Influence of amodiaquine on the antimalarial activity of ellagic acid: crystallographic and biological studies.

In the search for new antimalarial drugs, design of hybrid molecules is recommended to improve biological activity and to decrease the risk of parasite resistance development. Ellagic acid, as an inhibitor of Plasmodium glutathione, presents an original mode of action and thus appears as a promising antiplasmodial compound. A new complex (AQ-EA) consisting of the well-known antimalarial drug, amodiaquine, and ellagic acid was obtained. The studied crystal structure of AQ-EA showed that the triclinic centrosymmetrical unit cell of the crystal contains two molecules of amodiaquine (AQ) and two symmetrically independent molecules of ellagic acid (EA). The packing of the molecules in the crystal is dominated by hydrogen bonds between AQ and EA. The antiplasmodial activity of the hybrid complex AQ-EA was also determined and compared with the values of IC50 for AQ and EA separately. Potentiation assays between both molecules were conducted to understand the pharmacological interactions between AQ and EA against Plasmodium falciparum in vitro. The hybrid complex AQ-EA (IC50 of 47 nm) showed improved antiplasmodial activity in comparison with EA alone.

N-(2-Bromo-benz-yl)cinchoninium bromide.

The title compound {systematic name: 1-(2-bromo-benz-yl)-5-ethenyl-2-[hy-droxy(quinolin-4-yl)meth-yl]-1-aza-bicyclo-[2.2.2]octan-1-ium bromide}, C(26)H(28)BrN(2)O(+)·Br(-), is a chiral quater-nary ammonium salt of one of the Cinchona alkaloids. The planes of the quinoline and of the bromo-benzyl substituent are inclined to one another by 9.11 (9)°. A weak intra-molecular C-H⋯O hydrogen bond occurs. The crystal structure features strong O-H⋯Br hydrogen bonds and weak C-H⋯Br inter-actions.

In search of the malarial parasite: biographical sketches of the blood stain contributors.

Methylene blue was synthesized by Caro in 1876 at BASF, a chemical company. Six years later, Koch employed methylene blue when he discovered the tubercle bacillus. In 1880, Ehrlich described what he termed "neutral" dyes: mixtures of acidic and basic dyes for the differentiation of cells in peripheral blood smears. Bernthsen prepared in 1886 a relatively pure dye, obtained by decomposition of methylene blue, and called it methylene azure. In 1891, Malachowski developed a method which used mixtures of eosin and "ripened" methylene blue that not only differentiated blood cells, but also demonstrated the nuclei of malarial parasites. Romanowsky later performed the same feat with an unrepeatable method. A number of "ripening" (polychroming) techniques were investigated by different groups (Nocht 1899) but the aqueous dye solutions produced were unstable and precipitated rapidly. Subsequently, methanol was introduced as a solvent for the dye precipitate (Jenner 1899) and techniques were developed that utilized the fixative properties of the methanolic solution prior to aqueous dilution for staining (Wright 1902). Giemsa (1902) further improved these techniques by developing more precise methods of methylene blue demethylation and adding glycerol as a stabilizing agent to the methanol solvent. Today, the Malachowski-Wright-Giemsa stain continues to be regarded as the world's standard diagnostic technique for malaria.

X-ray and molecular modelling in fragment-based design of three small quinoline scaffolds for HIV integrase inhibitors.

Crystal structures of three small molecular scaffolds based on quinoline, 2-methylquinoline-5,8-dione, 5-hydroxy-quinaldine-6-carboxylic acid and 8-hydroxy-quinaldine-7-carboxylic acid, were characterised. 5-Hydroxy-quinaldine-6-carboxylic acid was co-crystallized with cobalt(II) chloride to form a model of divalent metal cation-ligand interactions for potential HIV integrase inhibitors. Molecular docking into active site of HIV IN was also performed on 1WKN PDB file. Selected ligand-protein interactions have been found specific for active compounds. Studied structures can be used as scaffolds in fragment-based design of new potent drugs.

Channel-like crystal structure of cinchoninium L-O-phosphoserine salt dihydrate.

Studies on the interactions between L-O- phosphoserine, as one of the simplest fragments of membrane components, and the Cinchona alkaloid cinchonine, in the crystalline state were performed. Cinchoninium L-O-phosposerine salt dihydrate (PhSerCin) crystallizes in a monoclinic crystal system, space group P2(1), with unit cell parameters: a = 8.45400(10) A, b = 7.17100(10) A, c = 20.7760(4) A, alpha = 90 degrees , beta = 98.7830(10) degrees , gamma = 90 degrees , Z = 2. The asymmetric unit consists of the cinchoninium cation linked by hydrogen bonds to a phosphoserine anion and two water molecules. Intermolecular hydrogen bonds connecting phosphoserine anions via water molecules form chains extended along the b axis. Two such chains symmetrically related by twofold screw axis create a "channel." On both sides of this channel cinchonine cations are attached by hydrogen bonds in which the atoms N1, O12, and water molecules participate. This arrangement mimics the system of bilayer biological membrane.

Bitter sweeteners: tetrazole derivatives of arylsulfonylalcanoids--synthesis, structure and comparative study.

Within a research project aimed at the design of new sweeteners, the tetrazole moiety was introduced to arylsulfonylalkanoic acids (ASA) as a bioisostere of the carboxyl group. The crystal structures of four newly synthesized tetrazole derivatives and one intermediate product of the reaction were determined in order to explain the bitter taste of these compounds. Three chiral compounds crystallize as racemic mixtures in centrosymmetric space groups of the monoclinic system, whereas the non-chiral compound, with a higher dipole moment, crystallizes in the polar space group Cc. Intermolecular N-H...N hydrogen bonds between tetrazole moieties were observed in all four structures and are compared with the analogous interactions observed in tetrazole derivatives deposited in the Cambridge Structural Database (CSD). Specifically, the typical N1-H...N4 as well as N1-H...N3 interactions, which are less abundant in the CSD, are described. The formation of the latter interaction type can be hypothetically explained by an asymmetry of pi-electron distribution in the tetrazole rings caused by the crystalline environment. Important features of the crystal architecture are the chains of molecules linked by N-H...N bonds. A possible reason for the lack of a sweet taste of the tetrazoles investigated may be the improper position of the tetrazole H atom, and the mutual orientation of the proton donor and acceptor in their molecules. This orientation does not allow the tetrazoles to interact with the sweet-taste receptor in a way similar to that of ASA. The bitter taste of the investigated compounds needs further study.

Geometry of GPPE binding to picrate and to the urokinase type plasminogen activator.

Crystal structure of 2-(4-guanidynephenyl)-1-phenyl-ethanone (GPPE) in two different environments was determined in order to compare the binding geometry of these compound to a simple picrate anion and to protein, urokinase-type plasminogen activator (uPA), which may be treated as a target for anti-cancer drugs. It was shown that the conformation and the hydrogen-bonding formation by GPPE molecule are similar in both environments, but several important differences were discovered and described.

Crystal and molecular structures of trichloro-cobalt(II) complexes of epiquinine, epiquinidine, and epidihydrocinchonine.

Cinchona alkaloids are very well known antimalarials but the mechanism of their biological action still remains to be elucidated. The structural studies of active erythro and inactive threo alkaloid complexes are an important step to this aim. In this paper results of crystal structure analysis of three cobalt complexes of threo alkaloids are presented: (epiquininium)trichlorocobalt(II) (EpiQnCoCl3), (epiquinidinium)trichlorocobalt(II) (EpiQdCoCl3) and (epidihydrocinchoninium)trichlorocobalt(II) (EpiCnCoCl3). The complexes are zwitterions in which trichlorocobalt substituents are coordinated to quinoline nitrogen atoms and quinuclidine nitrogen atoms are protonated. EpiQnCoCl3 adopts uncommon conformation with quinoline moiety oriented in the opposite direction in comparison to the analogous uncomplexed alkaloid. The packing in the crystal structures is determined mainly by the hydrogen bonds, in which the chlorine atoms of substituents and solvent molecules contribute. Atoms participating in hydrogen bonds in EpiQnCoCl3 and EpiQdCoCl3 form large rings, while in EpiCnCoCl3 only chains are present. Solvent molecules are very important for the packing mode. In contrast to most erythro alkaloids, the hydroxyl oxygen atom in the title complexes forms weak or not well defined hydrogen bonds. The contribution of very weak intramolecular interactions N1--H1...O12 cannot be excluded. Such "trace" interactions can be considered a relic of the unprotonated status of an epi alkaloid.

Antifungal properties of new series of quinoline derivatives.

The series of quinoline derivatives were prepared. The synthetic approach, analytical, and spectroscopic data of all synthesized compounds are presented. All the prepared derivatives were analyzed using the reversed-phase high performance liquid chromatography (RP-HPLC) method for the lipophilicity measurement. In the present study, the correlation between RP-HPLC retention parameter log K (the logarithm of capacity factor K) and various calculated log P data is shown. The relationships between the lipophilicity and the chemical structure of the studied compounds are discussed as well. The prepared compounds were tested for their in vitro antifungal activity. 2-[(3-Hydroxyphenylimino)methyl]quinolin-8-ol (8), 2-[(4-hydroxyphenylimino)methyl]quinolin-8-ol (9) and 2-[(2,5-dichloro-4-nitrophenylamino)methoxymethyl]quinolin-8-ol (10) showed in vitro antifungal activity comparable to or higher than that of the standard fluconazole. Structure-activity relationships among the chemical structure, the physical properties, and the biological activities of the evaluated compounds are discussed in the article.

The crystal structures of 3-TAPAP in complexes with the urokinase-type plasminogen activator and picrate.

The urokinase-type plasminogen activator (uPA) is a protein involved in tissue remodeling and other biological processes. The inhibitors of uPA have been shown to prevent the spread of metastasis and tumor growth, and accordingly this enzyme is widely accepted as a promising anticancer target. In this work, we have investigated the conformation of the uPA inhibitor 3-TAPAP in two different crystalline environments of a picrate and a uPA complex. These structures were compared to the known structure of the 3-TAPAP in the complex with trypsin. In the complexes with the proteins, trypsin, and uPA, the binding mode of 3-TAPAP is similar. A larger difference in the conformation, in the comparison to these structures, has been observed by us in the 3-TAPAP picrate crystal. This observation contradicts the hypothesis that 3-TAPAP derivatives inhibit serine proteinases in preformed stable conformations.

Intermolecular interactions in the crystal structures of potential HIV-1 integrase inhibitors.

2-[(2,5-dichloro-4-nitro-phenylamino)-methoxy-methyl]-8-hydroxy-quinoline 1 and 2-methyl-quinoline-5,8-dione-5-oxime 2 were obtained as potential HIV-1 integrase inhibitors and analyzed by X-ray crystallography. Semiempirical theoretical calculations of energy preferred conformations were also carried out. The crystal structures of both compounds are stabilized via hydrogen bonds and pi-pi stacking interactions. The planarity of compound 1 is caused by intramolecular hydrogen bonds.

Conformation stability and organization of mefloquine molecules in different environments.

The crystal structures of mefloquine base, [C17H16F6N2O], and two salts of mefloquine: hydrochloride [(C17H17F6N2O)+]3[Cl-]3.3H2O and hydrochloride tetrachlorocobaltate [(C17H17F6N2O)+]3Cl-[CoCl4]2-.C2H6O.H2O, were determined by X-ray diffraction measurements. A comparison of the crystal structures of mefloquine in three different crystalline environments shows that their conformations are stable regardless of mefloquine being a base or a salt. In addition, the conformation of mefloquine is similar to those of crystalline Cinchona alkaloids. The CF3 substituents in the quinoline moiety affect the packing of molecules.

Cobalt complexes with cinchonidine and quinidine: effect of C8/C9 stereochemistry and 6'-substitution on intermolecular interactions.

The title compounds, (cinchonidinium)trichlorocobalt(II) [(C(19)H(23)ON(2))CoCl(3)] (CoCdn) and (quinidinium)trichlorocobalt(II) [(C(20)H(25)O(2)N(2))CoCl(3)] (CoQd), are zwitterions that differ in absolute configuration and conformation. In both complexes, the sp(3) nitrogen of quinuclidine is protonated, whereas the sp(2) nitrogen of quinoline is linked to the Co(II) atom, which coordinates three chlorine atoms in distorted tetrahedral geometry. The mutual orientations of the quinoline and quinuclidine moieties in CoCdn and CoQd differ significantly because of different hydrogen bonding involving the hydroxyl group. In both complexes, the quinuclidine NH groups and hydroxyl groups are hydrogen-bond donors to the chlorine atoms of Co(II) tetrahedra. In CoQd the hydrogen bonding leads to formation of a nine-membered ring consisting of Co, two chlorines, and a fragment of the quinidine molecule. A comparison of the crystal structures of four Cinchona alkaloid complexes with trichlorocobalt(II) shows that their space groups are determined by the absolute configuration of the alkaloid, whereas the hydrogen-bonding pattern is mainly affected by the substituent in the quinoline ring, i.e., by hydrogen or methoxyl group.

Crystal and molecular structures of new enantiopure quinuclidines.

X-ray crystal structure analysis was performed on single crystals of two diastereomeric enantiopure quinuclidines, (3R,8R)-3-vinyl-8-hydroxymethyl-quinuclidine (quincoridine, QCD) and (3R,8S)-3-vinyl-8-hydroxymethyl-quinuclidine (quincorine, QCI) as their salts with tartaric and p-toluenesulphonate anions, respectively. The molecules of these quinuclidine derivatives are considered here as fragments of the Cinchona alkaloids, quinidine and quinine. A comparison of the conformational features of QCD, QCI, and Cinchona alkaloids in the crystalline state shows that the molecular geometry of the title compounds is similar to that of threo-alkaloids (e.g., R,R isomer of epicinchonine) rather than to quinidine and quinine. The packing of the molecules in both structures is dominated by intermolecular hydrogen bonds.

Cobalt complex of cinchonine: intermolecular interactions in two crystalline modifications.

Two crystalline modifications of cinchonine cobalt complex, C19H23Cl3CoN2O, were obtained from mixture of saturated alcohol solutions of CoCl3 x 6H2O and cinchonine. The X-ray structure analysis revealed that the asymmetric unit of one modification, CoCn1, contains only zwitterionic molecules of the complex. In the asymmetric unit of the other, CoCn2, there are two molecules of the title compound and two molecules of ethanol. The influence of the absolute configuration, the CoCl3 coordination with quinoline, and the presence of alcohol molecules on the studied structures was established by comparison of the crystal and molecular structures of both cobalt complexes with the analogous quinine complex and zinc complex of cinchonine. The interactions that dominate in the packing of the molecules in both structures are intermolecular hydrogen bonds. They form characteristic ring systems, depending on the presence of the alcohol molecules. The ring features are also related to the absolute configuration of the alkaloid.

New crystalline complex of quinine and quinidine.

A new complex of diastereoisomeric pair, quinine and quinidine (QQd), was obtained from a mixture of saturated ethanol solutions of quinine and quinidine (0.5:1). The complex crystallises in the triclinic system, space group P1, and contains two molecules of quinine, two molecules of quinidine and four water molecules in the asymmetric unit. The X-ray structure analysis of a single crystal revealed that quinine and quinidine molecules occur in the so-called open conformation, characteristic for Cinchona alkaloids, whenever they are engaged in intermolecular hydrogen bonds. Quinine and quinidine molecules are organized in two very similar kinds of chains. In each chain the links that contain 14-membered rings can be distinguished. Within these rings quinine and quinidine molecules interact via intermolecular hydrogen bonds between the quinuclidine nitrogens and hydroxyl groups, mediated by water molecules. The links are connected with each other by hydrogen bonds between water molecules and nitrogens of the quinoline moieties, which interact via pi-pi stacking. The architecture of the hydrogen bond system in QQd, compared to those observed in the crystal structures of nonhydrated quinidine, cinchonine and cinchonidine, reveals the effect of the co-crystallizing water on the molecular packing. In nonhydrated alkaloid structures the hydrogen-bonded molecules form helical chains, different from those observed in the hydrated QQd complex and hydrated quinine toluene solvate (QTol). Comparison of QQd structure with that of QTol suggests that while the intermolecular hydrogen bonds in the system quinine-water-quinidine-water are very similar to those in quinine-water-quinine-water system, the mode of pi-pi interaction between their quinoline moieties depends on the absolute configuration of the interacting alkaloid molecules.