The West Nile Virus (WNV) NS2B-NS3 protease is an attractive target for the development of therapeutics against this arboviral pathogen. In the present investigation, the screening of a small library of fifty-eight synthetic compounds against the NS2-NB3 protease of WNV is described. The following groups of compounds were evaluated: 3-(2-aryl-2-oxoethyl)isobenzofuran-1(3H)-ones; eugenol derivatives bearing 1,2,3-triazolic functionalities; and indan-1,3-diones with 1,2,3-triazolic functionalities. The most promising of these was a eugenol derivative, namely 4-(3-(4-allyl-2-methoxyphenoxy)-propyl)-1-(2-bromobenzyl)-1H-1,2,3-triazole (35), which inhibited the protease with IC50 of 6.86 μmol L-1. Enzyme kinetic assays showed that this derivative of eugenol presents competitive inhibition behaviour. Molecular docking calculations predicted a recognition pattern involving the residues His51 and Ser135, which are members of the catalytic triad of the WNV NS2B-NS3 protease.

In the present investigation, a collection of nineteen 3-(2-aryl-2-oxoethyl)isobenzofuran-1(3H)-ones was synthesized and screened for their cytotoxic activity against a panel of three leukemia cancer cell lines. The compounds were prepared via ZrOCl2·8H2O catalyzed condensation reactions between phthalaldehydic acid and different acetophenones. The reactions were carried out free of solvent and the isobenzofuran-1(3H)-ones were obtained in good yields (80-92%). The identities of the synthesized compounds were confirmed upon IR and NMR ((1)H and (13)C) spectroscopy as well as high resolution mass spectrometry analyses. Structures of compounds 1, 4 and 16 were also investigated by X-ray analysis. The synthesized compounds were submitted to in vitro bioassays against HL-60, K562 and NALM6 cancer cell lines using MTT cytotoxicity assay. After 48h of treatment, twelve derivatives were able to reduce cell viability and presented IC50 values equal to or below 20μmolL(-1) against at least one of the evaluated lineages. The most active compound corresponded to 3-(3-methylphenyl-2-oxoethyl)isobenzofuran-1(3H)-one (18) (IC50 values obtained for HL-60, K562 and NALM6 were, respectively, 13.5μmolL(-1), 8.83μmolL(-1), and 5.24μmolL(-1)). In addition, compound 18 was capable of triggering apoptosis on NALM6 cells. All isobenzofuranones herein evaluated did not present cytotoxicity on peripheral blood mononuclear cells (PBMC), suggesting selective cytotoxic effect on leukemic cells. A computational study allowed prediction of pharmacokinetics and drug-likeness properties of the synthesized compounds. DFT calculations were performed to obtain the energy values of HOMO, LUMO, and dipole moments of isobenzofuranones.

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The molecular conformation and supramolecular architecture of cocaethylene [systematic name: ethyl (1R,2R,3S,5S)-3-benzoyloxy-8-methyl-8-azabicyclo[3.2.1]octane-2-carboxylate], CHNO, have been determined for the first time. Cocaethylene is a narcotic produced in vivo when cocaine and ethanol are administered concomitantly. The intra- and intermolecular features of cocaethylene and its less potent narcotic precursor cocaine are very similar. The only molecular difference is in the conformation of the methyl group of the ethoxycarbonyl group. Similar to cocaine, the carboxylate atoms and the α-C atom are coplanar in cocaethylene, but the methyl C atom of the ethyl group is bent by ca 90° away from this plane in the narcotic reported here. The main supramolecular motif is a one-dimensional chain stabilized by weak C-H...O contacts.

Unusual conformations have been found in a new calix[8]arene and in new solvates of two known calix[6]arenes. The chair-like conformation with 2/m point group symmetry was found for the first time in the dimethylformamide (DMF) disolvate of the basic calix[6]arene (1) without substituents in the lower and upper rims. Such symmetry is driven by the guest geometry allowing for two equivalent hydrogen bonding patterns in the chair seat. This avoids cone distortion found in the other chair-like conformers, although they have energies lower than that of new symmetrical conformer. The molecular conformation of hexa(carboxymethoxy)calix[6]arene (2) is also described as a dimethylsulfoxide (DMSO) pentasolvate. Its conformation can be described as a 1,3,5-closed cone with three alternate phenyl rings inclined inwards to the cone, thereby closing the cone entrance. Such a conformation also suggests five acid groups are pointed towards the same side of the calyx base and are able to bind metal ions or basic compounds in the lower rim, while inclusion of guests into the cone cavity is hindered. Both inclusion and cooperative acid binding/coordination abilities are still more hindered in the lowest energy 1,2,3-alternate cone conformer of 2. The role of the solvent in avoiding cone distortion was highlighted by inspecting the conformations of 5,11,17,23,29,35,41,47-octanitro-49,50,51,52,53,54,55,56-octa-n-butoxycalix[8]arene (3) and the known nitro analogues having methyl instead of n-butyl groups. Cone distortion is found in the non-solvated crystal form of 3, while non-classical hydrogen bonds with tetrahydrofuran preclude this in the literature analogue.