Publications

Abstract In the present work, a detailed thermochemical, experimental and theoretical, study of benzocaine is presented. The enthalpy of formation in crystalline state at T = 298.15 K was obtained from combustion calorimetry experiments [ΔfHm°cr=-415.2±1.7kJ∙mol-1], within an oxygen atmosphere, using a static bomb calorimeter. The phase transition enthalpies (fusion, vaporization, and sublimation) were obtained by different techniques, namely differential scanning calorimetry, Calvet microcalorimetry, thermogravimetry, and the Knudsen effusion method. The results obtained by the different techniques are as follows: ΔcrlHm°298.15 K=21.4±0.1 kJ⋅mol−1; ΔlgHm°298.15 K=84.9±1.0 kJ⋅mol−1; ΔcrgHm°298.15 K=106.8±0.4 kJ⋅mol−1. From the experimental results, the enthalpy of formation of the aforesaid compound, in the gas phase, was calculated at T = 298.15 K as: ΔfHm°g=-308.4±1.8kJ∙mol-1. Theoretical enthalpies were computed using the Gaussian G4 composite method, atomization reactions, and the weighted Boltzmann average method. For the latter, the conformational diversity of the molecular structure of the compound was considered. Using the above data and using a similar approach, the theoretical entropy of benzocaine was computed as well. The experimental and theoretical values obtained were compared and an excellent accordance was found. Using the experimental and theoretical results, Gibbs energy of formation in crystalline and gaseous states of benzocaine, at T = 298.15 K were calculated as: ΔfGm°cr=-164.4kJ∙mol-1 and ΔfGm°g=-123.9kJ∙mol-1, respectively. Finally, the results obtained from the enthalpies of phase change are compared with those previously reported in the literature, in order to propose an exact value for these properties. © 2020 Elsevier Ltd

Abstract The energy involved in the structural switching of acyl and hydroxyl substituents in the title compounds was evaluated combining experimental and computational studies. Combustion calorimetry and Knudsen effusion techniques were used to determine the enthalpies of formation, in the crystalline state, and of sublimation, respectively. The gas-phase enthalpy of formation of both isomers was derived combining these two experimental data. Concerning the computational study, the G3(MP2)//B3LYP composite method was used to optimize and determine the energy of the isomers in the gaseous state. From a set of hypothetical reactions it has been possible to estimate the gas-phase enthalpy of formation of the title compounds. The good agreement between the experimental and computational gas-phase enthalpies of formation of the 1-acetyl-2-naphthol and 2-acetyl-1-naphthol isomers, provided the confidence for extending the computational study to the 2-acetyl-3-naphthol isomer. The structural rearrangement of the substituents in position 1 and 2 in the naphthalene ring and the energy of the intramolecular hydrogen bond are the factors responsible for the energetic differences exhibited by the isomers. The gas phase tautomeric keto <-> enol equilibria of theo-acetylnaphthol isomers were analyzed using the Boltzmann's distribution.

Abstract Ethnopharmacological use of plant natural extracts has been known since ancient times. The optimization of plant molecule extraction is fundamental in obtaining relevant extraction yields. The main purpose of this study was to understand the role of different extraction techniques (solid-liquid, ultrasound, Soxhlet, and microwave) and solvents (water, methanol, ethanol, acetone, dichloromethane, and hexane) on the antimicrobial and antioxidant activities of extracts from Olea europaea (olive) and Acacia dealbata (mimosa). Crude plant extracts were evaluated for their antimicrobial activity against Staphylococcus aureus and Escherichia coli by the disk diffusion method. The antioxidant capacity of the extracts was determined by ABTS (2,2-azinobis (3-ethyl-benzothiazoline-6-sulfonic acid)) and DPPH (2,2-diphenyl-1-picrylhydrazyl) methods. In terms of extraction yield, ultrasound extraction and the solvents methanol, acetone (O. europaea) or water (A. dealbata) were found to be the best options. However, ethanol and acetone proved to be the best solvents to extract compounds with antimicrobial activity and antioxidant capacity, respectively (regardless of the extraction method employed). Soxhlet and microwave were the best techniques to extract compounds with antimicrobial activity, whereas any of the tested techniques showed the ability to extract compounds with antioxidant capacity. In most of the cases, both plant extracts (mimosa and olive) were more efficient against S. aureus than E. coli. In the present study, both mimosa and olive leaf crude extracts proved to have antimicrobial and antioxidant activities, increasing the demand of these natural products as a source of compounds with health benefits.

Abstract Piperine has been associated with neuroprotective effects and monoamine oxidase (MAO) inhibition, thus being an attractive scaffold to develop new antiparkinsonian agents. Accordingly, we prepared a small library of piperine derivatives and screened the inhibitory activities towards human MAO isoforms (hMAO-A and hMAO-B). Structure-activity relationship (SAR) studies pointed out that the combination of alpha-cyano and benzyl ester groups increased both potency and selectivity towards hMAO-B. Kinetic experiments with compounds 7, 10 and 15 indicated a competitive hMAO-B inhibition mechanism. Compounds 15 and 16, at 10 mu M, caused a small but significant decrease in P-gp efflux activity in Caco-2 cells. Compound 15 stands out as the most potent piperine-based hMAO-B inhibitor (IC50 = 47.4 nM), displaying favourable drug-like properties and a broad safety window. Compound 15 is thus a suitable candidate for lead optimization and the development of multitarget-directed ligands.

Abstract This article presents a promising application of Fourier transform-mid infrared (FT-MIR) spectroscopy with multivariate curve resolution - alternating least-squares (MCR-ALS) as an at-line process analytical technology (PAT) to enhancing the understanding and continuous control of a pharmaceutical manufacturing process. Its objective was to monitor the synthesis of pharmaceutical multicomponent crystals in solid-state, namely the mixture between lamivudine (active pharmaceutical ingredient-API) and saccharin (coformer) using liquid assisted grinding (LAG) in proportion of 1:1 in a ball mill. The continuous monitoring of synthesis procedure ensured product quality, revealing some of the events that can be detected during mechanochemical synthesis by FT-MIR spectroscopy with MCR-ALS. The concentration profiles retrieved by MCR-ALS allowed to identify the end of the salt synthesis. In fact, this is one of the advantages of real-time monitoring using FT-MIR spectroscopy and MCR-ALS, because it can be helpful not only to monitor and control a pharmaceutical manufacturing process, but also to optimize efficient use of energy, time and raw materials for lamivudine-saccharinate salt synthesis. Moreover, it allowed to understand that the antiretroviral lamivudine-saccharinate salt synthetized by LAG showed a fast reaction mechanism due to the presence of ethanol as catalyst. Differential scanning calorimetry (DSC) and X-ray powder diffraction (XRPD) techniques provided additional information needed to fully characterize pharmaceutical lamivudine-saccharinate salt synthetized by LAG technique.

Abstract Alzheimer disease (AD) is the most common neurodegenerative disease featuring progressive and degenerative neurological impairments resulting in memory loss and cognitive decline. The specific mechanisms underlying AD are still poorly understood, but it is suggested that a deficiency in the brain neurotransmitter acetylcholine, the deposition of insoluble aggregates of fibrillar beta-amyloid 1-42 (A beta(42)), and iron and glutamate accumulation play an important role in the disease progress. Despite the existence of approved cholinergic drugs, none of them demonstrated effectiveness in modifying disease progression. Accordingly, the development of new chemical entities acting on more than one target is attracting progressively more attention as they can tackle intricate network targets and modulate their effects. Within this endeavor, a series of mitochondriotropic antioxidants inspired on hydroxycinnamic (HCA's) scaffold were synthesized, screened toward cholinesterases and evaluated as neuroprotectors in a differentiated human SH-SY5Y cell line. From the series, compounds 7 and 11 with a 10-carbon chain can be viewed as multi-target leads for the treatment of AD, as they act as dual and bifunctional cholinesterase inhibitors and prevent the neuronal damage caused by diverse aggressors related to protein misfolding and aggregation, iron accumulation and excitotoxicity.

Abstract This work reports the synthesis and multifunctionality of 2D layered coordination polymers formulated as [Ln(2)(H(3)nmp)(2)]xH(2)O (1, where Ln = Sm3+, Eu3+, Tb3+, Dy3+, Ho3+, Er3+ and Y3+) (x = 1 to 4). We describe detailed synthesis of the materials using various methods [typical hydrothermal reaction (HT), microwave-assisted synthesis (MWAS) and one-pot method (OP)], while discussing the various crystal morphologies which can be fine tuned by varying systematically the conditions. We further explore the multifunctionality of this material by studying its heterogeneous catalytic activity in the ring opening of styrene oxide, its photoluminescence behaviour and its cytotoxicity. A conversion of 88%/100% yield at 4 h/24 h reaction respectively, with excellent selectivity towards 2-methoxy-2-phenylethanol product (100%) was observed. Photoluminescence properties of the optically-active [Eu-2(H(3)nmp)(2)]xH(2)O (1Eu) and the mixed-lanthanide [(Gd0.95Eu0.5)(2)(H(3)nmp)(2)]xH(2)O (1GdEu), on the other hand, show potential use for UV-to-visible light converters, with lifetimes of 2.31 +/- 0.01 and 2.61 +/- 0.01 ms at ambient temperature for 1Eu and 1GdEu samples. Preliminary cytotoxic studies showed no effects on metabolic activity of both in vitro human epithelial kidney (HK-2) and human hepatocellular carcinoma (HepG2) cell lines. A reduction of NR uptake was, however, observed indicating some cytotoxic effect on lysosomal activity.

Abstract We report herein the design, synthesis and biological evaluation of new antioxidant and neuroprotective multitarget directed ligands (MTDLs) able to block Ca2+ channels. New dialkyl 2,6-dimethyl-4-(4-(prop-2-yn-1-yloxy)phenyl)-1,4-dihydropyridine-3,5-dicarboxylate MTDLs 3a-t, resulting from the juxtaposition of nimodipine, a Ca2+ channel antagonist, and rasagiline, a known MAO inhibitor, have been obtained from appropriate and commercially available precursors using a Hantzsch reaction. Pertinent biological analysis has prompted us to identify the MTDL 3,5-dimethyl-2,6-dimethyl-4-[4-(prop-2-yn-1-yloxy)phenyl]-1,4-dihydro- pyridine- 3,5-dicarboxylate (3a), as an attractive antioxidant (1.75 TE), Ca2+ channel antagonist (46.95% at 10 mu M), showing significant neuroprotection (38%) against H2O2 at 10 mu M, being considered thus a hit-compound for further investigation in our search for anti-Alzheimer's disease agents.

Abstract Background: Half of human cancers harbour TP53 mutations that render p53 inactive as a tumor suppressor. As such, reactivation of mutant (mut)p53 through restoration of wild-type (wt)-like function represents one of the most promising therapeutic strategies in cancer treatment. Recently, we have reported the (S)-tryptophanolderived oxazoloisoindolinone SLMP53-1 as a new reactivator of wt and mutp53 R280K with in vitro and in vivo p53-dependent antitumor activity. The present work aimed a mechanistic elucidation of mutp53 reactivation by SLMP53-1. Methods and results: By cellular thermal shift assay (CETSA), it is shown that SLMP53-1 induces wt and mutp53 R280K thermal stabilization, which is indicative of intermolecular interactions with these proteins. Accordingly, in silico studies of wt and mutp53 R280K DNA-binding domain with SLMP53-1 unveiled that the compound binds at the interface of the p53 homodimer with the DNA minor groove. Additionally, using yeast and p53-null tumor cells ectopically expressing distinct highly prevalent mutp53, the ability of SLMP53-1 to reactivate multiple mutp53 is evidenced. Conclusions: SLMP53-1 is a p53-activating agent with the ability to directly target wt and a set of hotspot mutp53. General Significance: This work reinforces the encouraging application of SLMP53-1 in the personalized treatment of cancer patients harboring distinct p53 status.