Caterina Fattorusso

Combining 4-aminoquinoline- and clotrimazole-based pharmacophores toward innovative and potent hybrid antimalarials.

Antimalarial agents structurally based on novel pharmacophores, synthesized by low-cost synthetic procedures and characterized by low potential for developing resistance are urgently needed. Recently, we developed an innovative class of antimalarials based on a polyaromatic pharmacophore. Hybridizing the 4-aminoquinoline or the 9-aminoacridine system of known antimalarials with the clotrimazole-like pharmacophore, characterized by a polyarylmethyl group, we describe herein the development of a unique class (4a-l and 5a-c) of antimalarials selectively interacting with free heme and interfering with Plasmodium falciparum (Pf) heme metabolism. Combination of the polyarylmethyl system, able to form and stabilize radical intermediates, with the iron-complexing and conjugation-mediated electron transfer properties of the 4(9)-aminoquinoline(acridine) system led to potent antimalarials in vitro against chloroquine sensitive and resistant Pf strains. Among the compounds synthesized, 4g was active in vivo against P. chabaudi and P. berghei after oral administration and, possessing promising pharmacokinetic properties, it is a candidate for further preclinical development.

Clotrimazole Scaffold as an Innovative Pharmacophore Towards Potent Antimalarial Agents : Design, Synthesis, and Biological and Structure-Activity Relationship Studies

We describe herein the design, synthesis, biological evaluation, and structure-activity relationship (SAR) studies of an innovative class of antimalarial agents based on a polyaromatic pharmacophore structurally related to clotrimazole and easy to synthesize by low-cost synthetic procedures. SAR studies delineated a number of structural features able to modulate the in vitro and in vivo antimalarial activity. A selected set of antimalarials was further biologically investigated and displayed low in vitro toxicity on a panel of human and murine cell lines. In vitro, the novel compounds proved to be selective for free heme, as demonstrated in the beta-hematin inhibitory activity assay, and did not show inhibitory activity against 14-alpha-lanosterol demethylase (a fungal P450 cytochrome). Compounds 2, 4e, and 4n exhibited in vivo activity against P. chabaudi after oral administration and thus represent promising antimalarial agents for further preclinical development.

Novel antipsychotic agents: recent advances in the drug treatment of schizophrenia

Several new potential antipsychotic agents have been disclosed in the patent literature over the last 3 years and a sizeable number of drugs are actually in advanced stages of investigation. The majority of these cases involve compounds characterised by a high affinity for dopamine or 5-HT2A receptors, associated or not to low dopamine receptor affinity or by affinity for other serotonin receptors such as 5-HT6 and 5-HT7, which may indirectly modulate mesolimbic dopaminergic neurons, producing efficacy against positive and negative symptoms of schizophrenia. Other patents have focused on chemical entities capable of relieving schizophrenic symptoms by interaction with less obvious receptors, such as glutamate or sigma receptors. A few patents claim the development of atypical antipsychotic drugs, structurally related to olanzapine and aripiprazole, characterised by high efficacy and low propensity to induce motor disturbances and blood disorders. Starting from the typical antipsychotics, taking into account the challenging pharmacological profile of clozapine, olanzapine and aripiprazole, this update will focus on the recent and ongoing activity in the development of novel antipsychotic drugs.

Selective targeting of the HIV-1 reverse transcriptase catalytic complex through interaction with the ''primer grip'' region by pyrrolobenzoxazepinone non-nucleoside inhibitors correlates with increased activity towards drug-resistant mutants

PBO (pyrrolobenzoxazepinone) derivatives are non-nucleoside reverse transcriptase inhibitors (NNRTIs), which display a selective interaction with the catalytic ternary complex of HIV-1 reverse transcriptase (RT) and its substrates. In order to develop novel PBOs with improved resistance profiles, we synthesised additional PBO derivatives, specifically designed to target highly conserved residues in the beta12-beta13 hairpin, the so-called primer grip region of HIV-1 RT. Here, we investigated the biochemical and enzymological mechanism of inhibition of HIV-1 RT wild type and carrying NNRTIs-resistance mutations, by these derivatives. Our kinetic analysis indicates that the ability of PBOs to selectively target the catalytic ternary complex of RT with its substrates directly correlates with greatly reduced sensitivity to NNRTIs-resistance mutations, particularly the K103N substitution. Molecular modeling and docking studies provided an explanation for this correlation at the structural level.