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Second-Generation Phenylthiazole Antibiotics with Enhanced Pharmacokinetic Properties.
Seleem, Mohammed A; Disouky, Ahmed M; Mohammad, Haroon; Abdelghany, Tamer M; Mancy, Ahmed S; Bayoumi, Sammar A; Elshafeey, Ahmed; El-Morsy, Ahmed; Seleem, Mohamed N; Mayhoub, Abdelrahman S.
Afiliación
  • Seleem MA; Department of Pharmaceutical Organic Chemistry, College of Pharmacy, Al-Azhar University , Cairo 11884, Egypt.
  • Disouky AM; Department of Pharmaceutical Organic Chemistry, College of Pharmacy, Al-Azhar University , Cairo 11884, Egypt.
  • Mohammad H; Department of Comparative Pathobiology, Purdue University, College of Veterinary Medicine , West Lafayette, Indiana 47907, United States.
  • Abdelghany TM; Department of Pharmacology, College of Pharmacy, Al-Azhar University , Cairo 11884, Egypt.
  • Mancy AS; Department of Clinical Pharmacy, College of Pharmacy, Heliopolis University , Cairo 11777, Egypt.
  • Bayoumi SA; Department of Pharmaceutics, College of Pharmacy, Heliopolis University , Cairo 11777, Egypt.
  • Elshafeey A; Bioequivalence Section, Genuine Research Center , Heliopolis, Cairo 11757, Egypt.
  • El-Morsy A; Department of Pharmaceutics & Industrial Pharmacy, Faculty of Pharmacy, Cairo University , Kasr El-Ainy, Cairo 11562, Egypt.
  • Seleem MN; Department of Pharmaceutical Organic Chemistry, College of Pharmacy, Al-Azhar University , Cairo 11884, Egypt.
  • Mayhoub AS; Department of Comparative Pathobiology, Purdue University, College of Veterinary Medicine , West Lafayette, Indiana 47907, United States.
J Med Chem ; 59(10): 4900-12, 2016 05 26.
Article en En | MEDLINE | ID: mdl-27187739
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.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Tiazoles / Staphylococcus aureus Resistente a Meticilina / Hidrazinas / Antibacterianos Límite: Humans Idioma: En Revista: J Med Chem Asunto de la revista: QUIMICA Año: 2016 Tipo del documento: Article País de afiliación: Egipto Pais de publicación: Estados Unidos
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Tiazoles / Staphylococcus aureus Resistente a Meticilina / Hidrazinas / Antibacterianos Límite: Humans Idioma: En Revista: J Med Chem Asunto de la revista: QUIMICA Año: 2016 Tipo del documento: Article País de afiliación: Egipto Pais de publicación: Estados Unidos