title: Second-Generation Phenylthiazole Antibiotics with Enhanced Pharmacokinetic Properties.
abstract: A series of second-generation analogues for 2-(1-(2-(4-butylphenyl)-4-methylthiazol-5-yl)ethylidene)aminoguanidine (1) have been synthesized and tested against methicillin-resistant Staphylococcus aureus (MRSA). The compounds were designed with the objective of improving pharmacokinetic properties. This main aim has been accomplished by replacing the rapidly hydrolyzable Schiff-base moiety of first-generation members with a cyclic, unhydrolyzable pyrimidine ring. The hydrazide-containing analogue 17 was identified as the most potent analogue constructed thus far. The corresponding amine 8 was 8 times less active. Finally, incorporating the nitrogenous side chain within an aromatic system completely abolished the antibacterial character. Replacement of the n-butyl group with cyclic bioisosteres revealed cyclohexenyl analogue 29, which showed significant improvement in in vitro anti-MRSA potency. Increasing or decreasing the ring size deteriorated the antibacterial activity. Compound 17 demonstrated a superior in vitro and in vivo pharmacokinetic profile, providing compelling evidence that this particular analogue is a good drug candidate worthy of further analysis.
authors.affiliation: Department of Pharmaceutical Organic Chemistry, College of Pharmacy, Al-Azhar University , Cairo 11884, Egypt.
authors.forename: Mohammed A
authors.initials: MA
authors.lastname: Seleem
authors.affiliation: Department of Pharmaceutical Organic Chemistry, College of Pharmacy, Al-Azhar University , Cairo 11884, Egypt.
authors.forename: Ahmed M
authors.initials: AM
authors.lastname: Disouky
authors.affiliation: Department of Comparative Pathobiology, Purdue University, College of Veterinary Medicine , West Lafayette, Indiana 47907, United States.
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 Clinical Pharmacy, College of Pharmacy, Heliopolis University , Cairo 11777, Egypt.
authors.forename: Ahmed S
authors.initials: AS
authors.lastname: Mancy
authors.affiliation: Department of Pharmaceutics, College of Pharmacy, Heliopolis University , Cairo 11777, Egypt.
authors.forename: Sammar A
authors.initials: SA
authors.lastname: Bayoumi
authors.affiliation: Bioequivalence Section, Genuine Research Center , Heliopolis, Cairo 11757, Egypt.|Department of Pharmaceutics & Industrial Pharmacy, Faculty of Pharmacy, Cairo University , Kasr El-Ainy, Cairo 11562, Egypt.
authors.forename: Ahmed
authors.initials: A
authors.lastname: Elshafeey
authors.affiliation: Department of Pharmaceutical Organic Chemistry, College of Pharmacy, Al-Azhar University , Cairo 11884, Egypt.
authors.forename: Ahmed
authors.initials: A
authors.lastname: El-Morsy
authors.affiliation: Department of Comparative Pathobiology, Purdue University, College of Veterinary Medicine , West Lafayette, Indiana 47907, United States.|Purdue Institute for Inflammation, Immunology, and Infectious Diseases, Purdue University , West Lafayette, Indiana 47907, United States.
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.
authors.forename: Abdelrahman S
authors.initials: AS
authors.lastname: Mayhoub
mesh_terms: D000900:Anti-Bacterial Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000493:pharmacokinetics* / Q000494:pharmacology; D018938:Caco-2 Cells; D004305:Dose-Response Relationship, Drug; D006801:Humans; D006834:Hydrazines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D015603:Keratinocytes / Q000187:drug effects; 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 / Q000493:pharmacokinetics* / Q000494:pharmacology
chemical_list: C000619431:2-(4-butylphenyl)-5-(2-hydrazinylpyrimidin-4-yl)-4-methylthiazole; D000900:Anti-Bacterial Agents; D006834:Hydrazines; D013844:Thiazoles