Targeting Dopamine D₃ and Serotonin 5‑HT_1A and 5‑HT_2A Receptors for Developing Effective Antipsychotics: Synthesis, Biological Characterization, and Behavioral Studies

Combination of dopamine D₃ antagonism, serotonin 5-HT_1A partial agonism, and antagonism at 5-HT_2A leads to a novel approach to potent atypical antipsychotics. Exploitation of the original structure–activity relationships resulted in the identification of safe and effective antipsychotics devoid of extrapyramidal symptoms liability, sedation, and catalepsy. The potential atypical antipsychotic <b>5bb</b> was selected for further pharmacological investigation. The distribution of <i>c-fos</i> positive cells in the ventral striatum confirmed the atypical antipsychotic profile of <b>5bb</b> in agreement with behavioral rodent studies. <b>5bb</b> administered orally demonstrated a biphasic effect on the MK801-induced hyperactivity at dose levels not able to induce sedation, catalepsy, or learning impairment in passive avoidance. In microdialysis studies, <b>5bb</b> increased the dopamine efflux in the medial prefrontal cortex. Thus, <b>5bb</b> represents a valuable lead for the development of atypical antipsychotics endowed with a unique pharmacological profile for addressing negative symptoms and cognitive deficits in schizophrenia

Optimization of 4‑Aminoquinoline/Clotrimazole-Based Hybrid Antimalarials: Further Structure–Activity Relationships, in Vivo Studies, and Preliminary Toxicity Profiling

Despite recent progress in the fight against malaria, the emergence and spread of drug-resistant parasites remains a serious obstacle to the treatment of infections. We recently reported the development of a novel antimalarial drug that combines the 4-aminoquinoline pharmacophore of chloroquine with that of clotrimazole-based antimalarials. Here we describe the optimization of this class of hybrid drug through in-depth structure–activity relationship studies. Antiplasmodial properties and mode of action were characterized in vitro and in vivo, and interactions with the parasite’s 'chloroquine resistance transporter' were investigated in a <i>Xenopus laevis</i> oocyte expression system. These tests indicated that piperazine derivatives <b>4b</b> and <b>4d</b> may be suitable for coadministration with chloroquine against chloroquine-resistant parasites. The potential for metabolism of the drugs by cytochrome P450 was determined in silico, and the lead compounds were tested for toxicity and mutagenicity. A preliminary pharmacokinetic analysis undertaken in mice indicated that compound <b>4b</b> has an optimal half-life

Harnessing the Role of HDAC6 in Idiopathic Pulmonary Fibrosis: Design, Synthesis, Structural Analysis, and Biological Evaluation of Potent Inhibitors.

Idiopathic pulmonary fibrosis (IPF) is an interstitial lung disease characterized by a progressive-fibrosing phenotype. IPF has been associated with aberrant HDAC activities confirmed by our immunohistochemistry studies on HDAC6 overexpression in IPF lung tissues. We herein developed a series of novel hHDAC6 inhibitors, having low inhibitory potency over hHDAC1 and hHDAC8, as potential pharmacological tools for IPF treatment. Their inhibitory potency was combined with low in vitro and in vivo toxicity. Structural analysis of 6h and structure–activity relationship studies contributed to the optimization of the binding mode of the new molecules. The best-performing analogues were tested for their efficacy in inhibiting fibrotic sphere formation and cell viability, proving their capability in reverting the IPF phenotype. The efficacy of analogue 6h was also determined in a validated human lung model of TGF-β1-dependent fibrogenesis. The results highlighted in this manuscript may pave the way for the identification of first-in-class molecules for the treatment of IPF