Synthesis, Characterization, and Preliminary In Vitro Cytotoxic Evaluation of a Series of 2-Substituted Benzo [d] [1,3] Azoles.

A series of benzo [d] [1,3] azoles 2-substituted with benzyl- and allyl-sulfanyl groups were synthesized, and their cytotoxic activities were in vitro evaluated against a panel of six human cancer cell lines. The results showed that compounds BTA-1 and BMZ-2 have the best inhibitory effects, compound BMZ-2 being comparable in some cases with the reference drug tamoxifen and exhibiting a low cytotoxic effect against healthy cells. In silico molecular coupling studies at the tamoxifen binding site of ERα and GPER receptors revealed affinity and the possible mode of interaction of both compounds BTA-1 and BMZ-2.

Further Approaches in the Design of Antitumor Agents with Response to Cell Resistance: Looking toward Aza Crown Ether-dtc Complexes.

The dianionic aza crown ether-dtc N,N'-bis(dithiocarbamate)-1,10-diaza-18-crown-6 (L2-) is a versatile ligand capable of yielding binuclear complexes with group 10 elements, also known as Ni-triade, [µ-(κ2-S,-S'-L)M2(PPh3)4]Cl2 (M = Pd (1), Pt (2)), [µ-(κ2-S,-S'-L)M2(PPh3)4](BPh4)2 (M = Pd (3), Pt (4)), and µ-(κ-S,-S'-L)Ni2(PPh3)2Cl2 (5), and has proven to be an excellent option to the design of metal-based drugs able to provide multiple response to cell resistance. Palladium and platinum complexes, 1 and 2, were tested for cytotoxicity in the human cervix carcinoma cell line HeLa-229, the human ovarian carcinoma cell line A2780, and the cisplatin-resistant mutant A2780cis, finding significant activity toward all three cancer cell lines, with low micromolar IC50 values, comparable to cisplatin. Markedly, against the cisplatin resistant cell line A2780cis, compound 2 exhibits better cytotoxic activity than the clinical drug (IC50 = 2.3 ± 0.2 µM for 2 versus 3.6 ± 0.5 µM for cisplatin). Moreover, an enhancement of the antitumor response is achieved when adding an equimolar amount of alkali metal chloride (NaCl or KCl) to the medium, for instance, testing compound 1 against the cisplatin-resistant A2780cis cells, the IC50 decreases from 9.3 ± 0.4 to 7.4 ± 0.3 and 5.4 ± 0.1 µM, respectively, after addition of the salt solution. For the platinum derivative 2, the IC50 improves by ca. 40% reaching 1.3 ± 0.1 µM when potassium chloride is added. Likewise, the resistant factor found for 2 (RF = 1) confirms that this complex circumvents cisplatin-resistance in A2780cis and is improved with the addition of potassium chloride (RF = 0.65). The presence of the aza crown ether moiety as linker in the systems studied herein is a key point since, in addition to allowing and facilitating interaction with alkali metal ions, this unit is flexible enough to adapt to a variety of environments, as confirmed by the X-ray crystal structures described, where different conformations and ways to fold in are found. In order to gain insight into the electronic and structural facts involved in the interaction of complex 2 with the alkali metal ions, a DFT study was performed, and the description of the molecular electrostatic potentials (MEPs) is also presented.

Facile Synthesis of a Series of Non-Symmetric Thioethers Including a Benzothiazole Moiety and Their Use as Efficient In Vitro anti-Trypanosoma cruzi Agents.

A series of 2-benzylsulfanyl benzothiazole (BTA) derivatives were synthesized and fully characterized and in vitro tested against two strains of T. cruzi (NINOA and INC-5), exhibiting good activities at low concentrations.

(tert-But-yl)(2-hy-droxy-eth-yl)ammonium chloride.

In the cation of the title mol-ecular salt, C6H16NO(+)·Cl(-), the N-C-C-O torsion angle is 176.5 (2)°. In the crystal, the cations and chloride ions are linked by N-H⋯O and O-H⋯O hydrogen bonds, generating a two-dimensional network parallel to (100).

Bis(2,3-di-chloro-phen-yl) di-sulfide.

The title compound, C12H6Cl4S2, features an S-S bond [2.0252 (8) Å] that bridges two 2,3-di-chloro-phenyl rings with a C-S-S-C torsion angle of 88.35 (11)°. The benzene rings are normal one to the other with a dihedral angle of 89.83 (11)°. The crystal structure features inter-molecular Cl⋯Cl [3.4763 (11) Å] and π-π stacking inter-actions [centroid-centroid distances = 3.696 (1) and 3.641 (2) Å]. Intra-molecular C-H⋯S inter-actions are also observed.

Di-chlorido-(4,4'-di-tert-butyl-2,2'-bi-pyridine-κ(2) N,N')palladium(II) dimethyl sulfoxide monosolvate monohydrate.

The title compound, [PdCl2(C18H24N2)]·(CH3)2SO·H2O, the Pd(II) ion is in a distorted square-planar geometry. The Pd-N bond distances are 2.022 (2) and 2.027 (2) Å, the Pd-Cl bond distances are 2.2880 (7) and 2.2833 (7) Å, and the ligand bite angle is 80.07 (9)°. The dimethyl sulfoxide and water mol-ecules form linear chains along [100] by O-H⋯O and O-H⋯S hydrogen bonds, generating eight- and 12-membered rings. C-H⋯Cl inter-actions link the chains, forming a three-dimensional arrangement. In addition, the 4,4-di-tert-butyl-2,2'-bi-pyridine ligand exhibits π-π stacking inter-actions [centroid-centroid distances = 3.8741 (15) and 3.8353 (15) Å]. The DMSO solvent is disordered and was refined with an occupancy ratio of 0.866 (3):0.134 (3).

(2,2'-Bi-pyridine-κ(2) N,N')di-chloridopalladium(II) 1,4-dioxane hemisolvate.

The asymmetric unit of the title compound, [PdCl2(C10H8N2)]·0.5C4H8O2, consists of one Pd(II) complex mol-ecule and a half-mol-ecule of 1,4-dioxane, the complete mol-ecule being generated by inversion symmetry. The Pd(II) atom has an almost square-planar coordination formed by the 2,2'-bi-pyridine ligand and two chloride ligands. Two intra-molecular C-H⋯Cl hydrogen bonds occur. In the crystal, the Pd(II) complex and 1,4-dioxane mol-ecules are connected by C-H⋯O hydrogen bonds, forming a layer parallel to (10-1). Within the layer, weak π-π inter-actions [centroid-centroid distance = 3.817 (4) Å] are observed between the pyridine rings.

trans-Chlorido-(4-fluoro-benzene-thiol-ato-κS)bis-(tri-phenyl-phosphane-κP)palladium(II) methanol hemisolvate.

The title compound, [Pd(SC6H4F-p)Cl(PPh3)2]·0.5CH3OH, features a Pd(II) complex with two tri-phenyl-phosphane (PPh3) ligands arranged in a trans conformation, with one chloride and one 4-fluoro-benzene-thiol-ate ligand completing the coordination sphere, giving rise to a slightly distorted square-planar geometry of the Pd(II) ion. The methanol solvent mol-ecule is disordered about an inversion centre with an occupancy of 0.25 for each molecule. In the crystal, weak C-H⋯Cl hydrogen-bonding inter-actions between the complex mol-ecules generate chain frameworks parallel to [010].

Chlorido[2,3,5,6-tetra-kis-(tert-butyl-sulfanylmeth-yl)phenyl-κ(3) S (2),C (1),S (6)]palladium(II) dichloro-methane monosolvate.

The title compound, [Pd(C26H45S4)Cl]·CH2Cl2, crystallizes with a disordered dichloro-methane solvent mol-ecule [occupancy ratio = 0.67 (4):0.33 (4)]. Two of the tert-butyl groups are also disordered [occupancy ratios = 0.70 (5):0.30 (5) and 0.63 (4):0.37 (4)]. Although the pincer ligand offers the possibility for coordination of two different metal atoms, the present structure shows only the coordination of a single Pd(II) atom in a typical S-C-S tridentate pincer manner. The Pd(II) atom is in a slightly distorted square-planar environment with the two tert-butyl-sulfanyl groups arranged in a trans con-formation and with a chloride ligand trans to the σ-bonded aromatic C atom. The structure exhibits a durene-like ligand frame, forming a dihedral angle of 13.6 (4)° with the metal coordination (Pd/S/S/Cl/C) environment. It is noteworthy that the tert-butyl groups are found in a syn arrangement, this being different to that found previously by Loeb, Shimizu & Wisner [(1998). Organometallics, 17, 2324-2327].

cis-Bis(O-methyl-dithio-carbonato-κ(2) S,S')bis-(tri-phenyl-phosphane-κP)ruthenium(II).

In the title compound, [Ru(CH3OCS2)2(C18H15P)2], the Ru(II) atom is in a distorted octa-hedral coordination by two xanthate anions (CH3OCS2) and two tri-phenyl-phosphane (PPh3) ligands. Both bidentate xanthate ligands coordinate the Ru(II) atom with two slightly different Ru-S bond lengths but with virtually equal bite angles [71.57 (4) and 71.58 (3)°]. The packing of the complexes is assured by C-H⋯O and C-H⋯π inter-actions.

1-(4-Chloro-phenyl)-2-[tris-(4-methyl-phenyl)-λ(5)-phosphanyl-idene]butane-1,3-dione.

In the title ylide, C(31)H(28)ClO(2)P [common name α-acetyl-α-p-chloro-benzoyl-methyl-enetri(p-tol-yl)phospho-rane], the dihedral angle between the 4-chloro-phenyl ring and that of the ylide moiety is 66.15 (10)°. The geometry around the P atom is slightly distorted tetra-hedral [angle range = 105.22 (8)-115.52 (9)°] and the carbonyl O atoms are syn-oriented with respect to the P atom. The ylide group is close to planar [maximum deviation from the least-squares plane = 0.006 (2) Å] and the P-C, C-C and C=O bond lengths are consistent with electron delocalization involving the O atoms.

1,3-Bis[(tert-butylsulfanyl)methyl]-2,4,6-trimethylbenzene.

The complete mol-ecule of the title compound, C(19)H(32)S(2), is generated by crystallorgaphic twofold symmetry, with three C atoms lying on the axis. The C(ar)-C-S-C (ar = aromatic) torsion angle is 156.2 (2) °. In the crystal, the mol-ecules are linked by very weak C-H⋯S inter-actions, generating [001] chains.

A second monoclinic polymorph of (E)-phen-yl(pyridin-2-yl)methanone oxime.

The title compound, C(12)H(10)N(2)O, a second monoclinic poly-morph of (E)-phen-yl(pyridin-2-yl)methanone oxime crystallizes in the space group P2(1)/n (Z = 4). The previously reported polymorph [Taga et al. (1990 ▶). Acta Cryst. C46, 2241-2243] occurs in the space group C2/c (Z = 8). In the crystal, pairs of bifurcated O-H⋯(N,O) hydrogen bonds link the mol-ecules into inversion dimers. The dimers are linked by C-H⋯π inter-actions, forming a linear arrangement. The dihedral angle between the pyridine and phenyl rings is 67.70 (8)°.

trans-Bis(µ-benzene-thiol-ato-κ(2) S:S)bis[chlorido-(tri-phenyl-phosphane-κP)palladium(II)] chloro-form disolvate.

The title compound, [Pd2Cl2(C6H5S)2(C18H15P)2]·2CHCl3, contains a centrosymmetric dinuclear palladium complex with the Pd(II) cation in a slightly distorted square-planar coordination environment. The Pd(II) cations are bridged by the S atoms of two benzene-thiol-ate ligands with different Pd-S distances [2.2970 (11) and 2.3676 (11) Å]. The coordination of the metal atom is completed by a chloride anion [2.3383 (11) Å] and a tri-phenyl-phosphane ligand [2.2787 (11) Å]. Weak C-H⋯Cl inter-actions are present between complex mol-ecules and the CHCl3 solvent mol-ecule. The latter is disordered over two positions in a 0.792 (8):0.208 (8) ratio. The crystal under investigation was found to be twinned by nonmerohedry, with a fraction of 73.4 (1)% for the major twin component.

N-{1,2-Bis(pyridin-3-yl)-2-[(E)-(pyridin-3-yl)methyl-idene-amino]-eth-yl}nicotinamide.

In the title compound, C24H20N6O, the pyridin-3-yl groups on the ethyl-ene fragment are found in a trans conformation with a C(py)-C(e)-C(e)-C(py) (py = pyridine, e = ethylene) torsion angle of 179.2 (3)°. The dihedral angle between the pyridine rings is 3.5 (1)°. In the crystal, N-H⋯N and C-H⋯O=C inter-actions form a layer arrangement parallel to the bc plane. The compound displays disorder of the ethyl-ene fragment over two positions with an occupancy ratio of 0.676 (7) to 0.324 (7) that extends into the amide section of the nicotinamide moiety.

N-Benzyl-2-hy-droxy-ethanaminium cyanurate.

In the cation of the title compound C9H14ON(+)·C3H2O3N3 (-), the benzyl-amine C-N bond subtends a dihedral angle of 78.3 (2)° with the phenyl ring. The cyanurate anion is in the usual keto-form and shows an r.m.s. deviation from planarity of 0.010 Å. In the crystal, the cyanurate anions form N-H⋯O hydrogen-bonded zigzag ribbons along [001]. These ribbons are crosslinked by the organocations via O-H⋯N and N-H⋯O hydrogen bonds, forming bilayers parallel to (010) which are held together along [010] by slipped π-π inter-actions between pairs of cyanurate anions [shortest contact distances C⋯C = 3.479 (2), O⋯N = 3.400 (2); centroid-centroid distance= 4.5946 (9) Å] and between cyanurate and phenyl rings [centroid-centroid distance = 3.7924 (12) Å, ring-ring angle = 11.99 (10)°].

Role of Metal Cations of Copper, Iron, and Aluminum and Multifunctional Ligands in Alzheimer's Disease: Experimental and Computational Insights.

Alzheimer's disease (AD) is the most common form of dementia, affecting millions of people around the world. Even though the causes of AD are not completely understood due to its multifactorial nature, some neuropathological hallmarks of its development have been related to the high concentration of some metal cations. These roles include the participation of these metal cations in the production of reactive oxygen species, which have been involved in neuronal damage. In order to avoid the increment in the oxidative stress, multifunctional ligands used to coordinate these metal cations have been proposed as a possible treatment to AD. In this review, we present the recent advances in experimental and computational works aiming to understand the role of two redox active and essential transition-metal cations (Cu and Fe) and one nonbiological metal (Al) and the recent proposals on the development of multifunctional ligands to stop or revert the damaging effects promoted by these metal cations.

Pincer Ligands as Multifunctional Agents for Alzheimer's Copper Dysregulation and Oxidative Stress: A Computational Evaluation.

Alzheimer's disease (AD) is the most common form of dementia worldwide, affecting millions of people around the globe. AD is characterized by different pathologies being beta-amyloid (Aß) plaque formation, metal ion dysregulation, and oxidative stress (OS) central topics under investigation. Copper-Aß complexes have been shown to induce catalytic hydrogen peroxide formation and increase OS in the brain leading to neuronal death. Pincer-type compounds are tridentate ligands that coordinate metals in a planar fashion whose properties can be tuned via group substitutions, giving rise to many possibilities in catalysis and drug discovery. In this work we evaluated the potential pharmaceutical activity of 26 pincer compounds in AD's copper ion-related oxidative stress framework. In this sense, four key aspects were considered: 1) Lipinski's rule of five, 2) blood-brain barrier permeation, 3) standard reduction potential (SRP) of the formed copper complexes, and 4) the ligand's affinity towards copper cations. The evaluation of these criteria was performed by means of bioinformatic tools and electronic structure calculations at the DFT level of theory. Our results suggest that two compounds from this set are potential antioxidant agents, whereas five of them are promissory distributor-like compounds in the context of AD.

Computational Evaluation of the Potential Pharmacological Activity of Salen-Type Ligands in Alzheimer's Disease.

BACKGROUND: Alzheimer's disease (AD) is the most common form of dementia representing from 60% to 70% of the cases globally. It is a multifactorial disease that, among its many pathological characteristics, has been found to provoke the metal ion dysregulation in the brain, along with an increase in the oxidative stress. There is proof that metallic complexes formed by the amyloid-ß peptide (Aß) and extraneuronal copper can catalyze the production of reactive oxygen species, leading to an increase in oxidative stress, promoting neuronal death. Due to this interaction, bioavailable copper has become an important redox active target to consider within the search protocols of multifunctional agents for AD's treatment. OBJECTIVE: In this study, we examined by using bioinformatics and electronic structure calculations the potential application of 44 salen-type copper chelating ligands and 12 further proposed molecules as possible multifunctional agents in the context of AD. METHODS: The candidates were evaluated by combining bioinformatic tools and electronic structure calculations, which allowed us to classify the molecules as potential antioxidants, redistributor-like compounds, and the newly proposed suppressor mechanism. RESULTS: This evaluation demonstrate that salen-type ligands exhibit properties suitable for interfering in the chain of copper-induced oxidative stress reactions present in AD and potential redistributor and suppressor activity for copper ions. Finally, a novel set of plausible candidates is proposed and evaluated. CONCLUSION: According to the evaluated criteria, a subset of 13 salen-type candidates was found to exhibit promissory pharmacological properties in the AD framework and were classified according to three plausible action mechanisms.

Ball-Milling Preparation of the Drug-Drug Solid Form of Pioglitazone-Rosuvastatin at Different Molar Ratios: Characterization and Intrinsic Dissolution Rates Evaluation.

Ball-milling using neat grinding (NG) or liquid-assisted grinding (LAG) by varying the polarity of the solvents allowed access to various drug-drug solid forms of pioglitazone hydrochloride (PGZ·HCl) and rosuvastatin calcium (RSV). Using NG, the coamorphous form was formed from the reaction of pioglitazone hydrochloride (PGZ·HCl) and rosuvastatin calcium (RSV) in a 2:1 molar ratio. The formation of the expected coamorphous salt could not be corroborated by FT-IR, but DSC data showed that it was indeed a single-phase amorphous mixture. By varying the molar ratios of the reactants, either keeping PGZ·HCl constant and varying RSV or vice versa, another coamorphous form was obtained when a 1:1 molar ratio was employed. In the case of the other outcomes, it was observed that they were a mixture of solid forms coexisting simultaneously with the coamorphous forms (1:1 or 2:1) together with the drug that was in excess. When RSV was in excess, it was in an amorphous form. In the case of PGZ·HCl, it was found in a semicrystalline form. The intrinsic dissolution rates (IDRs) of the solid forms of PGZ·HCl-RSV in stoichiometric ratios (1:1, 2:1, 1:4, 6:1, and 1:10) were evaluated. Interestingly, a synchronized release of both drugs in the dissolution medium was observed. In the case of the release of RSV, there were no improvements in the dissolution profiles, because the acidic media caused the formation of degradation products, limiting any probable modification in the dissolution processes. However, the coamorphous 2:1 form exhibited an improvement of 1.03 times with respect to pure PGZ·HCl. It is proposed that the modification of the dissolution process of the coamorphous 2:1 form was limited by changes in the pH of the media as RSV consumes protons from the media due to degradation processes.