title: Phenylthiazole antibiotics: A metabolism-guided approach to overcome short duration of action.
abstract: Antibacterial resistance is a pressing global health challenge that necessitates the development of new therapeutic agents. Phenylthiazole antibacterial agents have been extensively studied, by our group, as a potential novel class of antibiotics to circumvent the scourge of antibacterial resistance. Previously, the phenylthiazole lead compound 1 was shown to possess potent activity against clinical isolates of methicillin- and vancomycin-resistant Staphylococcus aureus (MRSA and VRSA). The promising activity of this novel class of antibiotics is hampered by their short half-life due to rapid hepatic metabolism. In the present study, a metabolic methylene soft spot in the lead 1 was identified and replaced with an oxygen atom. The newly developed phenylthiazoles, with alkoxy side chains, demonstrate high metabolic stability (t1/2> 4 h), while maintaining their potent anti-MRSA activity. Furthermore, compound 5p demonstrated a selective advantage over vancomycin with its ability to kill intracellular MRSA.
authors.affiliation: Department of Pharmaceutical Organic Chemistry, College of Pharmacy, Al-Azhar University, Cairo 11884, Egypt.
authors.forename: Eman
authors.initials: E
authors.lastname: Yahia
authors.affiliation: Department of Comparative Pathobiology, Purdue University, College of Veterinary Medicine, West Lafayette, IN 47907, USA.
authors.forename: Haroon
authors.initials: H
authors.lastname: Mohammad
authors.affiliation: Department of Pharmacology, College of Pharmacy, Al-Azhar University, Cairo 11884, Egypt.
authors.forename: Tamer M
authors.initials: TM
authors.lastname: Abdelghany
authors.affiliation: Department of Pharmaceutical Organic Chemistry, College of Pharmacy, Al-Azhar University, Cairo 11884, Egypt.
authors.forename: Eman
authors.initials: E
authors.lastname: Fayed
authors.affiliation: Department of Comparative Pathobiology, Purdue University, College of Veterinary Medicine, West Lafayette, IN 47907, USA; Purdue Institute for Inflammation, Immunology, and Infectious Diseases, West Lafayette, IN 479067, USA. Electronic address: mseleem@purdue.edu.
authors.forename: Mohamed N
authors.initials: MN
authors.lastname: Seleem
authors.affiliation: Department of Pharmaceutical Organic Chemistry, College of Pharmacy, Al-Azhar University, Cairo 11884, Egypt; Biomedical Sciences, University of Science and Technology, Zewail City of Science and Technology, Giza, Egypt. Electronic address: amayhoub@azhar.edu.eg.
authors.forename: Abdelrahman S
authors.initials: AS
authors.lastname: Mayhoub
mesh_terms: D000900:Anti-Bacterial Agents / Q000737:chemistry / Q000378:metabolism / Q000493:pharmacokinetics*; D002478:Cells, Cultured; D024881:Drug Resistance, Bacterial; D004355:Drug Stability; D006207:Half-Life; D006801:Humans; D015603:Keratinocytes / Q000187:drug effects / Q000382:microbiology; D055624:Methicillin-Resistant Staphylococcus aureus / Q000187:drug effects; D013329:Structure-Activity Relationship; D013844:Thiazoles / Q000138:chemical synthesis* / Q000378:metabolism / Q000493:pharmacokinetics
chemical_list: D000900:Anti-Bacterial Agents; D013844:Thiazoles
keywords: Antibiotic-resistance; MRSA; VRSA