Discovery of Quaternized Pyridine-Thiazole-Pleuromutilin Derivatives with Broad-Spectrum Antibacterial and Potent Anti-MRSA Activity

Abstract

The quaternization of compounds has emerged as a promising molecular design strategy for the development of antibiotics. Herein, we report the design, synthesis, antibacterial activities, and structure–activity relationships of a series of novel pleuromutilin derivatives containing a quaternary amine C-14 side chain. Most of these derivatives exhibited broad-spectrum antibacterial activity against the tested bacteria. 10b was the most effective antibacterial agent that displayed excellent antibacterial activity against five clinical methicillin-resistant Staphylococcus aureus (MRSA) isolates, remarkable antimycoplasma activity, rapid bactericidal effects, and a strong ability to damage bacterial biofilms. Further mechanistic studies indicated that 10b destroyed bacterial cell membranes to exert its antibacterial effects. Moreover, 10b exhibited high survival protection and potent in vivo antibacterial efficacy (ED50 = 4.94 mg/kg) in a mouse model of systemic MRSA infection. These findings suggest that 10b is a promising candidate for the treatment of multi-drug-resistant infectious diseases, especially MRSA infections.

Design, Synthesis, and Biological Evaluation of 5-(5-Iodo-2-isopropyl-4-methoxyphenoxy)pyrimidine-2,4-diamine (AF-353) Derivatives as Novel DHFR Inhibitors against Staphylococcus aureus

“…This assay was evaluated by Cell Counting Kit-9 (CCK-8) using trimethoprim as the reference drug. 30 As shown in Table 5, most derivatives exhibited no significant cytotoxicity at 100 μM. Although the cytotoxicity of j9 against HEK293 slightly exceeds 50% and not as well as the positive control trimethoprim in two cell lines, compound j9 possesses good antimicrobial selectivity based on its excellent antibacterial activity against ATCC25923, USA300, and three strains of clinical TMP-resistant strains (MICs of 0.031−4 μg/mL).…”

“…We measured the inhibition rate of the target compounds at a concentration of 100 μM in two human cell lines: human embryonic kidney (HEK293) and human colonic mucosal epithelial cells (NCM460). This assay was evaluated by Cell Counting Kit-9 (CCK-8) using trimethoprim as the reference drug …”

Chemoselectivity of the CuAAC/Ring Cleavage/Cyclization Reaction between Enaminones and α-Acylketenimine

“…Pyridines and their derivatives display useful properties, including the antimicrobial and antiviral activities, antibacterial, antifungal, and/or anticancer agents, etc . Indeed, most of them have considerable therapeutic potential.…”

Hit-to-Lead Identification and Validation of a Triaromatic Pleuromutilin Antibiotic Candidate

“…The natural product pleuromutilin ( 1 , Figure ), discovered in 1951, , is an attractive foundation for new antibiotics. This is emphasized by the more than 40 pleuromutilin medicinal chemistry and total synthesis articles published within the field over the last 5 years, with some reporting very potent activity and high clinical potential, − and in some cases also by employing novel and unique strategies. ,,,,,− …”