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We report the synthesis of 3-hydroxyl-2-naphthoylhydrazones containing pyrrole (HL1), furane (HL2) and thiophene (HL3) moieties and their V(IV)O-, Cu(II)- and Zn(II)-complexes. All compounds are characterized by the usual analytical techniques and coordination of the ligands to the metal ions is discussed based on spectroscopic data (FTIR, UV-vis, EPR and NMR) as well as CAMB3LYP DFT/TDDFT calculations, indicating the formation of neutral ML2 type complexes. The photophysical properties of ligands and complexes are disclosed. The binding to Bovine Serum Albumin (BSA) is evaluated in detail using several spectroscopic tools. Circular dichroism shows that the compounds, and particularly the ligand precursors, stabilize BSA, increasing its a-helical content. Fluorescence studies indicate the formation of 1 : 1 protein-compound adducts, which is corroborated by molecular docking studies that show the interaction between Trp 213 of BSA and the naphthalene rings. The general toxicity is evaluated using the Artemia salina lethality assay, with all compounds showing general toxicity towards the brine shrimp model. The cytotoxicity on human cancer cells (H1299, MCF7, and HCT116) is assessed for all compounds and the half-maximal inhibitory concentration (IC50) values are in the range from 0.57 to 27.35 mu M. Compounds containing L-1 (pyrrole derivative) are the most cytotoxic, with the vanadium and zinc complexes performing better than the copper ones, and some of them depicting IC50 values lower than 1.1 mM. However, selectivity needs improvement as the compounds show toxicity towards Artemia salina and normal fibroblasts. Fundacao para a Ciencia e a Tecnologia (FCT)Portuguese Foundation for Science and Technology [UID/QUI/00100/2019, UID/MULTI/04349/2013, UID/BIO/04565/2013, RECI/QEQ-QIN/0189/2012, RECI/QEQ-MED/0330/2012, UID/DTP/04567/2016] Programa Operacional Regional de Lisboa [LISBOA-01-0145-FEDER-007317] [UID/04138/2019] [SAICTPAC/0019/2015] [PTDC/QUI-QAN/32242/2017] [PD/BD/128320/2017] [SFRH/BD/135797/2018] [SFRH/BPD/107834/2015] [UID/QUI/50006/2019] [RECI/BBB-BEP/0124/2012] [UID/DTP/04567/2019] [SFRH/BD/119144/2016] info:eu-repo/semantics/publishedVersion

A computer-aided campaign boosted the discovery of potent human neutrophil elastase (HNE) inhibitors. A pharmacophoric model was developed, validated and applied to filter an oxo-beta-lactam library previously generated by de novo design. This campaign led us to compound 1 which showed an inhibitory activity of 6.9 nM against HNE, more active than the only commercially available HNE inhibitor for therapeutic usage. Computer-aided methodologies proved again to be powerful tools to increase the rate of success for HNE inhibitor discovery either for therapeutic or activity-based probing development.

The activity screening of a library of aurones led to the identification of sub-micromolar human neutrophil elastase (HNE) inhibitors. The activity is rationalized by a C-shape conformation that allows tight binding to HNE S1 and S2 pockets.

Herein we report the discovery of new modulators of human phenylalanine hydroxylase (hPAH) inspired by the structure of its substrate and regulator L-phenylalanine. These new hPAH modulators were simply prepared in good-to-excellent yields and excellent diastereoselectivities, based on a boron promoted assembly of L-phenylalanine, salicylaldehyde and aryl boronic acids. Iminoboronate 8, prepared with L-phenylalanine, para-methoxy-salicylaldehyde and phenyl boronic acid, was identified as the most efficient hPAH modulator, with an apparent binding affinity nearly identical to the natural allosteric activator L-phenylalanine.

Time-resolved photoacoustic calorimetry (TR-PAC) was used to investigate the energetics of O–H bonds of phenol, catechol, pyrogallol, and phloroglucinol. Values of −27.1 ± 3.9, −44.1 ± 4.4 and −1.6 ± 3.8 kJ mol−1, respectively, were obtained for the solution-phase (acetonitrile) O–H bond dissociation enthalpies of the last three compounds relative to the O–H bond dissociation enthalpy in phenol, ΔDHosln(ArO–H) = DHosln(ArO–H) − DHosln(PhO–H). A value of 388.7 ± 3.7 kJ mol−1 was determined for the PhO–H bond dissociation enthalpy in acetonitrile. Density functional theory (MPW1PW91/aug-cc-pVDZ) calculations and complete basis set (CBS-4M) calculations were carried out to analyse intramolecular hydrogen bonding and to predict gas-phase O–H bond dissociation enthalpies, DHo(ArO–H). A microsolvation model, based on the DFT calculations, was used to study the differential solvation of the phenols and their radicals in acetonitrile and to bridge solution- and gas-phase data. The results strongly suggest that ΔDHosln(ArO–H) ≈ ΔDHo(ArO–H). Hence, to calculate absolute gas-phase O–H bond dissociation enthalpies in substituted phenols from the corresponding solution-phase values, the solvation enthalpies of the substituted phenols and their radicals are not required.

Recent measurements of the dielectric permittivity of hydrofluorocarbons in the liquid phase have allowed calculation of the dipole moments in a liquid environment. These values were based on Kirkwood theory, and were significantly greater than the corresponding gas phase dipole moments. In order to understand some features suggesting possible hindered rotation of the molecules in the liquid, density functional and self-consistent-reaction-field calculations for a series of HFC molecules including CHF2CF3 (HFC-125), CH2FCF3 (HFC-134a), CH3CF3 (HFC-143a), CH2F2 (HFC-32) and CHF2CH3 (HFC-152a) are reported. Particular emphasis has been given to the calculation of dimerisation energies, rotational potentials, polarisabilities and dipole moments. We discuss hydrogen bonding in hydrofluorocarbon dimers and the relationship between the structure and charge distribution of the dimers and the dipole moment in the liquid predicted by relative permittivity measurements. For HFC-32 we have calculated the average dipole moment in small clusters (n = 2–10). The structure of the clusters has been determined by density functional theory optimisations (n = 2–6) and Monte Carlo simulations (n = 2–10). The average dipole moment of the HFC-32 decamer is 2.35 D, which represents a 17% increase relative to the free monomer (2.0 D). We find that the enhancement of the monomer dipole induced by hydrogen bonding in HFC-32 clusters is much less pronounced in comparison with the considerable increase (50%) observed in water clusters.

Human neutrophil elastase (HNE) plays an important role in the Chronic Obstructive Pulmonary Disease (COPD) inflammatory process. Over the last few decades HNE inhibitors have been evaluated as potential drug candidates; nevertheless their development was discontinued for various reasons and only sivelestat has been approved for clinical use in Acute Respiratory Distress Syndrome (ARDS). Hence, there is an urgent need for new chemotypes that allow efficient and selective HNE inhibition. With the aim of searching for a new HNE inhibitor we carried out a structure-based virtual screening of the Molecular Operating Environment (MOE) database of drug-like compounds. A commercial library of 653 214 drug-like compounds from different suppliers was docked into the HNE enzyme active site and 28 compounds were selected for purchase and tested. Four new HNE inhibitors in the low micromolar range were identified, displaying selectivity towards HNE when compared with other neutrophil serine proteases. Moreover, the inhibitors 19 and 27 exhibited a non-cytotoxic profile. Compound 19 has shown to be stable toward human plasma and pooled rat microsomal activity whereas ester 27 revealed stability issues toward hydrolytic enzymes. Compounds 19 and 27 appear to be promising leads for further development of HNE inhibitors. This study confirms the extra value of using structure-based chemoinformatic protocols and has successfully identified novel distinct chemotypes for development as new agents against HNE.