title: Synthesis and antibacterial evaluation of a novel series of synthetic phenylthiazole compounds against methicillin-resistant Staphylococcus aureus (MRSA).
abstract: Methicillin-resistant Staphylococcus aureus infections are a significant global health challenge in part due to the emergence of strains exhibiting resistance to nearly all classes of antibiotics. This underscores the urgent need for the rapid development of novel antimicrobials to circumvent this burgeoning problem. Previously, whole-cell screening of a library of 2,5-disubstituted thiazole compounds revealed a lead compound exhibiting potent antimicrobial activity against MRSA. The present study, conducting a more rigorous analysis of the structure-activity relationship of this compound, reveals a nonpolar, hydrophobic functional group is favored at thiazole-C2 and an ethylidenehydrazine-1-carboximidamide moiety is necessary at C5 for the compound to possess activity against MRSA. Furthermore, the MTS assay confirmed analogs 5, 22d, and 25 exhibited an improved toxicity profile (not toxic up to 40 μg/mL to mammalian cells) over the lead 1. Analysis with human liver microsomes revealed compound 5 was more metabolically stable compared to the lead compound (greater than eight-fold improvement in the half-life in human liver microsomes). Collectively the results presented demonstrate the novel thiazole derivatives synthesized warrant further exploration for potential use as future antimicrobial agents for the treatment of multidrug-resistant S. aureus infections.
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 Medicinal Chemistry and Molecular Pharmacology, Purdue University College of Pharmacy, and the Purdue Center for Cancer Research, West Lafayette, IN 47907, USA.
authors.forename: P V Narasimha
authors.initials: PV
authors.lastname: Reddy
authors.affiliation: Department of Medicinal Chemistry and Molecular Pharmacology, Purdue University College of Pharmacy, and the Purdue Center for Cancer Research, West Lafayette, IN 47907, USA.
authors.forename: Dennis
authors.initials: D
authors.lastname: Monteleone
authors.affiliation: Department of Organic Chemistry, Al Azhar University, Cairo 11884, Egypt.
authors.forename: Abdelrahman S
authors.initials: AS
authors.lastname: Mayhoub
authors.affiliation: Department of Medicinal Chemistry and Molecular Pharmacology, Purdue University College of Pharmacy, and the Purdue Center for Cancer Research, West Lafayette, IN 47907, USA.
authors.forename: Mark
authors.initials: M
authors.lastname: Cushman
authors.affiliation: Department of Comparative Pathobiology, Purdue University College of Veterinary Medicine, West Lafayette, IN 47907, USA. Electronic address: mseleem@purdue.edu.
authors.forename: Mohamed N
authors.initials: MN
authors.lastname: Seleem
mesh_terms: D000900:Anti-Bacterial Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D055624:Methicillin-Resistant Staphylococcus aureus / Q000187:drug effects*; D008826:Microbial Sensitivity Tests; D015394:Molecular Structure; D013329:Structure-Activity Relationship; D013844:Thiazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D000900:Anti-Bacterial Agents; D013844:Thiazoles
keywords: Antimicrobials; Drug-resistance; HEK293 toxicity; Methicillin-resistant Staphylococcus aureus (MRSA); Thiazole compounds