Discovery of Arylpiperazines with Broad-Spectrum Antimicrobial Activity and Favorable Pharmacokinetic Profiles.

Microorganisms can induce diseases with significant clinical implications for human health. Multidrug-resistant microorganisms have been on the rise worldwide over the past few decades, and no new antibiotics have been introduced to the market in a considerable amount of time. Such situation highlights the urgency of discovering new antimicrobial drugs to address this pressing issue. Therefore, the objective of this study was to identify bioactive compounds against 15 species of bacteria and 5 species of fungi of clinical relevance through in vitro screening of 58 synthetic compounds from four chemical classes of our internal library of synthetic compounds. Our findings highlight arylpiperazines 18, 20, 26, 27, and 29, and the aminothiazole 50, as potent broad-spectrum antimicrobials (MICs = 12.5 - 15.6 mg.mL-1) against clinically relevant bacteria and fungi. Additionally, these compounds displayed low cytotoxicity against various host cells and a favorable in vitro pharmacokinetic profile for oral administration. Indeed, all six showed adequate lipophilicity, high gastrointestinal permeability, metabolic stability in human and mouse liver microsomes, and satisfactory aqueous solubility. Thus, they emerge as promising starting points for hit-to-lead studies towards new antibacterial and antifungal agents, especially against Staphylococcus epidermidis, Staphylococcus aureus, Lactobacillus paracasei and Candida orthopsilosis.

Synthesis, design, and optimization of a potent and selective series of pyridylpiperazines as promising antimalarial agents.

An optimization of the pyridylpiperazine series against Plasmodium falciparum has been performed, exploring a structure-activity relationship carried out on the toluyl fragment of hit 1, a compound with low micromolar activity against Plasmodium falciparum discovered by high-throughput screening. After confirming the crucial role played by this aryl fragment in the antiplasmodial activity, the replacement of the ortho-methyl substituent of 1 by halogenated ones led to an improvement for four analogs, either in terms of potency, expected pharmacokinetics profile, or both. Further introduction of endocyclic nitrogens in this fragment identified two more optimized compounds, 20 and 23, which are expected to be much more metabolically stable than 1. Additional assessment of the cytotoxicity, Ligand Lipophilic Efficiency, potency against the chloroquine-resistant Dd2 strain and in silico ADMET predictions revealed a satisfactory profile for most compounds, ultimately identifying the four optimized compounds 7, 9, 20 and 23 as promising compounds for further lead optimization of this series against Plasmodium falciparum.

Hit-to-lead optimization of a pyrazinylpiperazine series against Leishmania infantum and Leishmania braziliensis.

An early hit-to-lead optimization of a novel pyrazinylpiperazine series against L. infantum and L. braziliensis has been performed after an extensive SAR focusing on the benzoyl fragment of hit (4). Deletion of the meta-Cl of (4) led to the obtention of the para-hydroxyl derivative (12), on which the design of most monosubstituted derivatives of the SAR was based. Further optimization of the series, involving disubstituted benzoyl fragments and the hydroxyl substituent of (12), allowed the obtention of a total of 15 compounds with increased antileishmanial potency (IC50 < 10 µM), nine of which displayed activity in the low micromolar range (IC50 < 5 µM). This optimization ultimately identified the ortho, meta-dihydroxyl derivative (46) as an early lead for this series (IC50 (L. infantum) = 2.8 µM, IC50 (L. braziliensis) = 0.2 µM). Additional assessment of some selected compounds against other trypanosomatid parasites revealed that this series is selective towards Leishmania parasites, and in silico ADMET predictions revealed satisfactory profiles for these compounds, allowing further lead optimization of the pyrazinylpiperazine class against Leishmania.