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Design, synthesis and molecular modeling of novel aryl carboximidamides and 3-aryl-1,2,4-oxadiazoles derived from indomethacin as potent anti-inflammatory iNOS/PGE2 inhibitors.
Mohamed, Mamdouh F A; Marzouk, Adel A; Nafady, Ayman; El-Gamal, Dalia A; Allam, Rasha M; Abuo-Rahma, Gamal El-Din A; El Subbagh, Hussein I; Moustafa, Amr H.
Afiliación
  • Mohamed MFA; Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Sohag University, 82524 Sohag, Egypt. Electronic address: mamdouh.fawzi@pharm.sohag.edu.eg.
  • Marzouk AA; Pharmaceutical Chemistry Department, Faculty of Pharmacy, Al-Azhar University, 71524 Assiut, Egypt.
  • Nafady A; Department of Chemistry, College of Science, King Saud University, Riyadh, Saudi Arabia.
  • El-Gamal DA; Histology Department, Faculty of Medicine, Assiut University, 71526 Assiut, Egypt.
  • Allam RM; Pharmacology Department, National Research Centre, Giza 11865, Egypt.
  • Abuo-Rahma GEA; Department of Medicinal Chemistry, Faculty of Pharmacy, Minia University, Minia 61519, Egypt.
  • El Subbagh HI; Department of Medicinal Chemistry, Faculty of Pharmacy, Mansoura University, 35516 Mansoura, Egypt.
  • Moustafa AH; Department of Chemistry, Faculty of Science, Sohag University, Sohag 82524, Egypt.
Bioorg Chem ; 105: 104439, 2020 12.
Article en En | MEDLINE | ID: mdl-33161252
The development of NSAIDs/iNOS inhibitor hybrids is a new strategy for the treatment of inflammatory diseases by suppression of the overproduction of PGE2 and NO. A novel series of aryl carboximidamides 4a-g and their cyclized 3-aryl-1,2,4-oxadiazoles 5a-g counterparts derived from indomethacin 1 were synthesized. Most of the target compounds displayed lower LPS-induced NO production IC50 in RAW 264.7 cells and potent in vitro iNOS and PGE2 inhibitory activity than indomethacin. Moreover, in carrageenan-induced rat paw oedema method, most of them exhibited higher in vivo anti-inflammatory activity than the reference drug indomethacin. Notably, 4 hrs after carrageenan injection, compound 4a proved to be the most potent anti-inflammatory agent in this study, with almost two- and eight-fold more active than the reference drugs indomethacin (1) and celecoxib, respectively. Compound 4a proved to be inhibitor to LPS-induced NO production, iNOS activity and PGE2 with IC50 of 10.70 µM, 2.31 µM, and 29 nM; respectively. Compounds 4a and 5b possessed the lowest ulcerogenic liabilities (35% and 38%, respectively) compared to 1. Histopathological analysis revealed that compounds 4a and 5b demonstrated reduced degeneration and healing of ulcers. Molecular docking studies into the catalytic binding pocket of the iNOS protein receptor (PDB ID: 1r35) showed good correlation with the obtained biological results. Parameters of Lipinski's rule of five and ADMET analysis were calculated where compound 4a had reasonable drug-likeness with acceptable physicochemical properties so it could be used as promising orally absorbed anti-inflammatory therapy and entitled to be used as future template for further investigations.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Oxadiazoles / Dinoprostona / Antiinflamatorios no Esteroideos / Indometacina / Inhibidores Enzimáticos / Óxido Nítrico Sintasa de Tipo II Límite: Animals / Humans / Male Idioma: En Revista: Bioorg Chem Año: 2020 Tipo del documento: Article

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Oxadiazoles / Dinoprostona / Antiinflamatorios no Esteroideos / Indometacina / Inhibidores Enzimáticos / Óxido Nítrico Sintasa de Tipo II Límite: Animals / Humans / Male Idioma: En Revista: Bioorg Chem Año: 2020 Tipo del documento: Article
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