title: Diphenylurea derivatives for combating methicillin- and vancomycin-resistant Staphylococcus aureus.
abstract: A new class of diphenylurea was identified as a novel antibacterial scaffold with an antibacterial spectrum that includes highly resistant staphylococcal isolates, namely methicillin- and vancomycin-resistant Staphylococcus aureus (MRSA & VRSA). Starting with a lead compound 3 that carries an aminoguanidine functionality from one side and a n-butyl moiety on the other ring, several analogues were prepared. Considering the pharmacokinetic parameters as a key factor in structural optimization, the structure-activity-relationships (SARs) at the lipophilic side chain were rigorously examined leading to the discovery of the cycloheptyloxyl analogue 21n as a potential drug-candidate. This compound has several notable advantages over vancomycin and linezolid including rapid killing kinetics against MRSA and the ability to target and reduce the burden of MRSA harboring inside immune cells (macrophages). Furthermore, the potent anti-MRSA activity of 21n was confirmed in vivo using a Caenorhabditis elegans animal model. The present study provides a foundation for further development of diphenylurea compounds as potential therapeutic agents to address the burgeoning challenge of bacterial resistance to antibiotics.
authors.affiliation: Department of Pharmaceutical Organic Chemistry, College of Pharmacy, Al-Azhar University, Cairo 11884, Egypt.
authors.forename: Ibrahim H
authors.initials: IH
authors.lastname: Eissa
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 Pharmaceutical Organic Chemistry, College of Pharmacy, Al-Azhar University, Cairo 11884, Egypt.
authors.forename: Omar A
authors.initials: OA
authors.lastname: Qassem
authors.affiliation: Department of Comparative Pathobiology, Purdue University, College of Veterinary Medicine, West Lafayette, IN 47907, USA.
authors.forename: Waleed
authors.initials: W
authors.lastname: Younis
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 Pharmaceutics, College of Pharmacy, Cairo University, Cairo 11777, Egypt; Bioequivalence Section, Genuine Research Center, Heliopolis, Cairo 11757, Egypt.
authors.forename: Ahmed
authors.initials: A
authors.lastname: Elshafeey
authors.affiliation: Department of Pharmaceutical Chemistry, College of Clinical Pharmacy, University of Dammam, Eastern Province, P.O. Box 1982, Dammam 31441, Kingdom of Saudi Arabia.
authors.forename: Mahmoud M
authors.initials: MM
authors.lastname: Abd Rabo Moustafa
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: D000818:Animals; D000900:Anti-Bacterial Agents / Q000737:chemistry* / Q000494:pharmacology; D017173:Caenorhabditis elegans; D002224:Carbanilides / Q000737:chemistry* / Q000494:pharmacology; D024881:Drug Resistance, Bacterial / Q000187:drug effects; D055624:Methicillin-Resistant Staphylococcus aureus / Q000187:drug effects*; D013203:Staphylococcal Infections / Q000188:drug therapy; D013211:Staphylococcus aureus / Q000187:drug effects; D020713:Vancomycin Resistance / Q000187:drug effects*
chemical_list: D000900:Anti-Bacterial Agents; D002224:Carbanilides
keywords: Antibiotic drug resistance; Caenorhabditis elegans; Intracellular infection; MRSA; Methicillin-resistant Staphylococcus aureus; Pharmacokinetics