Norma R. Sperandeo

Antibacterial effect of 2-hydroxy-N-(3,4-dimethyl-5-isoxazolyl)-1,4-naphthoquinone-4-imine onStaphylococcus aureus

The mechanism by which a new naphthoquinone derivative, the 2-hydroxy-N-(3,4-dimethyl-5-isoxazolyl)-1,4-naphthoquinone-4-imine (INQI-E) has antibacterial effect againstStaphylococcus aureus was studied. The interaction of INQI-E with the bacteria was followed by absorption spectroscopy at 323 and 490 nm. The absorption band of INQI-E at 490 nm undergoes a hypochromic shift with a decrease of intensity. This effect was found to be reversible by oxygenation during the first hours of incubation. The participation of an oxidation-reduction process related to the respiratory chain was demonstrated by oxygen consumption. An increase in O2 uptake and inhibition ofS. aureus growth was observed. Experiments with three inhibitors of the respiratory chain demonstrated that the pathway induced by INQI-E was antimycin-resistant and KCN- and salicylhydroxamic acid (SHAM)-sensitive, which suggests that INQI-E is capable of diverting the normal electron flow to an alternate superoxide-producing route. On the other hand, experiments with Tiron, a specific scavenger of superoxide, hindered the effect of INQI-E againstS. aureus, indicating that the inhibitory growth effect of this quinone-imine is mainly due to the production of the cytotoxic superoxide radical.

The crystal structure and physicochemical characteristics of 2-hydroxy-N-[3(5)-pyrazolyl]-1,4-naphthoquinone-4-imine, a new antitrypanosomal compound

This study was designed to investigate the physical characteristics and crystalline structure of 2-hydroxy-N-[3(5)-pyrazolyl]-1,4-naphthoquinone-4-imine (PNQ), a new active compound againstTrypanosoma cruzi, the causative agent of American trypanosomiasis. Methods used included differential scanning calorimetry, thermogravimetry, hot stage microscopy, polarized light microscopy (PLM), Fourier-transform infrared (FTIR) spectroscopy, and high-resolution X-ray powder diffraction (HR-XRPD). According to PLM and HR-XRPD data, PNQ crystallized as red oolitic crystals (absolute methanol) or prisms (dimethyl sulfoxide [DMSO]-water) with the same internal structure. The findings obtained with HR-XRPD data (applying molecular location methods) showed a monoclinic unit cell [a=18.4437(1)Å, b=3.9968(2) Å, c=14.5304(1) Å, α=90°, β=102.71(6)°, γ=90°, V=1044.9(1) Å3, Z=4, space group P21/c], and a crystal structure (excluding H-positions) described by parallel layers in the direction of theb-axis, with molecules held by homochemical (phenyl-phenyl and pyrazole-pyrazole) van der Waals interactions. In addition, FTIR spectra displayed the NH-pyrazole stretch overlapped with the OH absorption at 3222 cm−1, typical of-NH and-OH groups associated through H-bondings; and a carbonyl stretching absorption at 1694 cm−1, indicating a non-extensively H-bonded quinonic C=O, which was in accordance with the solved crystal structure of PNQ. The existence of such cohesive forces shed light on the thermo-analytical data, which revealed that PNQ is a stable solid, unaffected by oxygen that decomposed without melting above 260°C.

Preparation and characterization of polymorphs of the glucocorticoid deflazacort

Abstract The polymorphism of new and old active pharmaceutical ingredients (APIs) is of great importance due to performance, stability and processability aspects. The objective of this study was to investigate the polymorphism of deflazacort (DEF), a glucocorticoid discovered >40 years ago, since this phenomenon has not been previously investigated for this API. Using different methods for solid form screening, it was determined for the first time that DEF is able to exist as three forms: a crystalline (DEF-1); a hydrated X-ray amorphous (DEF-t-bw) and an anhydrous amorphous phase (DEF-g) obtained from manually grinding DEF-1. The in vitro and in vivo dissolution rates (DRs) of DEF-1 and DEF-t-bw, which were measured using the rotating disk method in water at 37 °C and the pellet implantation technique in rats, respectively, indicated that DEF-t-bw exhibited slightly faster in vitro and in vivo DRs than those of the crystalline form, but the values were not significantly different. In addition, it was determined that DEF-t-bw devitrifies to DEF-1 by the effect of pressure, humidity and heat. It was concluded that DEF is glucorticoid with low tendency to exhibit different crystalline forms and that DEF-t-bw has no advantages over DEF-1 in terms of solubility, DRs and solid-state stability.

Thermal studies of isoxazolylnaphthoquinones by simultaneous DTA-TG-DTG

The tautomeric binary system consisting of N-(3,4-dimethyl-5-isoxazolyl)-4-amino-1,2-naphthoquinone (1),m.p. 156‡C, and 2-hydroxy-N-(3,4-dimethyl-5-isoxazolyl)-1,4-naphthoquinon-4-imine (2),m.p. 218‡C, was studied by DTA-TG-DTG and IR spectrometry. Crystals of 1, left in contact with their mother liquor during 4 months, exhibited thermal behaviour similar to that of physical mixtures of 1 and 2, which reveal the presence of a eutectic at about 146‡C.The effects of light, heat and humidity on the stabilities of 1 and 2 were also studied. Heat (up to 110‡C) did not induce any change observable by DTA-TG-DTG in either 1 or 2. Moisture and daylight affected only 1. Upon melting, interconversion of the isomers was not observed.

Solid state characterization of potential protozoocidal agents: aminoisoxazolylnaphthoquinones

Abstract As part of their preformulation evaluation, four in vitro protozoocidal 3,4-dimethyl-5-isoxazolylnaphthoquinones (ANQ-1–4) were investigated by differential scanning calorimetry (DSC), simultaneous differential thermal analysis–thermogravimetry–derivative thermogravimetry (DTA–TG–DTG), and Fourier transform infrared spectroscopy (FTIR). X-ray powder diffractometry (XRPD), thermomicroscopy and polarized light microscopy were used as an aid to interpret the thermoanalytical curves. The study demonstrated that the compounds are crystalline solids, unaffected by oxygen, safely manipulated at room temperature (RT) and also at higher temperatures as solids; however, all decompose exothermically at about their mp. Polycrystalline mixtures or undesirable solvates were not detected. All the compounds are insoluble in water and n-hexane and slightly soluble in ethanol, indicating that all are candidates to improve their solubilities in order to avoid formulation problems.

Synthesis and Characterization of New Naphthoquinonic Derivatives Containing the Pyrazole Ring: Pyrazolylnaphthoquinones

The reaction of 3-aminopyrazole (1) with 1,2-naphthoquinone-4-sulfonic acid sodium salt (2) was studied in different aqueous media. The novel pyrazolylnaphthoquinones synthesized were physical and spectroscopically characterized, including 2D NMR spectroscopy (HETCOR). The possible reaction mechanism is proposed.

Evidence of Polymorphism on the Antitrypanosomal Naphthoquinone (4E)-2-(1H-Pyrazol-3-ylamino)- 4-(1H-pyrazol-3-ylimino)naphthalen-1(4H)-one

The aim of this study was to characterize the solid state properties of (4E)-2-(1H-pyrazol-3-ylamino)-4-(1H-pyrazol-3-ylimino)naphthalen-1(4H)-one (BiPNQ), a compound with a significant inhibitory activity against Trypanosoma cruzi, the etiological agent of Chagas disease (American trypanosomiasis). Methods used included Differential Scanning Calorimetry (DSC), Thermogravimetry (TG), Fourier Transform Infrared Spectroscopy (FTIR), Powder X-Ray Diffraction (PXRD), Hot Stage, and Confocal Microscopy. Two BiPNQ samples were obtained by crystallization from absolute methanol and 2-propanol-water that exhibited different thermal behaviours, PXRD patterns, and FTIR spectra, indicating the existence of an anhydrous form (BiPNQ-I) and a solvate (BIPNQ-s), which on heating desolvated leading to the anhydrous modification BiPNQ-I. It was determined that FTIR, DSC, and PXRD are useful techniques for the characterization and identification of the crystalline modifications of BiPNQ.