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 μg 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.