Ultrahigh proton conductivity of four ionic hydrogen-bonded organic frameworks based on functionalized terephthalates.

Recently, the utilization of hydrogen-bonded organic frameworks (HOFs) with high crystallinity and inherent well-defined H-bonding networks in the field of proton conduction has received increasing attention, but obtaining HOFs with excellent water stability and prominent proton conductivity (σ) remains challenging. Herein, by employing functionalized terephthalic acids, 2,5-dihydroxyterephthalic acid, 2-hydroxyterephthalic acid, 2-nitro terephthalic acid, and terephthalic acid, respectively, four highly water-stable ionic HOFs (iHOFs), [(C8H5O6)(Me2NH2)]∙2H2O (iHOF 1), [(C8H5O5)(Me2NH2)] (iHOF 2), [(C8H4NO6)(Me2NH2)] (iHOF 3) and [(C8H5O4)(Me2NH2)] (iHOF 4) were efficiently prepared by a straightforward synthesis approach in DMF and H2O solutions. The alternating-current (AC) impedance testing in humid conditions revealed that all four iHOFs were temperature- and humidity-dependent σ, with the greatest value reaching 10-2 S·cm-1. As expected, the high density of free carboxylic acid groups, crystallization water, and protonated [Me2NH2]+ units offer adequate protons and hydrophilic environments for effective proton transport. Furthermore, the σ values of these iHOFs with different functional groups were compared. It was discovered that it dropped in the following order under 100 °C and 98 % relative humidity (RH): σ iHOF 1 (1.72 × 10-2 S·cm-1) > σ iHOF 2 (4.03 × 10-3 S·cm-1) > σ iHOF 3 (1.46 × 10-3 S·cm-1) > σ iHOF 4 (4.86 × 10-4 S·cm-1). Finally, we investigated the causes of the above differences and the proton transport mechanism inside the framework using crystal structure data, water contact angle tests, and activation energy values. This study provides new motivation to develop highly proton-conductive materials.

Ligand-Functionalized MIL-68-type Indium(III) Metal-Organic Frameworks with Prominent Intrinsic Proton Conductivity.

Indium-based metal-organic frameworks (In-MOFs) have now become an attractive class of porous solids in materials science and electrochemistry due to their diverse structures and promising applications. In the field of proton conduction, to find more crystalline MOFs with splendid proton-conductive properties, herein, five three-dimensional isostructural In-MOFs, MIL-68-In or MIL-68-In-X (X = NH2, OH, Br, or NO2) using terephthalic acid (H2BDC) or functionalized terephthalic acids (H2BDC-X) as multifunctional linkages were efficiently fabricated. First, the outstanding structural stability of the five MOFs, including thermal and water stability, was verified by thermal analysis and powder X-ray diffraction. Subsequently, the H2O-mediated proton conductivities (σ) were fully assessed and compared. Notably, their σ evinced a significant positive correlation between the temperature or relative humidity (RH) and varied with the functional groups on the organic ligands. Impressively, their highest σ values are up to 10-3-10-4 S/cm (100 °C/98% RH) and change in this order: MIL-68-In-OH (1.72 × 10-3 S/cm) > MIL-68-In-NH2 (1.70 × 10-3 S/cm) > MIL-68-In-NO2 (4.47 × 10-4 S/cm) > MIL-68-In-Br (4.11 × 10-4 S/cm) > MIL-68-In (2.37 × 10-4 S/cm). Finally, the computed activation energy values under 98 or 68% RHs are assessed, and the related proton conduction mechanisms are speculated. Moreover, after electrochemical testing, these MOFs illustrate remarkable structural rigidity, laying a meritorious material foundation for future applications.

Picomolar inhibitor of reverse transcriptase featuring significantly improved metabolic stability.

Considering the undesirable metabolic stability of our recently identified NNRTI 5 (t1/2 = 96 min) in human liver microsomes, we directed our efforts to improve its metabolic stability by introducing a new favorable hydroxymethyl side chain to the C-5 position of pyrimidine. This strategy provided a series of novel methylol-biphenyl-diarylpyrimidines with excellent anti-HIV-1 activity. The best compound 9g was endowed with remarkably improved metabolic stability in human liver microsomes (t1/2 = 2754 min), which was about 29-fold longer than that of 5 (t1/2 = 96 min). This compound conferred picomolar inhibition of WT HIV-1 (EC50 = 0.9 nmol/L) and low nanomolar activity against five clinically drug-resistant mutant strains. It maintained particularly low cytotoxicity (CC50 = 264 µmol/L) and good selectivity (SI = 256,438). Molecular docking studies revealed that compound 9g exhibited a more stable conformation than 5 due to the newly constructed hydrogen bond of the hydroxymethyl group with E138. Also, compound 9g was characterized by good safety profiles. It displayed no apparent inhibition of CYP enzymes and hERG. The acute toxicity assay did not cause death and pathological damage in mice at a single dose of 2 g/kg. These findings paved the way for the discovery and development of new-generation anti-HIV-1 drugs.

Fragment Hopping-Based Design of Novel Biphenyl-DAPY Derivatives as Potent Non-Nucleoside Reverse Transcriptase Inhibitors Featuring Significantly Improved Anti-Resistance Efficacy.

To enhance the anti-resistance efficacy of our previously reported non-nucleoside reverse transcriptase inhibitor (NNRTI) 4, a series of novel biphenyl-DAPY derivatives were developed using the fragment-hopping strategy. Most of the compounds 8a-v exhibited remarkably improved anti-HIV-1 potency. The most active compound 8r proved to be exceptionally potent against the wild-type HIV-1 (EC50 = 2.3 nM) and five mutant strains, such as K103N (EC50 = 8 nM) and E138K (EC50 = 6 nM), significantly better than 4. The new DAPY analogue was 8-fold less cytotoxic and had a 17-fold higher selectivity index (CC50 = 40.77 µM, SI > 17391) than etravirine and rilpivirine. Also, it displayed favorable pharmacokinetic properties with an oral bioavailability of 31.19% and weak sensitivity toward both CYP and hERG. No apparent acute toxicity (2 g/kg) and tissue damage occurred. These findings will further expand the possibility of successfully identifying biphenyl-DAPY analogues as highly potent, safe, and orally active NNRTIs for HIV treatment.

Synthesis, Crystal Structures and Antibacterial Activities of N,N'-Ethylene-bis(3-bromosalicylaldimine) and Its Copper(II) and Cobalt(III) Complexes.

A bis-Schiff base N,N'-ethylene-bis(3-bromosalicylaldimine) (H2L) was prepared from 3-bromosalicylaldehyde and ethane-1,2-diamine. With H2L as ligand, a new copper(II) complex [CuL] (1) and a new cobalt(III) complex [CoL(NCS)(DMF)] (2) were prepared and characterized by physico-chemical methods and single crystal X-ray analysis. X-ray analysis indicates that the Cu atom in complex 1 is in square planar coordination, and the Co atom in complex 2 is in octahedral coordination. The compounds were tested in vitro for their antibacterial activities on Bacillus subtilis, Staphylococcus aureus, Escherichia coli and Pseudomonas fluorescens. Both complexes have effective activities on the bacteria.

Two Zinc(II) Complexes with Similar Hydrazone Ligands: Syntheses, Crystal Structures and Antibacterial Activities.

A pair of new mononuclear zinc(II) complexes with hydrazone ligands 4-methoxybenzoic acid (1-pyridin-2-ylmethylidene)hydrazide (HLa) and benzoic acid (1-pyridin-2-ylethylidene)hydrazide (HLb) were prepared. They are [Zn(La)2] (1) and [Zn(Lb)2] (2). The complexes were characterized by physico-chemical methods and single crystal X-ray determination. The tridentate hydrazone ligands coordinate to the Zn atoms through the pyridine nitrogen, imino nitrogen and enolate oxygen atoms. The Zn atom in each complex is six coordinated by two hydrazone ligands, to form octahedral coordination. The complexes have effective activities against the bacteria Bacillus subtilis, Staphylococcus aureus, Escherichia coli and Pseudomonas fluorescens.

Synthesis and Crystal Structure of a Polymeric Copper(II) Complex Derived from 2-Hydroxy-5-methylbenzaldehyde Oxime with Antibacterial Activities.

A centrosymmetric O-bridged polynuclear copper(II) complex, [CuL2]n, where L is the deprotonated form of the Schiff base ligand 2-hydroxy-5-methylbenzaldehyde oxime, has been prepared and characterized by IR, UV and single-crystal X-ray determination. There is a crystallographic inversion center in the complex. The Cu atom in the complex is coordinated by the phenolate oxygen, imino nitrogen and hydroxyl oxygen atoms from two Schiff base ligands, forming octahedral geometry. The complex was tested in vitro for its antibacterial activity.

Indole-based, Antiproliferative Agents Targeting Tubulin Polymerization.

Indole is a potential lead for drug design which has been found in numerous pharmaceutically important compounds due to its medicinal properties, such as anti-tumor, anti-bacterial, anti-virus and anti-inflammatory. In the last decade, interfering with microtubule polymerization, a potential orientation to cause cell cycle arrest and apoptosis has become a promising method for cancer therapy. Thus, indole-based agents capable to modulate the microtubule assembly have gained considerable interest among scientists. This review describes the synthesis, bioactivities and SARs of indole-based agents targeting tubulin polymerization during the past decade.

Synthesis, Crystal Structures and Antibacterial Activities of Trifluoromethylsulfonate Salts of 2-[(3-Chloropyridinium-2-yl)hydrazonomethyl]-6-methoxyphenol and its Copper(II) and Cobalt(III) Complexes.

A new trifluoromethylsulfonate salt of 2-[(3-chloropyridinium-2-yl)hydrazonomethyl]-6-methoxyphenol, (HL)CF3SO3, and its copper(II) and cobalt(III) complexes, [CuL(OH2)]CF3SO3 · 0.5H2O (1) and [CoL2]CF3SO3 · CH3OH (2), were prepared and characterized by physico-chemical methods and single crystal X-ray analysis. A trifluoromethylsulfonate anion is present in each of the compounds. The Cu atom in complex 1 is coordinated by the phenolate O, imino N and pyridine N atoms of L ligand, giving square planar geometry. The Co atom in complex 2 is coordinated by two phenolate O, two imino N and two pyridine N atoms from two L ligands, giving octahedral geometry. The three compounds were tested in vitro for their antibacterial activities.

Discovery and molecular modeling of novel 1-indolyl acetate--5-nitroimidazole targeting tubulin polymerization as antiproliferative agents.

A series of 18 novel 1-indolyl acetate-5-nitroimidazole 3a-3r were designed, synthesized, and evaluated for their in vitro biological activities as potential tubulin polymerization inhibitors. Among these compounds, 3p displayed strong antitumor activity with IC50 of 2.00, 1.05, 0.87 µM against A549, Hela and U251 respectively, and also showed the most potent PLK1 inhibitory activity with IC50 of 2.4 µM. Molecular docking studies within the colchicine binding site of tubulin were in good agreement with the tubulin polymerization inhibitory data and confirmed the importance of the configuration of the synthesized 1-indolyl acetate-5-nitroimidazolefor potential tubulin polymerization inhibitors.

Design and synthesis of 2-styryl of 5-Nitroimidazole derivatives and antimicrobial activities as FabH inhibitors.

A series of 2-Styryl-5-Nitroimidazole derivatives (25-48) have been synthesized and their biological activities were also evaluated against two Gram-negative bacterial strains: Escherichia coli and Pseudomonas aeruginosa and two Gram-positive bacterial strains: Bacillus subtilis and Bacillus thuringiensis as potential FabH inhibitors. All the compounds were structurally determined by (1)H NMR, MS, and elemental analysis. E. coli ß-ketoacyl-acyl carrier protein synthase III inhibitory assay and docking simulation indicated that compound 33 with IC50 of 9.0-36.4 µg/mL and compound 47 with IC50 of 6.3-34.3 µg/mL against bacterial strains were most potent inhibitors of E. coli FabH. And more, compounds 33 and 47 which possessed a broad-spectrum of antibacterial activities didn't exhibit any toxicity towards macrophage.

Exploration of structure-based on imidazole core as antibacterial agents.

Imidazole, a five-membered heterocycle having three carbon atoms, and two double bonds, having efficient antibacterial Escherichia coli, Bacillus subtili, Bacillus proteus, Staphylococcus aureus, Pseudomonas aeruginosa, and Helicobacter pyloriurease etc, shows a broad-spectrum of antibacterial activities. To Search new antibacterial drugs to overcome resistance of microorganisms to antibiotics, to date hundreds of this sort of derivatives have been synthesized and possess potent antibacterial activity. As the structure of imidazole derivatives is various, the target of antibacterial is also diverse including ß-Lactamases, ß-ketoacyl-acyl carrier protein synthase III (FabH), DNA gyrase and topoisomerase, glutamate racemase and urease. In this review, we will discuss the emergence of resistance to antibiotics and attempt to summarize the main developments of imidazole derivatives in the past ten years. We hope that increasing knowledge of the structure-activity relationship (SAR) will be beneficial to the rational design of new generation of small molecule antibacterial drugs.

Sulfonamides containing coumarin moieties selectively and potently inhibit carbonic anhydrases II and IX: design, synthesis, inhibitory activity and 3D-QSAR analysis.

A series of sulfonamides containing coumarin moieties had been prepared that showed a very interesting profile for the inhibition of two human carbonic anhydrase inhibitors. These compounds were evaluated for their ability to inhibit the enzymatic activity of the physiologically dominant isozymes hCA II and the tumor-associated isozyme hCA IX. The most potent inhibitor against hCA II and IX were compounds 5d (IC50 = 23 nM) and 5l (IC50 = 24 nM), respectively. These sulfonamides containing coumarin moieties may prove interesting lead candidates to target tumor-associated CA isozymes, wherein the CA domain is located extracellularly. Eighteen compounds were scrutinized by CoMFA and CoMSIA techniques of 3D quantitative structure-activity relationship. Nine of the compounds were evaluated for cytotoxicity against human macrophage.

Potentiating 1-(2-hydroxypropyl)-2-styryl-5-nitroimidazole derivatives against antibacterial agents: design, synthesis and biology analysis.

A series of novel 1-(2-hydroxypropyl)-2-styryl-5-nitroimidazole derivatives had been designed, synthesized, isolated and evaluated as potentiators of antibacterial agents. All these synthesized compounds were determined by elemental analysis, (1)H NMR, and MS. Their biological activities were also evaluated against two Gram-negative bacterial strains: Escherichia coli and Pseudomonas aeruginosa and two Gram-positive bacterial strains: Bacillus thuringiensis and Bacillus subtilis by MTT method as potential FabH inhibitory. The results showed that compound 30 exhibited the most potent E. coli FabH inhibitory activity with IC50 of 4.6 µM. Molecular modeling simulation studies were performed in order to predict the biological activities of the proposed compounds. All compounds have been tested for toxicity by MTT assay on human macrophage.

N'-(3,5-Dibromo-2-hydroxy-benzyl-idene)-3,4-methyl-enedioxy-benzohydrazide.

In the asymmetric unit of the title hydrazone compound, C(15)H(10)Br(2)N(2)O(4), there are two independent mol-ecules. In each mol-ecule, the five-membered ring adopts a flattened envelope conformation; the flap atoms are displaced by 0.114 (2) and 0.219 (2) Šfrom the planes of the other four atoms. In one mol-ecule the dihedral angle between the two benzene rings is 22.8 (2)°, while in the other it is 40.8 (2)°. Each mol-ecule displays an E configuration with respect to the C=N bond. In both mol-ecules, intra-molecular O-H⋯N hydrogen bonds are observed. In the crystal structure, mol-ecules are linked through inter-molecular N-H⋯O hydrogen bonds, forming chains along the a axis.

N'-(5-Bromo-2-methoxy-benzyl-idene)-3,4-methyl-enedioxy-benzohydrazide.

In the title mol-ecule, C(16)H(13)BrN(2)O(4), the two benzene rings form a dihedral angle of 74.9 (2)°. In the crystal, mol-ecules are linked via inter-molecular N-H⋯O hydrogen bonds into chains propagating along the c axis.

N'-(5-Bromo-2-methoxy-benzyl-idene)-2-methoxy-benzohydrazide.

The title hydrazone compound, C(16)H(15)BrN(2)O(3), adopts an E configuration about the C=N double bond. The mol-ecule is twisted, the dihedral angle between the two substituted benzene rings being 22.0 (2)°. In the crystal structure, mol-ecules are linked through inter-molecular N-H⋯O hydrogen bonds, forming chains along the c axis.

N'-(5-Bromo-2-methoxy-benzyl-idene)-4-hydroxy-benzohydrazide methanol solvate.

In the title hydrazone compound, C(15)H(13)BrN(2)O(3)·CH(3)OH, the methanol solvate is linked to the benzohydrazide molecule through O-H⋯N and O-H⋯O hydrogen bonds. The benzohydrazide mol-ecule adopts an E configuration about the C=N double bond. The mol-ecule is twisted, with a dihedral angle between the two substituted benzene rings of 35.7 (2)°. In the crystal structure, mol-ecules are linked through inter-molecular N-H⋯O and O-H⋯O hydrogen bonds, forming layers parallel to the ac plane.