title: New CYP17 hydroxylase inhibitors: synthesis, biological evaluation, QSAR, and molecular docking study of new pregnenolone analogs.
abstract: A new series of pregnenonlone analogs were synthesized and evaluated for their inhibitory activity against cytochrome P450 (CYP17 hydroxylase enzyme). In general, the 5-aryl-1,3,4-thiadiazol-2-yl)-imino-pregnenolone derivatives 11-15 were more active than the sulfonate 24-31 and the ester 37-41 analogs. Derivative 12 showed optimal activity in this series, with IC50 values of 2.5 µM compared with the standard abiraterone (IC50  = 0.07 µM). However, the analogs 11 and 25 showed a better selectivity profile (81.5 and 82.7% inhibition of hydroxylase, respectively), which may be a useful lead in CYP17 inhibition studies. Molecular docking studies demonstrated quite similar binding patterns of all new pregnenolone derivatives at the active site of CYP17 through hydrogen bonding and hydrophobic interaction.
authors.affiliation: Department of Chemistry, College of Science, University of Basrah, Basrah, Iraq.
authors.forename: Najim A
authors.initials: NA
authors.lastname: Al-Masoudi
authors.forename: Dawood S
authors.initials: DS
authors.lastname: Ali
authors.forename: Bahjat
authors.initials: B
authors.lastname: Saeed
authors.forename: Rolf W
authors.initials: RW
authors.lastname: Hartmann
authors.forename: Matthias
authors.initials: M
authors.lastname: Engel
authors.forename: Sajid
authors.initials: S
authors.lastname: Rashid
authors.forename: Aamer
authors.initials: A
authors.lastname: Saeed
mesh_terms: D001665:Binding Sites; D020134:Catalytic Domain; D017076:Computer-Aided Design; D065607:Cytochrome P-450 Enzyme Inhibitors / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology*; D015195:Drug Design; D006860:Hydrogen Bonding; D057927:Hydrophobic and Hydrophilic Interactions; D062105:Molecular Docking Simulation; D015394:Molecular Structure; D011284:Pregnenolone / Q000031:analogs & derivatives / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology*; D021281:Quantitative Structure-Activity Relationship; D011994:Recombinant Proteins / Q000378:metabolism; D013254:Steroid 17-alpha-Hydroxylase / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D065607:Cytochrome P-450 Enzyme Inhibitors; D011994:Recombinant Proteins; D011284:Pregnenolone; C501892:CYP17A1 protein, human; D013254:Steroid 17-alpha-Hydroxylase
keywords: Anti-HIV activity; CYP17 hydroxylase enzyme; Molecular docking study; Pregnenolone; QSAR