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New CYP17 Hydroxylase Inhibitors: Synthesis, Biological Evaluation, QSAR, and Molecular Docking Study of New Pregnenolone Analogs
Author(s) -
AlMasoudi Najim A.,
Ali Dawood S.,
Saeed Bahjat,
Hartmann Rolf W.,
Engel Matthias,
Rashid Sajid,
Saeed Aamer
Publication year - 2014
Publication title -
archiv der pharmazie
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.468
H-Index - 61
eISSN - 1521-4184
pISSN - 0365-6233
DOI - 10.1002/ardp.201400255
Subject(s) - chemistry , pregnenolone , docking (animal) , stereochemistry , active site , selectivity , enzyme , cytochrome p450 , aryl , combinatorial chemistry , biochemistry , steroid , organic chemistry , alkyl , medicine , nursing , hormone , catalysis
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 IC 50 values of 2.5 µM compared with the standard abiraterone (IC 50 = 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.