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- The separation between solvent polarizability and solvent dipolarity: revisiting the Kamlet-Abraham-Taft model equationPublication . Moreira, L.; Elvas Leitao, Ruben; Martins, FilomenaQuantitative structure-property relationships were established using multiple linear regressions to cor-relate log k values for the heterolysis reaction of 3-bromo-3-ethylpentane using three well-known model equations, the Kamlet-Abraham-Taft (KAT), the Catalan (Cat) and the Laurence (Lau) equations. The a pri-ori exclusion of the hydrogen bond acceptor (HBA) basicity descriptor for all tested models led to similar responses, thus emptying the argument of an alleged use of a non-balanced set of solvents. Concurrently, a new method was devised to split the original Kamlet-Taft p* descriptor into two independent contri-butions which separately quantify the solvent's polarizability (DI) and dipolarity (Dip). A modified version of the KAT equation (mKAT) including both DI and Dip, together with the exclusion of the HBA basicity descriptor was applied to five selected solvent-dependent physicochemical processes. Results showed that the mKAT model provided significant improvements over the original KAT model. Additionally, it was shown that the introduction of DI in the truncated KAT equation could lead to misleading or, at best, inconclusive interpretations of solvent effects. Finally, the performance of mKAT model was compared with Catalan's and Laurence's model equations in terms of statistical results, relevance of descriptors and gas-phase predictions. In general, these three model equations show very similar outcomes although the mKAT model exhibits an overall better performance.
- Synthesis and the in vitro evaluation of antitumor activity of novel thiobenzanilidesPublication . Álvaro Martins, Maria Joao; Railean, Violeta; Martins, Filomena; Machuqueiro, Miguel; Pacheco, Rita; Santos, SusanaCancer is a generic term for a large group of diseases that are the second-leading cause of death worldwide, accounting for nearly 10 million deaths in 2020. Melanoma is a highly aggressive skin tumor with an increasing incidence and poor prognosis in the metastatic stage. Breast cancer still stands as one of the major cancer-associated deaths among women, and diagnosed cases are increasing year after year worldwide. Despite the recent therapeutic advances for this type of cancer, novel drugs and treatment strategies are still urgently needed. In this paper, the synthesis of 18 thiobenzanilide derivatives (17 of them new) is described, and their cytotoxic potential against melanoma cells (A375) and hormone-dependent breast cancer (MCF-7) cells is evaluated using the MTT assay. In the A375 cell line, most of the tested thiobenzanilides derivatives showed EC50 values in the order of mu M. Compound 17 was the most promising, with an EC50 (24 h) of 11.8 mu M. Compounds 8 and 9 are also interesting compounds that deserve to be further improved. The MCF-7 cell line, on the other hand, was seen to be less susceptible to these thiobenzanilides indicating that these compounds show different selectivity towards skin and breast cancer cells. Compound 15 showed the highest cytotoxic potential for MCF-7 cells, with an EC50 (24 h) of 43 mu M, a value within the range of the EC50 value determined for tamoxifen (30.0 mu M). ADME predictions confirm the potential of the best compounds. Overall, this work discloses a new set of thiobenzanilides that are worth being considered as new scaffolds for the further development of anticancer agents.
- Zooming in with QSPR on Friedel-Crafts acylation reactions over modified BEA zeolitesPublication . Aleixo, Odrigo; Elvas Leitao, Ruben; Martins, Filomena; Carvalho, Ana; Brigas, Amadeu Fernandes; Nunes, Ricardo; Fernandes, Auguste; Rocha, Joao; Martins, Angela; Nunes, NelsonThe catalytic behaviour of hierarchical BEA zeolites with Si/Al ratio of 12.5 and 32 was studied in Friedel-Crafts acylation reactions using furan, anisole and pyrrole as substrates and acetic anhydride as acylating agent. Hierarchical BEA samples were submitted to alkaline and alkaline + acid treatments. Kinetic modelling using nonlinear regressions applied to a simplified Langmuir-Hinshelwood equation showed that the Si/Al ratio of the parent materials strongly influenced the catalytic behaviour. Catalytic results were correlated with physicochemical properties using a Quantitative Structure-Property Relationship (QSPR) methodology. This approach provided detailed information about the role of key properties on the catalytic behaviour, and pointed out which properties should be modified through direct synthesis and/or post-synthesis treatments to obtain materials with optimized catalytic performance.
- Using solvatochromic probes to investigate intermolecular interactions in 1,4-dioxane/methanol/acetonitrile solvent mixturesPublication . Nunes, Ricardo; Nunes, Nelson; Elvas Leitao, Ruben; Martins, FilomenaUV–Vis absorption spectra of five solvatochromic probes namely, betaine (30), 4-nitrophenol, 4-nitroanisole, 4-nitroaniline and N,N-dimethyl-4-nitroaniline, were obtained at 298.15 K in the binary systems 1,4-dioxane/methanol (MeOH) and 1,4-dioxane/acetonitrile (MeCN), and in the ternary system 1,4-dioxane/methanol/acetonitrile, in a total of 40 new solvent mixtures. Preferential solvation trends were assessed through the Bosch and Rosès formalism for the binary mixtures, and the extended model approach for the ternary mixture, thus allowing the setting up of a preferential solvation order for all entities present in solution, including solvent “complexes”. Synergistic behaviors were spotted in most binary mixtures involving 1,4-dioxane but not in the ternary system which is dominated by a combination of contributions from the three underlying binary mixtures. Kamlet-Taft parameters π*, α and β were also computed for all 40 systems and their variation with composition was thoroughly examined. The addition of small amounts of 1,4-dioxane to the mixtures was seen to cause a significant variation in π*, whereas on the other extreme, in dioxane rich mixtures, a large effect in α was observed, particularly for the system 1,4-dioxane/methanol.
- Kinetic study of Friedel-Crafts acylation reactions over hierarchical MCM-22 zeolitesPublication . Aleixo, Rodrigo; Elvas Leitao, Ruben; Martins, Filomena; Carvalho, Ana; Brigas, Amadeu; Martins, Angela; Nunes, NelsonFriedel-Crafts acylation was studied under mild conditions using hierarchical MCM-22 zeolites prepared by desilication and by desilication + acid treatment, using furan, pyrrole and anisole as substrates, and acetic anhydride as acylating agent. Enhanced catalysis was observed for furan and anisole, especially at short reaction times. Kinetic results modelling using non-linear regressions applied to a simplified Langmuir-Hinshelwood equation showed that desilication treatment followed by acid treatment improved kinetics (higher k and TOF). A QSPR methodology using nine substrate and zeolite descriptors was applied to model kinetics and adsorption. For both processes, the best QSPR model equations lead to the same descriptors, namely, Bronsted acidity, as zeolite's feature, and both van der Waals volume and Dimroth-Reichardt E-T(N) parameter (related to dipolarity and Lewis acidity) as substrates' characteristics. Normalization of descriptors allowed quantification of each descriptor's relative importance leading to a better understanding of the catalytic and adsorption processes.
- Insights on the mechanism of action of INH-C-10 as an antitubercular prodrugPublication . Vila-Viçosa, Diogo; Victor, Bruno; Ramos, Jorge; Machado, Diana; Viveiros, Miguel; Switala, Jacek; Loewen, Peter C.; Elvas Leitao, Ruben; Martins, Filomena; Machuqueiro, MiguelTuberculosis remains one of the top causes of death worldwide, and combating its spread has been severely complicated by the emergence of drug-resistance mutations, highlighting the need for more effective drugs. Despite the resistance to isoniazid (INH) arising from mutations in the katG gene encoding the catalase-peroxidase KatG, most notably the S315T mutation, this compound is still one of the most powerful first-line antitubercular drugs, suggesting further pursuit of the development of tailored INH derivatives. The N'-acylated INH derivative with a long alkyl chain (INH-C-10) has been shown to be more effective than INH against the S315T variant of Mycobacterium tuberculosis, but the molecular details of this activity enhancement are still unknown. In this work, we show that INH N'-acylation significantly reduces the rate of production of both isonicotinoyl radical and isonicotinyl NAD by wild type KatG, but not by the S315T variant of KatG mirroring the in vivo effectiveness of the compound. Restrained and unrestrained MD simulations of INH and its derivatives at the water/membrane interface were performed and showed a higher preference of INH-C-10 for the lipidic phase combined with a significantly higher membrane permeability rate (27.9 cm s(-1), compared with INH-C-2 or INH (3.8 and 1.3 cm s-1, respectively). Thus, we propose that INH-C-10 is able to exhibit better minimum inhibitory concentration (MIC) values against certain variants because of its better ability to permeate through the lipid membrane, enhancing its availability inside the cell. MIC values of INH and INH-C-10 against two additional KatG mutations (S315N and D735A) revealed that some KatG variants are able to process INH faster than INH-C-10 into an effective antitubercular form (wt and S315N), while others show similar reaction rates (531ST and D735A). Altogether, our results highlight the potential of increased INH lipophilicity for treating INH-resistant strains.
- Quantifying solvent effects through QSPR: A new look over different model equationsPublication . Moreira, Luís; Elvas Leitao, Ruben; Abraham, Michael; Martins, FilomenaThe heterolysis reactions of 3 tertiary alkyl halides (2-chloro-2-methylpropane, 2-bromo-2-methylpropane and 3-bromo-3-ethylpentane) in a set of 21 protic and aprotic solvents, representative of various classes of solvents, were used to study solvent effects upon reactivity, at 298.15 K. Quantitative Structure-Property Relationships established through the use of multiple linear regressions, namely a model equation based on the solvatochromic parameters re, a and (3 (the KAT equation), was shown to provide robust and predictive quantifications of the main solute-solvent interactions which prevail in the studied reaction processes. Changes in the departing halogen and in the size of the carbonated skeleton induce well quantified sensitivities to each solvent descriptor depending on the type of interaction being modeled. Other model equations were tested, and results evidenced some weaknesses related to inadequate solvent description ability or ill-conceived scales' use.
- Probing substrate/catalyst effects using QSPR analysis on friedel-crafts acylation reactions over hierarchical BEA zeolitesPublication . Elvas Leitao, Ruben; Martins, Filomena; Borbinha, Leonor; Marranita, Catarina; Martins, Angela; Nunes, NelsonAttempts to optimize heterogeneous catalysis often lack quantitative comparative analysis. The use of kinetic modelling leads to rate (k) and relative sorption equilibrium constants (K), which can be further rationalized using Quantitative Structure-Property Relationships (QSPR) based on Multiple Linear Regressions (MLR). Friedel-Crafts acylation using commercial and hierarchical BEA zeolites as heterogeneous catalysts, acetic anhydride as the acylating agent, and a set of seven substrates with different sizes and chemical functionalities were herein studied. Catalytic results were correlated with the physicochemical properties of substrates and catalysts. From this analysis, a robust set of equations was obtained allowing inferences about the dominant factors governing the processes. Not entirely surprising, the rate and sorption equilibrium constants were found to be explained in part by common factors but of opposite signs: higher and stronger adsorption forces increase reaction rates, but they also make the zeolite active sites less accessible to new reactant molecules. The most relevant parameters are related to the substrates' molecular size, which can be associated with different reaction steps, namely accessibility to micropores, diffusion capacity, and polarizability of molecules. The relatively large set of substrates used here reinforces previous findings and brings further insights into the factors that hamper/speed up Friedel-Crafts reactions in heterogeneous media.
- Revisiting the reactions of t-BuX (X = Br, I) with monoalcohols: a mechanistic analysis through numerical integration and nonlinear regression methodsPublication . Elvas Leitao, Ruben; Martins, FilomenaThe reactions of two tertiary butyl halides, i.e., t-BuBr and t-BuI, with monoalcohols (methanol, i-propanol, and t-butanol) have been studied at several temperatures during extended periods of time to acquire kinetic data for both the solvolytic step and the subsequent reactions. Reaction progress was followed by conductimetry, and calibration curves were obtained for all systems under study to derive concentration versus time curves for the significant intermediate species, the formed acid, HX. The GMS comprehensive mechanism, previously proposed by Gonçalves, Martins, and Simões for these reactions, was successfully tested using numerical integration associated with nonlinear regression, confirming the predicted distinct behaviors for methanol (and for that matter also for primary alcohols), secondary, and tertiary alcohols. Results show that accurate rate constants could be obtained in all cases and that the step that follows solvolysis can affect significantly the solvolytic rate constant and therefore any consequent reliable mechanistic analysis.
- Properties of the tert-butyl halide solvolysis transition statesPublication . Abraham, Mchael; Martins, Filomena; Elvas Leitao, Ruben; Moreira, LuísWe have obtained properties (or descriptors) of the transition states in the solvolysis of tert-butyl chloride, bromide and iodide. We show that all three transition states, in both protic and in aprotic solvents, are highly dipolar and are strong hydrogen bond acids and strong hydrogen bond bases, except for the tert-butyl iodide transition state in aprotic solvents, which has a rather low hydrogen bond acidity. Thus, the transition states are stabilized by solvents that are hydrogen bond bases (nucleophiles) and are hydrogen bond acids (electrophiles). We show also that the partition of the transition states between water and solvents is aided by both nucleophilic and electrophilic solvents and conclude that the rate of solvolysis of the three halides is increased by both nucleophilic and electrophilic solvents.