Identification of a Family of Glycoside Derivatives Biologically Active against Acinetobacter baumannii and Other MDR Bacteria Using a QSPR Model.

As the rate of discovery of new antibacterial compounds for multidrug-resistant bacteria is declining, there is an urge for the search for molecules that could revert this tendency. Acinetobacter baumannii has emerged as a highly virulent Gram-negative bacterium that has acquired multiple resistance mechanisms against antibiotics and is considered of critical priority. In this work, we developed a quantitative structure-property relationship (QSPR) model with 592 compounds for the identification of structural parameters related to their property as antibacterial agents against A. baumannii. QSPR mathematical validation (R2 = 70.27, RN = -0.008, a(R2) = 0.014, and δK = 0.021) and its prediction ability (Q2LMO= 67.89, Q2EXT = 67.75, a(Q2) = -0.068, δQ = 0.0, rm2¯ = 0.229, and Δrm2 = 0.522) were obtained with different statistical parameters; additional validation was done using three sets of external molecules (R2 = 72.89, 71.64 and 71.56). We used the QSPR model to perform a virtual screening on the BIOFACQUIM natural product database. From this screening, our model showed that molecules 32 to 35 and 54 to 68, isolated from different extracts of plants of the Ipomoea sp., are potential antibacterials against A. baumannii. Furthermore, biological assays showed that molecules 56 and 60 to 64 have a wide antibacterial activity against clinically isolated strains of A. baumannii, as well as other multidrug-resistant bacteria, including Staphylococcus aureus, Escherichia coli, Klebsiella pneumonia, and Pseudomonas aeruginosa. Finally, we propose 60 as a potential lead compound due to its broad-spectrum activity and its structural simplicity. Therefore, our QSPR model can be used as a tool for the investigation and search for new antibacterial compounds against A. baumannii.

Boron-π interactions in two 3-(dihydroxyboryl)anilinium salts analyzed by crystallographic studies and supported by the noncovalent interactions (NCI) index theoretical approach.

In the title compounds, 3-(dihydroxyboryl)anilinium bisulfate monohydrate, C6H9BNO2+·HSO4-·H2O (I), and 3-(dihydroxyboryl)anilinium methyl sulfate, C6H9BNO2+·CH3SO4- (II), the almost planar boronic acid molecules are linked by pairs of O-H...O hydrogen bonds, forming centrosymmetric motifs that can be described by the graph-set R22(8) motif. In both crystals, the B(OH)2 group acquires a syn-anti conformation (with respect to the H atoms). The presence of the hydrogen-bonding functional groups B(OH)2, NH3+, HSO4-, CH3SO4- and H2O generates three-dimensional hydrogen-bonded networks, in which the bisulfate (HSO4-) and methyl sulfate (CH3SO4-) counter-ions act as the central building blocks within the crystal structures. Furthermore, in both structures, the packing is stabilized by weak boron-π interactions, as shown by noncovalent interactions (NCI) index calculations.

Crystal structure of caesium tetra-methyl-dithio-imidodiphosphinate.

In the title crystal, the salt [CsMe2P(S)NP(S)Me2] is self-assembled as an undulating supra-molecular two-dimensional polymeric structure, poly[(µ4-tetra-methyl-dithio-imidodiphosphinato)caesium], [Cs(C4H12NP2S2)] n , which is parallel to the bc plane. The Cs cations are hexa-coordinated, being chelated by two thio-imidophosphinate groups and two sulfur atoms from neighboring ligands. The anions are linked to the Cs cations by Cs⋯S and Cs⋯N electrostatic inter-actions.

Synthesis and crystallographic studies of two new 1,3,5-triazines.

The synthesis and characterization of two new 1,3,5-triazines containing 2-(aminomethyl)-1H-benzimidazole hydrochloride as a substituent are reported, namely, 2-{[(4,6-dichloro-1,3,5-triazin-2-yl)amino]methyl}-1H-benzimidazol-3-ium chloride, C11H9Cl2N6+·Cl- (1), and bis(2,2'-{[(6-chloro-1,3,5-triazine-2,4-diyl)bis(azanediyl)]bis(methylene)}bis(1H-benzimidazol-3-ium)) tetrachloride heptahydrate, 2C19H18ClN92+·4Cl-·7H2O (2). Both salts were characterized using single-crystal X-ray diffraction analysis and IR spectroscopy. Moreover, the NMR (1H and 13C) spectra of 1 were obtained. Salts 1 and 2 have triclinic symmetry (space group P\overline{1}) and their supramolecular structures are stabilized by hydrogen bonding and offset π-π interactions. In hydrated salt 2, the noncovalent interactions yield pseudo-nanotubes filled with chloride anions and water molecules, which were modelled in the refinement with substitutional and positional disorder.

Interaction of aromatic compounds and anions with naphthylimide-dansylamide fluorescent dyad: Experimental evidence of aryl C-H π and aryl C-H anion contacts and DFT calculations.

In this work the interaction of halide anions and simple aromatic compounds with a bichromophoric fluorescent dyad derived from 1,8-naphthalimide (NAPIM) and 5-(dimethylamino)naphthalene-1-sulfonyl (DANS) was studied using electronic spectroscopy, 1H, and 19F NMR spectroscopy and quantum chemistry modeling (b3lyp/def2-TZVP). The NAPIM-DANS dyad interacts with electron-rich guests with binding constants in the range of 6×103 to 8×103M-1 in CHCl3. The formed complexes are stabilized through aryl C-H … anion and aryl C-H … π interactions.

Design, synthesis, in vitro, in vivo and in silico pharmacological characterization of antidiabetic N-Boc-l-tyrosine-based compounds.

In this study, we synthesized five N-Boc-L-tyrosine-based analogues to glitazars. The in vitro effects of compounds 1-5 on protein tyrosine phosphatase 1B (PTP-1B), peroxisome proliferator-activated receptor alpha and gamma (PPARα/γ), glucose transporter type-4 (GLUT-4) and fatty acid transport protein-1 (FATP-1) activation are reported in this paper. Compounds 1 and 3 were the most active in the in vitro PTP-1B inhibition assay, showing IC50s of approximately 44 µM. Treatment of adipocytes with compound 1 increased the mRNA expression of PPARγ and GLUT-4 by 8- and 3-fold, respectively. Moreover, both compounds (1 and 3) also increased the relative mRNA expression of PPARα (by 8-fold) and FATP-1 (by 15-fold). Molecular docking studies were performed in order to elucidate the polypharmacological binding mode of the most active compounds on these targets. Finally, a murine model of hyperglycemia was used to evaluate the in vivo effectiveness of compounds 1 and 3. We found that both compounds are orally active using an exploratory dose of 100 mg/kg, decreasing the blood glucose concentration in an oral glucose tolerance test and a non-insulin-dependent diabetes mellitus murine model. In conclusion, we demonstrated that both molecules showed strong in vitro and in vivo effects and can be considered polypharmacological antidiabetic candidates.

Design, Synthesis and Biological Evaluation of 2-(2-Amino-5(6)-nitro-1H-benzimidazol-1-yl)-N-arylacetamides as Antiprotozoal Agents.

Parasitic diseases are a public health problem affecting millions of people worldwide. One of the scaffolds used in several drugs for the treatment of parasitic diseases is the benzimidazole moiety, a heterocyclic aromatic compound. This compound is a crucial pharmacophore group and is considered a privileged structure in medicinal chemistry. In this study, the benzimidazole core served as a model for the synthesis of a series of 2-(2-amino-5(6)-nitro-1H-benzimidazol-1-yl)-N-arylacetamides 1-8 as benznidazole analogues. The in silico pharmacological results calculated with PASS platform exhibited chemical structures highly similar to known antiprotozoal drugs. Compounds 1-8 when evaluated in silico for acute toxicity by oral dosing, were less toxic than benznidazole. The synthesis of compounds 1-8 were carried out through reaction of 5(6)-nitro-1H-benzimidazol-2-amine (12) with 2-chlroactemides 10a-h, in the presence of K2CO3 and acetonitrile as solvent, showing an inseparable mixture of two regioisomers with the -NO2 group in position 5 or 6 with chemical yields of 60 to 94%. The prediction of the NMR spectra of molecule 1 coincided with the experimental chemical displacements of the regioisomers. Comparisons between the NMR prediction and the experimental data revealed that the regioisomer endo-1,6-NO2 predominated in the reaction. The in vitro antiparasitic activity of these compounds on intestinal unicellular parasites (Giardiaintestinalis and Entamoebahistolytica) and a urogenital tract parasite (Trichomonasvaginalis) were tested. Compound 7 showed an IC50 of 3.95 µM and was 7 time more active against G.intestinalis than benznidazole. Compounds 7 and 8 showed 4 times more activity against T.vaginalis compared with benznidazole.

Synthesis, Screening and in silico Simulations of Anti-Parasitic Propamidine/Benzimidazole Derivatives.

BACKGROUND: We designed hybrid molecules between propamidine and benzimidazole in order to retain the antiprotozoal action, but decreasing the toxic effect of the molecule. OBJECTIVE: Design and prepare 12 hybrids for testing their antiparasitic effect over three protozoa: Giardia intestinalis, Trichomonas vaginalis and Leishmania mexicana, as well as conduct several in silico simulations such as toxicological profile, molecular docking and molecular dynamics in order to understand their potential mode of action. METHODS: Hybrids 1-3, 6-9 and 12 were obtained using a chemical pathway previously reported. Compounds 4, 5, 10 and 11 were prepared using a one-pot reduction-cyclization reaction. The in vitro antiparasitic and cytotoxic activities of these compounds were conducted. It was calculated several properties such as toxicity, PK behavior, as well as docking studies and molecular dynamics of the most active compound performed in a DNA sequence dodecamer in comparison with propamidine. RESULTS: Compound 2 was 183, 127 and 202 times more active against G. intestinalis than metronidazole, pentamidine and propamidine. It was eleven times more active than pentamidine against L. mexicana. This compound showed low in vitro mammalian cytotoxicity. Molecular simulations showed a stable complex 2-DNA that occurred in the minor groove, analogous to propamidine-DNA complex. CONCLUSION: Compound 2, exhibited the higher bioactivity, especially towards G. intestinalis and L. mexicana. This study demonstrated that the replacement of benzimidazole scaffold instead of toxic amidine group in propamidine, results in an enhancement of antiprotozoal bioactivity. The preliminary molecular dynamics simulation suggests that the ligand-DNA complex is stable.

Crystal structure of N,N'-bis[2-((benzyl){[5-(di-methyl-amino)naph-tha-len-1-yl]sulfonyl}amino)ethyl]naphthalene-1,8:4,5-tetracarboximide 1,2-di-chloro-benzene tris-olvate.

The asymmetric unit of the title compound, C56H50N6O8S2·3C6H4Cl2, contains two half-mol-ecules of the parent, A and B, which both have crystallographic inversion symmetry, together with three 2,3-di-chloro-benzene mol-ecules of solvation. Mol-ecules A and B are conformationally similar, with dihedral angles between the central naphthalenedi-imide ring and the peripheral naphthalene and benzyl rings of 2.43 (7), 81.87 (7)° (A) and 3.95 (7), 84.88 (7)° (B), respectively. The conformations are stabilized by the presence of intra-molecular π-π inter-actions between the naphthalene ring and the six-membered di-imide ring of the central naphthalenedi-imide moiety, with ring centroid-to-centroid distances of 3.5795 (8) Š(A) and 3.5640 (8) Š(B). In the crystal, C-H⋯O hydrogen bonds link the mol-ecules into infinite supra-molecular chains along the c axis. These chains are inter-connected through C-H⋯π and offset π-π inter-actions, generating supra-molecular nanotubes which are filled by 1,2-di-chloro-benzene mol-ecules.

Crystal structure of (±)-[trans-cyclo-hexane-1,2-diylbis(aza-nedi-yl)]di-phospho-nium dibromide dichloro-methane disolvate.

The cation of the title solvated salt, C42H42N2P2 (2+)·2Br(-)·2CH2Cl2, lies on a crystallographic twofold rotation axis. The 1,2-di-amino-cyclo-hexane fragment has a chair conformation with two N atoms in a transoid conformation [N-C-C-N = 163.4 (2)°]. In the crystal, the cations are linked to the anions by N-H⋯Br and C-H⋯Br hydrogen bonds, forming a chain structure along the c axis. The di-chloro-methane mol-ecule takes part in the hydrogen-bond network through C-H⋯π and C-H⋯Br inter-actions.

Crystal structure of 1,3-di-cyclo-hexyl-1-[3-(pyren-1-yl)prop-anoyl]urea.

In the title compound, C33H38N2O2, each of the cyclo-hexyl rings adopts a chair conformation. The two planes involving carbonyl groups, C-(C=O)-N and N-(C=O)-N, are oriented at a dihedral angle of 62.28 (10)°. In the crystal, two neighboring mol-ecules are linked by a pair of N-H⋯O inter-actions, generating an inversion dimer. The dimers are inter-connected by C-H⋯O hydrogen bonds into a supra-molecular chain along the a-axis direction.

Crystal structure of 2,5-bis-(di-phenyl-phosphan-yl)furan.

In the title compound, C28H22OP2, each of the P atoms has an almost perfect pyramidal geometry, with C-P-C angles varying from 100.63 (10) to 102.65 (9)°. In the crystal, neighbouring mol-ecules are linked via weak C-H⋯π inter-actions, forming supra-molecular chains along the b-axis direction.

Crystal structure of 1,3-bis-(1,3-dioxoisoindolin-1-yl)urea dihydrate: a urea-based anion receptor.

The whole mol-ecule of the title compound, C17H10N4O5·2H2O, is generated by twofold rotation symmetry and it crystallized as a dihydrate. The planes of the phthalimide moieties and the urea unit are almost normal to one another, with a dihedral angle of 78.62 (9)°. In the crystal, mol-ecules are linked by N-H⋯O and O-H⋯O hydrogen bonds, forming a three-dimensional framework structure. The crystal packing also features C-H⋯O hydrogen bonds and slipped parallel π-π inter-actions [centroid-centroid distance = 3.6746 (15) Å] involving the benzene rings of neighbouring phthalimide moieties.

Crystal structure of 4-methyl-7-prop-oxy-2H-chromen-2-one.

The asymmetric unit of the title compound, C13H14O3, contains two independent mol-ecules, A and B, that are inter-connected through an offset π-π inter-action [inter-centroid separation = 3.6087 (4) Å]. The fused benzene and pyran-2-one rings in each mol-ecule are essentially coplanar, having dihedral angles of 1.22 (12) and 1.57 (12)° for mol-ecules A and B, respectively. Similarly, the coumarin ring system and the 7-prop-oxy substituent are close to being coplanar [C-C-O-C torsion angles = 2.9 (2) and 1.4 (2)° for mol-ecules A and B, respectively]. In the crystal, the mol-ecules are connected by C-H⋯O hydrogen bonds, forming supra-molecular tapes along [100] that are linked into a three-dimensional network by C-H⋯π inter-actions, as well as by the aforementioned π-π inter-actions.

Synthesis of 2-{2-[(α/ß-naphthalen-1-ylsulfonyl)amino]-1,3-thiazol-4-yl} acetamides with 11ß-hydroxysteroid dehydrogenase inhibition and in combo antidiabetic activities.

Compounds 1-10 were designed using a bioisosteric approach and were prepared using a short synthetic route. The in vitro inhibitory activity of the compounds against 11ß-hydroxysteroid dehydrogenase type 1 (11ß-HSD1) was evaluated. Compounds 5 (α-series) and 10 (ß-series) had a moderate inhibitory enzyme activity (55.26% and 67.03% inhibition at 10 µM, respectively) and were as active as BVT.14225 (positive control). Both compounds have a piperidine ring in their structure, but the most active (10) was selected to establish its in vivo antidiabetic effect using a non insulin-dependent diabetes mellitus rat model. The antidiabetic activity of compound 10 was determined at 50 mg/kg single dose in an acute model, and also by short term sub-chronic administration for 5 days. The results indicated a significant decrease of plasma glucose levels, similar than BVT.14225. Additionally, a molecular docking of the most active compounds of each series into the ligand binding pocket of one subunit of human 11ß-HSD1 was performed. In this model the oxygen atom of the sulfonamide make hydrogen bond interactions with the catalytic residues Ser170 and Ala172. We also observed important π-π interactions between the naphthyl group and Tyr177.

Discovery, synthesis and in combo studies of a tetrazole analogue of clofibric acid as a potent hypoglycemic agent.

A tetrazole isosteric analogue of clofibric acid (1) was prepared using a short synthetic route and was characterized by elemental analysis, NMR ((1)H, (13)C) spectroscopy, and single-crystal X-ray diffraction. The in vitro inhibitory activity of 1 against 11ß-hydroxysteroid dehydrogenase type 1 (11ß-HSD1) was evaluated, showing a moderate inhibitory enzyme activity (51.17% of inhibition at 10 µM), being more active than clofibrate and clofibric acid. The antidiabetic activity of compound 1 was determined at 50 mg/Kg single dose using a non insulin dependent diabetes mellitus rat model. The results indicated a significant decrease of plasma glucose levels, during the 7h post-administration. Additionally, we performed a molecular docking of 1 into the ligand binding pocket of one subunit of human 11ß-HSD1. In this model, compound 1 binds into the catalytic site of 11ß-HSD1 in two different orientations. Both of them, show important short contacts with the catalytic residues Ser 170, Tyr 183, Asp 259 and also with the nicotinamide ring of NADP(+).

(Furfuryl-amino)-triphenyl-phospho-nium bromide.

In the title salt, C23H21NOP(+)·Br(-), the dihedral angles between the phenyl rings are 70.41 (18), 73.6 (2) and 80.85 (19)°. In the crystal, neighboring mol-ecules are linked through an N-H⋯Br hydrogen bond and four weak C-H⋯Br contacts, forming a three-dimensional network.

2-(4-Acetamido-phen-oxy)-2-methyl-propanoic acid.

In the title compound, C12H15NO4, the dihedral angle between the acetamide group and the ring is 29.6 (2)(su?)°. In the crystal mol-ecules are linked through N-H⋯O and O-H⋯O hydrogen bonds, thereby forming corrugated sheets propagating in the ac plane. These sheets are composed of R4(4)(28) graph-set motifs.

(E)-2-{[2-(2-Hy-droxy-ethyl-amino)-ethyl-imino]-meth-yl}phenol.

The asymmetric unit of the title compound, C(11)H(16)N(2)O(2), contains two independent conformational isomers which show intra-molecular aromatic-imine O-H⋯N hydrogen bonds. In the crystal, neighboring mol-ecules are linked through inter-molecular aliphatic-aliphatic O-H⋯N, aliphatic-aromatic N-H⋯O and C-H⋯O inter-actions into hydrogen-bonded layers parallel to the ab plane.

Benzene-1,4-diboronic acid-4,4'-bipyridine-water (1/2/2).

In the presence of water, benzene-1,4-diboronic acid (1,4-bdba) and 4,4'-bipyridine (4,4'-bpy) form a cocrystal of composition (1,4-bdba)(4,4'-bpy)(2)(H(2)O)(2), in which the molecular components are organized in two, so far unknown, cyclophane-type hydrogen-bonding patterns. The asymmetric unit of the title compound, C(6)H(8)B(2)O(4).2C(10)H(8)N(2).2H(2)O, contains two 4,4'-bpy, two water molecules and two halves of 1,4-bdba molecules arranged around crystallographic inversion centers. The occurrence of O-H...O and O-H...N hydrogen bonds involving the water molecules and all O atoms of boronic acid gives rise to a two-dimensional hydrogen-bonded layer structure that develops parallel to the (01-4) plane. This supramolecular organization is reinforced by pi-pi interactions between symmetry-related 4,4'-bpy molecules.