Antonio C. Doriguetto

Leishmanicidal activity of benzophenones and extracts from Garcinia brasiliensis Mart. fruits

Infections by protozoans of the genus Leishmania are the major worldwide health problem, with high endemicity in developing countries. The drugs of choice for the treatment of leishmaniasis are the pentavalent antimonials, which exert renal and cardiac toxicity. Thus, there is a strong need for safer and more effective treatments against leishmaniasis. The present study was designated to evaluate, by a bioguided assay, the leishmanicidal activity of extracts (hexane, ethyl-acetate and ethanolic) and molecules both obtained by means of extraction from pericarps of Garcinia brasiliensis fruits. The hexane extract presented the best activity on the extracellular (promastigotes) and intracellular (amastigotes) forms of Leishmania (L.) amazonensis, when compared to the other extracts. Based on these findings, this extract was fractionated by silica gel column chromatography, affording nine fractions then resulting in three purified prenylated benzophenones - 7-epi-clusianone (1), garciniaphenone (2) and guttiferone-a (3). They showed significant activity on Leishmania (L.) amazonensis, and little toxicity for mammalian cells. Structure-activity relationships were evaluated showing that the IC(50) value displayed is dependent of prenyl groups and phenolic hydroxyls number, and inversely proportional to the hydrophobicity. Our results are promising, showing that these compounds are biologically active on Leishmania (L.) amazonensis.

Conformation of the Z19 prolamin by FTIR, NMR, and SAXS.

The alpha zein, the maize storage prolamin, is a mixture of several homologous polypeptides that shows two bands in SDS-PAGE, called Z19 and Z22. The conformation studies carried out by several authors in this mixture are conflicting. To elucidate these inconsistencies, we analyzed the conformation of the Z19 fraction, extracted from BR451 maize variety by Fourier transform infrared spectroscopy, nuclear magnetic resonance, and small-angle X-ray scattering. The infrared results show that Z19 has 46% of alpha helix and 22% of beta sheet. The fast N-H to N-D exchange measured by (1)H NMR spectroscopy showed that Z19 is not a compact structure. The scattering measurements indicated an extended structure with 12 by 130 A. With these data, we have modeled the Z19 structure as a hairpin, composed of helical, sheet, turns, and secondary structures, folded back on itself.

Composition, and Anti‐Inflammatory and Antioxidant Activities of the Volatile Oil from the Fruit Peel of Garcinia brasiliensis

The composition of the volatile oil obtained by hydrodistillation from the fruit peel of Garcinia brasiliensis (Mart.) Planch. et Triana was determined by GC/MS. A total of 38 components were identified, including γ‐muurolene (10.3%), spathulenol (8.7%), δ‐cadinene (8.3%), torreyol (8.0%), α‐cadinol (7.0%), cadalene (6.3%), and γ‐cadinene (5.3%). Oxygenated sesquiterpenes (43%) were the main group of compounds. The anti‐inflammatory activity of the volatile oil was evaluated through the rat‐paw edema model induced by carrageenan. Inhibition of the inflammatory process was noticed 3 h after carrageenan administration. In addition, the volatile oil showed poor antioxidant activity.

Novel 6-methanesulfonamide-3,4-methylenedioxyphenyl-N-acylhydrazones: orally effective anti-inflammatory drug candidates.

We described herein the molecular design of novel in vivo anti-inflammatory 6-methanesulfonamide-3,4-methylenedioxyphenyl-N-acylhydrazone derivatives (1) planned by applying the molecular hybridization approach. This work also points out to the discovery of LASSBio-930 (1c) as a novel anti-inflammatory and anti-hyperalgesic prototype, which was able to reduce carrageenan-induced rat paw edema with an ED(50) of 97.8 micromol/kg, acting mainly as a non-selective COX inhibitor.

Complete assignment of the 1H and 13C NMR spectra of garciniaphenone and keto-enol equilibrium statements for prenylated benzophenones.

This article reports the structural elucidation by IR, UV and MS spectroscopic data along with 1H and 13C NMR chemical shift assignments of two benzophenones isolated from the fruit pericarp of Garcinia brasiliensis Mart. (Clusiaceae): garciniaphenone, (1R,5S,7S)‐3‐benzoyl‐4‐hydroxy‐6,6‐dimethyl‐5,7‐di(3‐methyl‐2‐butenyl)bicyclo[3.3.1]non‐3‐ene‐2,9‐dione, a novel triprenylated benzophenone; and 7‐epi‐clusianone, a tetraprenylated benzophenone that has already been extracted from another species of the same family. Furthermore, the keto‐enol tautomeric equilibrium at solution‐state was described for these compounds by 1D and 2D NMR spectral methods and one attempt to rationalize the different ratios between the noted tautomers was based on stereochemical features. Copyright

Natural Polyprenylated Benzophenones: Keto-Enol Tautomerism and Stereochemistry

The keto-enol tautomerism and stereochemistry study of a HIV-inhibitory natural benzophenone, (1R,5R,7R,8S)-(+)-3-(10-(3,4-dihydroxyphenyl)-10-hydroxymethylene)-8-methyl -1,5,7-tris(3-methyl-2-butenyl)-8-(4-methyl-3-pentenyl)-bicyclo[3.3.1]nonane-2,4,9-trione (a), isolated from Garcinia brasiliensis seeds is presented. The crystal structure of (a), which is also know as guttiferona A, was determined by X-ray diffraction and its intra and inter-molecular geometries discussed and compared with two analogue natural benzophenones: clusianone and epiclusianone. In (a), the hydroxyl H atom from enolizable 2,4,10-trione moiety is linked in the oxygen atom bonded to 10-(3,4-dihydroxyphenyl)methylene group, in opposition to the related natural benzophenones, where this analogue H-atom is placed in different O-atoms from bicyclo[3.3.1]nonane ring system. Such behaviour can be explained by the presence of aromatic OH6 group in (a) that origins a further delocalized resonance path along of 3,4-dihydroxyphenyl-C10-OH2 group. In addition, the (a) stereochemistry around C7 atom is compared with known structures of clusianone and epiclusianone and the influence from configuration in this chiral C-atom to structural features found in the enolizable system is proposed.

A discriminating dissolution method for glimepiride polymorphs

Glimepiride, an oral antidiabetic drug, is practically insoluble in water and exists in two polymorphic forms, I and II, of which form II has higher solubility in water. Because the dissolution rate of drugs can depend on the crystal form, there is a need to develop discriminating dissolution methods that are sensitive to changes in polymorphic forms. In this work, a dissolution method for the assessment of 4 mg glimepiride tablets was developed and validated. The optimal dissolution conditions were 1000 mL of phosphate buffer (pH 6.8) containing 0.1% (w/v) of sodium dodecyl sulfate as the dissolution medium and a stirring speed of 50 rpm using a paddle apparatus. The results demonstrated that all the data meet the validation acceptance criteria. Subsequently, tablets containing forms I and II of glimepiride were prepared and subjected to dissolution testing. A significant influence of polymorphism on the dissolution properties of glimepiride tablets was observed. These results suggested that the raw material used to produce glimepiride tablets must be strictly controlled because they may produce undesirable and unpredictable effects.

Menezesite, the first natural heteropolyniobate, from Cajati, São Paulo, Brazil: Description and crystal structure

Abstract Menezesite, ideally Ba2MgZr4(BaNb12O42)·12H2O, occurs as a vug mineral in the contact zone between dolomite carbonatite and “jacupirangite” (=a pyroxenite) at the Jacupiranga mine, in Cajati county, São Paulo state, Brazil, associated with dolomite, calcite, magnetite, clinohumite, phlogopite, ancylite-(Ce), strontianite, pyrite, and tochilinite. This is also the type locality for quintinite-2H. The mineral forms rhombododecahedra up to 1 mm, isolated or in aggregates. Menezesite is transparent and displays a vitreous luster; it is reddish brown with a white streak. It is non-fluorescent. Mohs hardness is about 4. Calculated density derived from the empirical formula is 4.181 g/cm3. It is isotropic, nmeas > 1.93(1) (white light); ncalc = 2.034. Menezesite exhibits weak anomalous birefringence. The empirical formula is (Ba1.47K0.53Ca0.31Ce0.17Nd0.10Na0.06La0.02)Σ2.66(Mg0.94Mn0. 23Fe0.23Al0.03)Σ1.43(Zr2.75Ti0.96Th0.29)Σ4.00 [(Ba0.72Th0.26U0.02)Σ1.00(Nb9.23Ti2.29Ta0.36Si0.12)Σ12.00O42]·12H2O. The mineral is cubic, space group Im3̅ (204), a = 13.017(1) Å, V = 2206(1) Å3, Z = 2. Menezesite is isostructural with the synthetic compound Mg7[MgW12O42](OH)4·8H2O. The mineral was named in honor of Luiz Alberto Dias Menezes Filho (born 1950), mining engineer, mineral collector and merchant. Both the description and the name were approved by the CNMMN-IMA (Nomenclature Proposal 2005-023). Menezesite is the first natural heteropolyniobate. Heteropolyanions have been employed in a range of applications that include virus-binding inorganic drugs (including the AIDs virus), homogeneous and heterogeneous catalysts, electro-optic and electrochromic materials, metal and protein binding, and as building blocks for nanostructuring of materials.

Solid state chemistry of the antibiotic doxycycline: structure of the neutral monohydrate and insights into its poor water solubility†

The active pharmaceutical ingredient (API) doxycycline (DOX) is a broad-spectrum antibiotic mainly used in the treatment of respiratory and urinary tract infections and, like many drugs, its efficacy may be affected by the crystal form. Up to now, only the crystal structure of doxycycline hyclate (DOX·HYC) (generic name of brand names such as DORYX®, PERIOSTAT®, ATRIDOX®, and VIBRAMYCIN®) has been reported. This study presents the single-crystal X-ray diffractometry structural characterisation of another crystal form, doxycycline monohydrate (DOX·H2O) (generic name of brand names such as MONODOX® and ORACEA®). The DOX·H2O structure was compared with the known DOX·HYC one in terms of intra- and intermolecular geometries, and their melting temperature, water solubility and dissolution rate were measured. These data allowed us to establish relationships between solid state properties related to the pharmaceutical performance of the two DOX crystal variants and their supramolecular structures for the first time. Both hyclate and monohydrate forms crystallise the DOX molecules as zwitterions in which their dimethylamine groups are protonated and one of their hydroxyl groups is deprotonated. Whereas two conformers were observed in the DOX·HYC (i.e., the amine group is next to the enolate in one of them (T1) and beside the carbonyl in the other one (T2)), only one (T2) was found in DOX·H2O. Additionally, in the hyclate form, the presence of ethanol in the crystal lattice could be related to a rotation around the C–C bond of the amide group, directing the oxygen toward the amine group in one (T1) of the two conformers present in this solid state phase. Meanwhile, in the other crystallographically independent molecule (T2), the amide nitrogen is on the same side as the amine. However, only the conformer similar to T1 in DOX·HYC was observed in DOX·H2O. The crystal packing of DOX·H2O was stabilised by several intermolecular hydrogen bonds, with each drug entity interacting with another two DOX and three water molecules in such a way that a compact supramolecular network was formed. This structure was saturated in terms of hydrogen bonding, which could be related to its lower solubility and dissolution rate relative to DOX·HYC.

Syntheses, characterization and X-ray structure of potassium hydrotris(2-mercaptothiazolyl)borate, KMt, and potassium hydrotris(methimazole)borate, KTm

Os compostos hidrotris(2-mercaptotiazolil)borato de potassio, KMt, (1), e hidrotris(2-metimazolil)borato de potassio, KTm, (2), foram preparados ao se reagir a amina tiol correspondente com KBH4. Foram caracterizados por metodos espectroscopicos e analise elementar. As estruturas no estado solido de KMt.4H2O e do composto 2 foram determinadas por analises de difracao de raios-X. A maior maciez do ânion em KMt.4H2O, em comparacao com 2, e indicada pela ausencia de interacao entre ele e o cation, que possui moleculas de agua em sua esfera de coordenacao. Em KMt.4H2O a geometria em torno do ion potassio e octaedrica distorcida e em 2, pirâmide de base quadrada distorcida. Em 2 o ion potassio esta coordenado a dois atomos de enxofre dos aneis de um mesmo ânion e a tres outros atomos de enxofre pertencentes a unidades KTm vizinhas. Ambos os compostos possuem uma estrutura polimerica.