Gil M. Viana

Selectivity Studies Towards the Synthesis of Novel Biaryl Ureas by (Hetero)Nanocatalysis: Size Control and Support Effects

A series of novel biaryl ureas containing different structural patterns have been prepared in good yields in the presence of palladium nanoparticles (PdNPs) with narrow particle size distribution. In particular, α, β‐, and γ‐hydroxypropylated cyclodextrins were used as reductants/stabilizers under different Pd‐to‐cyclodextrin ratios to tune the particle size and exploit the surface/cavity effects in the Suzuki–Miyaura reaction. Catalyst recovery in this process was pursued as well. Owing to its excellent performance, ceria was explored as a support for these PdNPs. The heterogeneous catalyst was characterized and investigated in the reaction of N‐(4‐iodo‐aryl),N′‐alkyl urea and phenylboronic acid. Our preliminary results revealed a high activity of the catalyst at 0.5 mol % Pd0 during three consecutive cycles. It is suggested that the specific interface between Pd0 and the high‐surface‐area ceria has a role in the catalytic performance.

Identification, characterization and in silico ADMET prediction of Roflumilast degradation products

&NA; The present study reports the degradation behavior of roflumilast (RFL), a new drug developed for the treatment of chronic obstructive pulmonary disease. The degradation of RFL was tested under various stress conditions as per the guidelines of the International Conference on Harmonization. The degradation products (DPs) of RFL were identified, characterized and in silico predictions were made of their pharmacokinetic properties, absorption, distribution, metabolism, excretion and toxicity (ADMET). RFL was subjected to various stress conditions including photodegradation, alkaline and acidic hydrolysis, oxidative and metallic degradation. After analysis by HPLC‐DAD, the DPs were isolated by preparative TLC and characterized by high resolution mass spectrometry (HRMS), 1H NMR, 13C NMR and infrared (IR) spectroscopy. RFL tablets were prepared by the addition of solid stressing substances such as excipients and storage in an accelerated stability chamber (40 °C; 75% r.h.) for sixteen months. Resulting DPs from the tablets were analyzed by UFLC‐QTOF. The most drastic degradation conditions for RFL were 5 M NaOH(aq), 6 M HCl(aq), 7.5% v/v peracetic acid, which resulted in the isolation of four DPs. However, milder degradation conditions (1 M NaOH(aq) and photolysis) generated six DPs (DP‐1, 2, 3, 5, 7 and 8), and are more similar to the actual conditions the drug will be exposed. For tablets containing RFL exposed to an alkaline reagent, two DPs were formed: DP‐1 and DP‐11. Whereas RFL‐containing tablets exposed to acid and oxidizing agents, formed one product DP‐11. Forced degradation of RFL led to the formation of eleven DPs, seven of which have never been previously reported. RFL is stable under metallic stress and it is relatively stable during photodegradation testing. The UFLC‐QTOF methodology detected a greater number of DPs that formed during the stress conditions tested when compared to the HPLC‐DAD methodology. In silico prediction of the ADMET properties of the RFL degradation products and metabolites produced in this study are potentially hepatotoxic. HighlightsRoflumilast produces eleven degradation products in alkaline/ acidic hydrolysis, photolysis and oxidative stress conditions.Roflumilast tablets produce two degradation products when exposed to temperature and humidity stressors.The UFLC‐QTOF method was able to detect all of the roflumilast degradation products.In silico prediction of ADMET properties suggests that roflumilast degradation products and its metabolites are hepatotoxic.

Design, Synthesis and Evaluation of New Fluoroamodiaquine Analogues.

Malaria is one of the most important tropical diseases; the use of amodiaquine as a current chemotherapy in the treatment of malaria has shown some problems such as hepatotoxicity and agranulocytosis. In this work we present the rational design, synthesis, and biological evaluation (antimalarial activity, cytotoxicity and genotoxicity) of four new fluoroamodiaquine analogues. The results showed significant correlation between MolDock score and IC50 values. The molecules 7b and c were the most active of the planned compounds, with lower IC50 against Plasmodium falciparum W2 strain (0.9 and 0.8 µM, respectively) and an excellent cytotoxicity profile. The present study revealed no mutagenicity or genotoxicity for the analogues. Confirming our docking results, the molecular dynamics showed that compound 7b remains stably bound to the heme group by means of π-stacking interactions between quinoline and the porphyrin ring. Based on these findings, this study may prove to be an efficient approach for the rational design of hemozoin inhibiting compounds to treat malaria.

Physical and chemical properties of model composites containing quaternary ammonium methacrylates

OBJECTIVE Investigate physical and chemical properties of model composites formulated with quaternary ammonium salt monomers (QAS) at different concentrations and alkyl chains lengths METHODS: QAS with 12 dimethylaminododecyl methacrylate (DMADDM) and 16 dimethylaminohexadecyl methacrylate (DMAHDM) chains lengths were synthesized and incorporated at 5 and 10% in model composites, resulting in four groups: G12.5 (DMADDM 5%), G12.10 (DMADDM 10%), G16.5 (DMAHDM 5%), G16.10 (DMAHDM 10%). One group was used as control group (CG 0%). Degree of conversion (DC); water sorption (WS) and solubility (SL); hygroscopic expansion (HE); degradation temperature (DT); glass transition temperature (Tg) and polymerization shrinkage (PS) were determined. Knoop hardness (KNH), flexural strength (FS) and elastic modulus (EM) were measured before and after storage Data were submitted to ANOVA and Tukeys test (p≤0.05). RESULTS DC ranged between 76.1 (G12.10) and 70.7 (G16.5) %; CG had the lowest WS, SL and HE. There was no statistical difference for PS and FS. KHN values ranged between 30.2 (GC) and 25 (G16.10) and after storage the performance was depended on QAS concentration and chain length. For EM, CG had the highest values before and after storage and no difference was observed in the QAS groups before storage. After storage, the results were dependent on QAS concentration (3.5-4.3GPa). SIGNIFICANCE In general, the addition of QAS increased composites degradation compared with the CG. In the tested QAS, the addition of DMADDM at 5% concentration resulted in a less degradable material.