This study investigated a set of new potential antidiabetes agents. Derivatives of usnic acid were designed and synthesized. These analogs and nineteen benzylidene analogs from a previous study were evaluated for enzyme inhibition of α-glucosidase. Analogs synthesized using the Dakin oxidative method displayed stronger activity than the pristine usnic acid (IC50>200 μM). Methyl (2E,3R)-7-acetyl-4,6-dihydroxy-2-(2-methoxy-2-oxoethylidene)-3,5-dimethyl-2,3-dihydro-1-benzofuran-3-carboxylate ( 6b ) and 1,1′-(2,4,6-trihydroxy-5-methyl-1,3-phenylene)di(ethan-1-one) ( 6e ) were more potent than an acarbose positive control (IC50 93.6±0.49 μM), with IC50 values of 42.6±1.30 and 90.8±0.32 μM, respectively. Most of the compounds synthesized from the benzylidene series displayed promising activity. (9bR)-2,6-Bis[(2E)-3-(2-chlorophenyl)prop-2-enoyl]-3,7,9-trihydroxy-8,9b-dimethyldibenzo[b,d]furan-1(9bH)-one ( 1c ), (9bR)-3,7,9-trihydroxy-8,9b-dimethyl-2,6-bis[(2E)-3-phenylprop-2-enoyl]dibenzo[b,d]furan-1(9bH)-one ( 1g ), (9bR)-2-acetyl-6-[(2E)-3-(2-chlorophenyl)prop-2-enoyl]-3,7,9-trihydroxy-8,9b-dimethyldibenzo[b,d]furan-1(9bH)-one ( 2d ), (9bR)-2-acetyl-6-[(2E)-3-(3-chlorophenyl)prop-2-enoyl]-3,7,9-trihydroxy-8,9b-dimethyldibenzo[b,d]furan-1(9bH)-one ( 2e ), (6bR)-8-acetyl-3-(4-chlorophenyl)-6,9-dihydroxy-5,6b-dimethyl-2,3-dihydro-1H-[1]benzofuro[2,3-f][1]benzopyran-1,7(6bH)-dione ( 3e ), (6bR)-8-acetyl-6,9-dihydroxy-5,6b-dimethyl-3-phenyl-2,3-dihydro-1H-[1]benzofuro[2,3-f][1]benzopyran-1,7(6bH)-dione ( 3h ), (6bR)-3-(2-chlorophenyl)-8-[(2E)-3-(2-chlorophenyl)prop-2-enoyl]-6,9-dihydroxy-5,6b-dimethyl-2,3-dihydro-1H-[1]benzofuro[2,3-f][1]benzopyran-1,7(6bH)-dione ( 4b ), and (9bR)-6-acetyl-3,7,9-trihydroxy-8,9b-dimethyl-2-[(2E)-3-phenylprop-2-enoyl]dibenzo[b,d]furan-1(9bH)-one ( 5c ) were the most potent α-glucosidase enzyme inhibitors, with IC50 values of 7.0±0.24, 15.5±0.49, 7.5±0.92, 10.9±0.56, 1.5±0.62, 15.3±0.54, 19.0±1.00, and 12.3±0.53 μM, respectively. 相似文献
In order to evaluate biological potential of a novel synthesized complex [Nd(dmp)2Cl3.OH2] where dmp is 29-dimethyl 110-phenanthroline, the DNA-binding, cleavage, BSA binding, and antimicrobial activity properties of the complex are investigated by multispectroscopic techniques study in physiological buffer (pH 7.2).The intrinsic binding constant (Kb) for interaction of Nd(III) complex and FS–DNA is calculated by UV–Vis (Kb = 2.7 ± 0.07 × 105) and fluorescence spectroscopy (Kb = 1.13 ± 0.03 × 105). The Stern–Volmer constant (KSV), thermodynamic parameters including free energy change (ΔG°), enthalpy change (?H°), and entropy change (?S°), are calculated by fluorescent data and Vant’ Hoff equation. The experimental results show that the complex can bind to FS–DNA and the major binding mode is groove binding. Meanwhile, the interaction of Nd(III) complex with protein, bovine serum albumin (BSA), has also been studied by using absorption and emission spectroscopic tools. The experimental results show that the complex exhibits good binding propensity to BSA. The positive ΔH° and ?S° values indicate that the hydrophobic interaction is main force in the binding of the Nd(III) complex to BSA, and the complex can quench the intrinsic fluorescence of BSA remarkably through a static quenching process. Also, DNA cleavage was investigated by agarose gel electrophoresis that according to the results cleavage of DNA increased with increasing of concentration of the complex. Antimicrobial screening test gives good results in the presence of Nd(III) complex system. 相似文献
New pyridine derivatives were designed and synthesized as Isonicotinic acid hydrazide (INH) analogues. The synthesized compounds were evaluated for their antitubercular activity against Mycobacterium tuberculosis strain H37Rv. Ten compounds (3c, 3e-g, 5a-c, 6h, 10 and 11b) showed promising antitubercular activity with MIC range 7.30 µM–19.39 µM. Compounds 3e, 3g, 5b and 11b were the most potent analogues, with MIC 7.30–8.74 µM. They were equipotent to the standard drug Ethambutol (MIC 7.64 µM) and more active than the standard drug Pyrazinamide (MIC 50.77 µM). They were further examined for cytotoxicity in human embryonic kidney (HEK) cell line at the concentration of 50 µg/mL using MTT assay. Results declared that most compounds showed acceptable safety margin. Molecular Docking studies into 2-trans-enoyl-acyl carrier protein reductase, called InhA have been conducted for compounds 3e, 3g, 5b and 11b using Molecular Operating Enviroment software (MOE 2016.0802), where reasonable binding interactions have been identified and effective overall docking scores have been recorded. Their drug-likeness has been assessed using Molinspiration and Osiris software. 相似文献
A series of thieno[2,3-d]pyrimidine alkyne Mannich base derivatives (7a-e, 8a-e) and thieno[2,3-d]pyrimidine 1,3,4-oxadiazole derivatives (9a-e, 10a-e) have been synthesized and evaluated for their neuroprotective and neurotoxicity activities where 9a, 10d displayed good neuroprotection 10.6 and 11.88?µg/mL respectively against the H2O2 induced cell death at the EC50 values and 9b, 9d showed respective toxic effects on PC12 cells at CC50 86.12 and 94.16?µg/mL. Compounds 9a, 9e, 10a and 10b showed strong antibacterial activity against two gram positive (S. aureus, B. subtilis) and two gram-negative strains (E. coli, P. aeruginosa) and showed good binding affinities with C(30) carotenoid dehydrosqualene synthase, Gyrase A and LpxC. This is the first report for the demonstration of thieno[2,3-d] pyrimidine derivatives as promising neuroprotective agents against H2O2 induced neurotoxicity on PC12 cells. 相似文献
The character of the bridged hydrogen atom (Hb) of B2H6 has become a hot issue in recent years. In this work, the complexes B2H6?·?·?·?NH3, B2H2X4?·?·?·?nNH3 (n?=?1, 2) and 2HF?·?·?·?B2H2X4?·?·?·?2NH3 (X?=?Cl, Br, I) were constructed and studied based on the M06-2X calculations to investigate how to enhance the Hb?·?·?·?N hydrogen-bonded interaction. When the terminal hydrogen atoms (Ht) of B2H6 were replaced by X (X?=?Cl, Br, I) atoms, the Hb?·?·?·?N hydrogen bond were strengthened. According to the electrostatic potentials in B2H2X4, two HF molecules were added to the interspace of the B-H-B-H four-membered ring of the B2H2X4?·?·?·?2NH3 complexes, and H?·?·?·?X hydrogen bond formed, resulting in further enhancing effect of Hb?·?·?·?N hydrogen bond. As a result, the positive cooperative effect of Hb?·?·?·?N hydrogen bond and H?·?·?·?X hydrogen bond do enhance the interactions of each other. The two measures not only enhance the strength of Hb?·?·?·?N hydrogen bond, but also achieve the goal to make the Hb?·?·?·?N hydrogen bond perpendicular to B?·?·?·?B direction.
The binding of [Dy(dmp)2Cl3(OH2)], where dmp is 2,9-dimethyl 1,10-phenanthroline, with Fish salmon DNA (FS-DNA) is investigated by absorption and emission spectroscopy, quenching studies, salt dependent, and gel electrophoresis. The binding constant (Kb) of the interaction is calculated as (1.27 ± .05) × 105 M?1 from absorption spectral titration data. The Stern–Volmer constant (KSV), thermodynamic parameters involves ΔG°, ?H°, and ?S° are calculated by fluorescent data and Van’t Hoff equation. The thermodynamic studies show that the reaction for the binding of the complex with FS-DNA is endothermic and entropically driven (ΔS° > 0, ΔH° > 0). The effect of the complex concentration on FS-DNA cleavage reactions is also investigated by gel electrophoresis. Furthermore, the Dy(III) complex has been screened for its antibacterial activity. The experimental results suggest that the Dy(III) complex binds significantly to FS-DNA by hydrophobic groove binding mode and the complex has more efficient antibacterial activity compared to its metal salt. 相似文献
[Pd{(C,N)–C6H4CH2NH(Et) (Qu)] (2) and [Pd{(C,N)–C6H4CH2NH(Et) (Nar)] (3) (Qu = Quercetin, Nar = Naringin) mononuclear palladium (II) complexes have been synthesized and characterized using elemental analysis, IR and electronic spectroscopy. The interaction of the prepared complexes with calf thymus DNA and bovine serum albumin (BSA), monitored by UV–visible and fluorescence titrations, respectively, have been carried out to better understand the mode of their action under biological conditions. Intercalative binding mode between the complexes and DNA is suggested by the binding constant (Kb) values of 2.5 × 106 and 3.2 × 106 for complexes 2 and 3, respectively. In particular, the in vitro cytotoxicity of the complexes on two cancer cells lines (bladder carcinoma TCC and breast cancer MCF7) showed that the compounds had broad spectrum, anti-cancer activity with low IC50 values and the order of in vitro anticancer activities is consistent with the DNA-binding affinities. In the meantime, the quenching of tryptophan emission with the addition of complexes using BSA as a model protein indicated the protein binding ability. The quenching mechanisms of BSA by the complexes were static processes, according to the results obtained. The competitive binding using Warfarin, Digoxin and Ibuprofen site markers, which contain definite biding sites, demonstrated that the complexes bind to site I on BSA. Ultimately, the binding sites of DNA and BSA with the complexes have been determined by molecular modelling studies. 相似文献
We have analyzed the role of individual heme-ligating histidine residues for assembly of holo-cytochrome b6, and we show that the two hemes bL and bH bind in two subsequent steps to the apo-protein. Binding of the low-potential heme bL is a prerequisite for binding the high-potential heme bH. After substitution of His86, which serves as an axial ligand for heme bL, the apo-protein did not bind heme, while substitution of the heme bL-ligating residue His187 still allowed binding of both hemes. Similarly, after replacement of His202, one axial ligand to heme bH, binding of only heme bL was observed, whereas replacement of His100, the other heme bH ligand, resulted in binding of both hemes. These data indicate sequential heme binding during formation of the holo-cytochrome, and the two histidine residues, which serve as axial ligands to the same heme molecule (heme bL or heme bH), have different importance during heme binding and cytochrome assembly. Furthermore, determination of the heme midpoint potentials of the various cytochrome b6 variants indicates a cooperative adjustment of the heme midpoint potentials in cytochrome b6. 相似文献
The aspartic protease inhibitory efficiency of rBm-33, an aspin from a filarial parasite Brugia malayi was investigated. rBm-33 was found to be thermostable up to 90°C and it forms a stable ‘enzyme-product’ complex with human pepsin. Aspartic protease inhibitory activity was investigated using UV spectroscopy and isothermal titration calorimetry. Our results suggest that rBm-33 inhibits the activity of important human aspartic proteases that were examined with binding constants (Kb) values between 10.23?×?103 and 6.52?×?103 M?1. The binding reactions were enthalpy driven with ΔHb values between ?50.99 and ?46.07 kJ mol?1. From kinetic studies, pepsin inhibition by rBm-33 was found to be linear competitive with an inhibition constant (Ki) of 2.5 (±0.8) nM. Because of the inhibitory efficacy of Bm-33 against important human aspartic proteases which play a vital role in immune-regulation along with other functions, Bm-33 can be projected as a drug target for the filariasis. 相似文献
The thermodynamics of metals ions binding to proteins and other biological molecules can be measured with isothermal titration
calorimetry (ITC), which quantifies the binding enthalpy (ΔH°) and generates a binding isotherm. A fit of the isotherm provides the binding constant (K), thereby allowing the free energy (ΔG°) and ultimately the entropy (ΔS°) of binding to be determined. The temperature dependence of ΔH° can then provide the change in heat capacity (ΔCp°) upon binding. However, ITC measurements of metal binding can be compromised by undesired reactions (e.g., precipitation,
hydrolysis, and redox), and generally involve competing equilibria with the buffer and protons, which contribute to the experimental
values (KITC, ΔHITC). Guidelines and factors that need to be considered for ITC measurements involving metal ions are outlined. A general analysis
of the experimental ITC values that accounts for the contributions of metal–buffer speciation and proton competition and provides
condition-independent thermodynamic values (K, ΔH°) for metal binding is developed and validated. 相似文献
The X-ray photoelectron spectra for (NH4)3 [Rh(S5)3]·2H2O and (NH4)2[PtS17]·2H2O are consistent with those previously reported for (NH4)2 [Pt(S5)3]·2H2O, where different electron binding energies were observed for the structurally distinct sulfur atoms in the polysulfido ligands. The 4f binding energies for the platinum polysulfides are lower than those for platinum(IV) bonded to elements other than sulfur, and the 3d binding energies for the rhodium complex are lower than most values for rhodium(III) bonded to oxygen or nitrogen. 相似文献
Interactions of Isatin and its derivatives, Isatin-3-isonicotinylhydrazone (IINH) and Isatin-β-thiosemicarbazone (IBT), with calf thymus DNA (ctDNA) have been investigated to delineate pharmaceutical-physicochemical properties using UV–Vis/fluorescence/circular dichroism (CD) spectroscopy, viscosity measurements, and multivariate chemometrics. IINH and IBT molecules intercalate between base pairs of DNA, hypochromism in UV absorptions, increase in the CD positive band, sharp increase in specific viscosity, and the displacement of the methylene blue and Neutral Red dye in complexes with ctDNA, by the IINH and IBT molecules, respectively. The observed intrinsic binding constants (Kb[IBT–ctDNA]?=?1.03 × 105 and Kb[IINH–ctDNA]?=?1.09 × 105 L mol?1) were roughly comparable to other intercalators. In contrast, Isatin binds with ctDNA via groove mode (Kb[Isatin–ctDNA]?=?7.32 × 104 L mol?1) without any significant enhancement in ctDNA viscosity. The fluorescence quenching of Isatin by ctDNA was observed as static. CD spectra indicated that Isatin effectively absorbs into grooves of ctDNA, leading to transition from B to C form. Thermodynamic parameters like enthalpy changes (?H < 0) and entropy changes (?S > 0) were calculated according to Van’t Hoff’s equation, indicating the spontaneous interactions. The common soft/hard chemometric methods were used not only to resolve pure concentration and spectral profiles of components using the acquired spectra but also to calculate Stern–Volmer quenching constants, binding stoichiometry, apparent binding constants (Ka), binding constants (Kb), and thermodynamic parameters. The Kb values for Isatin, IINH, and IBT were calculated as 9.18 × 103, 1.53 × 105, and 2.45 × 104 L mol?1, respectively. The results obtained from experimental-spectroscopic analyses showed acceptable agreement with chemometric outlines. 相似文献
The pentadentate ligand 2,6-diacetylpyridinedisemicarbazone, DAPSC, reacts with Cr(NO3)3·9H2O and forms two kinds of complexes. At pH=3, the ligand is singly-deprotonated and crystals of [Cr- (DAPSCH)(H2O)2](NO3)2·H2O (Ia) are obtained. Evaporation of a solution at pH=0, yields crystals of [Cr(DAPSC)(H2O)2](NO3)3·2H2O (II) in which the ligand is fully protonated. The reaction of DAPSC with UO2(O2CCH3)2 in methanol, followed by crystallization of the product from DMSO yields crystals of [UO2(DAPSC2H)(H2O)]·2DMSO (III) in which the ligand is fully deprotonated. Compound Ia is monoclinic, space group P21/n with a=11.746(1), b=14.752(2), c=11.866(1) Å,β=105.53(2)°, V= 1981(1) Å3 and Z=4. Compound II is monoclinic, space group, P21/n with a=38.000(3), b= 14.939(2), c=8.233(1) Å, β=96.12(2)°, V= 4647(1) Å and Z=8. Compound III is monoclinic, space group P21/n with a=18.048(2), b=15.207(2), c=8.842(1) Å,β=97.72(2)°, V=2405(1) Å3 and Z=4. The structures were refined using 2084, 4169 and 2516 reflections to R values of 4.4%, 7.8% and 4.8% respectively. 相似文献
Electrostatic interactions have a central role in some biological processes, such as recognition of charged ligands by proteins. We characterized the binding energetics of yeast triosephosphate isomerase (TIM) with phosphorylated inhibitors 2-phosphoglycollate (2PG) and phosphoglycolohydroxamate (PGH). We determined the thermodynamic parameters of the binding process (Kb, ΔGb, ΔHb, ΔSb and ΔCp) with different concentrations of NaCl, using fluorimetric and calorimetric titrations in the conventional mode of ITC and a novel method, multithermal titration calorimetry (MTC), which enabled us to measure ΔCp in a single experiment. We ruled out specific interactions of Na+ and Cl- with the native enzyme and did not detect significant linked protonation effects upon the binding of inhibitors. Increasing ionic strength (I) caused Kb, ΔGb and ΔHb to become less favorable, while ΔSb became less unfavorable. From the variation of Kb with I, we determined the electrostatic contribution of TIM−2PG and TIM−PGH to ΔGb at I = 0.06 M and 25 °C to be 36% and 26%, respectively. The greater affinity of PGH for TIM is due to a more favorable ΔHb compared to 2PG (by 19-24 kJ mol-1 at 25 °C). This difference is compatible with PGH establishing up to five more hydrogen bonds with TIM. Both binding ΔCps were negative, and less negative with increasing ionic strength. ΔCps at I = 0.06 M were much more negative than predicted by surface area models. Water molecules trapped in the interface when ligands bind to protein could explain the highly negative ΔCps. Thermodynamic binding functions for TIM−2PG changed more with ionic strength than those for TIM−PGH. This greater dependence is consistent with linked, but compensated, protonation equilibriums yielding the dianionic species of 2PG that binds to TIM, process that is not required for PGH. 相似文献
The successive enthalpy changes for the four steps of oxygen binding by diphosphoglycerate-free adult human hemoglobin have been measured by direct calorimetry at pH 7.4 and 6°. Average results in kcal/(mole O2) are: ΔH1 = ?25.1 ± 2.8; ΔH2 = ?12.6 ± 3.0, ΔH3 = ?12.5 ± 3.0, and ΔH4 = ?10.1 ± 1.4. These results imply a substantial temperature dependence for the cooperativity of O2 binding by the protein and generally resemble the van't Hoff results by Roughton . [Roy. Soc. of London Proc., , 29 (1955)] for sheep hemoglobin at pH 9.1 and a temperature range of 2° to 19°. 相似文献
The binding of lithium ions to phosphatidylserine has been studied by differential scanning calorimetry for dialkyl and diacyl lipid forms and by X-ray diffraction for dihexadecylphosphatidylserine (DHPS). On first mixing DHPS with LiCl solutions an ordered Lβ (Lc) phase is formed with a bilayer repeat distance of 5.55 nm and one strong wide-angle, chain-chain reflection at 0.405 nm (26°C), corresponding to bilayers of little, (mono)hydrated lipid with chains approximately perpendicular to the membrane surface. On heating, this phase transforms to an inverted hexagonal phase (H11, Hα) with a repeat distance of 3.75 nm, at a chain-melting transition temperature of approximately 90°C (DHPS). Cooling, after equilibration of the DHPS−·Li+ sample in the fluid phase, creates a new low-temperature phase (Lc') which has a repeat distance of 4.0 nm, corresponding to strongly tilted chains (ϕ=42°). The Lc phase also transforms on heating to the Hα phase, but at a considerably lower chain-melting temperature of approx. 70°C (DHPS). The calorimetric behavior as a function of Li+ concentration is qualitatively very similar for the different dialkyl- and diacylphosphatidylserines studied, and is analogous to the results obtained on pH titration. After an initial small increase in transition temperature, that is caused by coulombic ion binding and concomitant surface charge neutralization, a much larger increase in the chain-melting transition temperature occurs, caused by dehydration of the lipid, as a consequence of a further stereospecific ion binding. This suggests that Li+ and H+ have similar binding sites on the PS headgroup. 相似文献
A new convenient method for preparation of 2-aroyl-[1]benzopyrano[4,3-c]pyrazol-4(1H)-one derivatives 5b–g and coumarin containing hydrazide-hydrazone analogues 4a–e was presented. The antimycobacterial activity against reference strain Mycobacterium tuberculosis H37Rv and cytotoxicity against the human embryonic kidney cell line HEK-293 were tested in vitro. All compounds demonstrated significant minimum inhibitory concentrations (MIC) ranging 0.28–1.69 μM, which were comparable to those of isoniazid. The cytotoxicity (IC50 > 200 µM) to the “normal cell” model HEK-293T exhibited by 2-aroyl-[1]benzopyrano[4,3-c]pyrazol-4(1H)-one derivatives 5b–e, was noticeably milder compared to that of their hydrazone analogues 4a–e (IC50 33–403 µM). Molecular docking studies on compounds 4a–e and 5b–g were also carried out to investigate their binding to the 2-trans-enoyl-ACP reductase (InhA) enzyme involved in M. tuberculosis cell wall biogenesis. The binding model suggested one or more hydrogen bonding and/or arene-H or arene-arene interactions between hydrazones or pyrazole-fused coumarin derivatives and InhA enzyme for all synthesized compounds. 相似文献