.67 and log β−3,1,1,1=23.45, respectively. The formation of these mixed complexes avoids the precipitation of iron until pH>7 when the ratio [citric acid]/[Fe(III)]=1.5 and until pH>9 for higher values.

Coordinating ability of the acetate ion towards cis-(1,3-diamine-2-hydroxypropane)palladium(II) chelate units in aqueous solutions. Preliminary study about the possibility of the acetato ligand to be involved in complex formation equilibria with palladium(II)-based anticancer drugs

Cis-dichloro(1,3-diamino-2-propanol)palladium(II), cis-[Pd(dapol)Cl 2], reacts with stoichiometric amounts of AgClO 4 to give chloride free solutions of cis-[Pd(dapol)(H 20) 2](ClO 4) 2 (compound 1). Twelve mixed compound I/acetic acid (AcOH) solutions having three different I/AcOH molar ratios and/or total molar complex concentration have been titrated with NaOH 0.1 mol dm −3 at 37°C and I = 0.15 mol dm −3 (NaClO 4). Formation constants (log β pqr ) of mixed hydroxoacetato complexes were fitted for the equilibrium: pPdL( H 2 O) 2 + gAcO − rH ⇄ (PdL) p (AcO) q (H 2 O) 2- r (OH) r using the log β of acetate ion protonation (also determined) and the corresponding log β pqr data for aqua- and/or hydroxo-complexes previously reported (as fixed values). New calculations were performed by the HYPERQUAD program. Simulated and experimental titrations agree well. Several distribution diagrams are used to show that acetate ions prevent the alkaline hydrolysis of compound I to a lesser extent than they do chloride ions. Both chloride and acetate ions could compete but also contribute to preventing such hydrolysis in weakly acid or nearly neutral solutions. These findings also apply inside cells at physiological conditions (pH = 7.2–7.4 and [Cl −] ∼4 mM) for a total molar complex concentration of ∼1 mM in which compound I could react with DNA and related biopolymers @ 1998 Elsevier Science B.V All rights reserved.

COPPER(II) COMPLEXES OF N-CARBOXYMETHYL-D,L-THREONINE IN AQUEOUS SOLUTION. STRUCTURE OF AQUA (N-CARBOXYMETHYL-D,L-THREONINATO (2-)) COPPER(II)

Abstract Formation constants for Cu(II) complexes with N-carboxymethyl-D,L-threonine (H2CMT = H2L) have been determined (I = 0.1M KNO3, 25°C) using the HYPERQUAD program with 652 potentiometric data from the titration of twelve solutions having different H2L concentrations and/or Cu(II)/H2L ratios. Refined values of long βpqr for the species CupLqLr = CuL, CuL2, CuL(OH) and CuL(OH)2 allow simulation of experimental titration curves with good agreement. Aqua (N-carboxymethyl-D,L-threoninato (2-)) copper(II) was synthesized and studied by X-ray diffraction and other physical methods. The structure (monoclinic system, space group P21/c, final R = 0.044 and Rw = 0.051) consists of infinite zigzag chains of [Cu(CMT) (H2O)] groups linked together by hydrogen bonds. The Cu(II) atom exhibits square pyramidal coordination with an additional sixth weak interaction (Cu-O = 2.568(4)A) which involves a terdentate-bridged carboxy-late group closely related to that already claimed in the structure of [Cu(CMPhe) (H2O)], ...

CHARACTERIZATION OF AMINO HYDROXAMIC METAL CHELATES AND THEIR ACTIVITY IN BIOLOGICAL SYSTEMS. FORMATION CONSTANTS BETWEEN 2-AMINO-N, 3-DIHYDROXYPROPANAMIDE AND 2-AMINO-N, 3-DIHYDROXYBUTANAMIDE AND IRON(III) IONS IN AQUEOUS SOLUTION

Abstract Complex formation equilibria and relative stability constants for species present in aqueous solutions of ion(III) with “L-serinehydroxamic acid” (2-amino-N,3-dihydroxypropanamide, adhp) and “DL-threoninehydroxamic acid” (2-amino-N,3-dihydroxybutanamide, adhb) have been investigated by potentiometric titrations at 25 ± 0.1°C and I = 0.5 mol dm−3 (KCl). Overall formation constants of several metal complexes were computed from potentiometric data with the hyperquad program. The following cumulative association constants (relative standard deviation values are given in parentheses) β pqr = [MpHqLr]/[M]p [H]q [L]r were obtained: adhp, log β011 = 12.72(1), log β021 = 21.62(1), log β031 = 28.38(1), log β122 = 32.88(6), log β111 = 17.07(6), log β112 = 28.80(6), log β102 = 22.15(8), log β123 = 41.17(7), log β133 = 46.26(13), log β113 = 34.83(7), log β103 = 28.06(7), log β2–22 = 22.51(12); adhb, log β011 = 12.75(1), log β021 = 21.61(1), log β031 = 28.39(1), log β122 = 32.73(3), log β111 = 16.90(4), log β1...