Publication: Synthesis, molecular docking, and QSAR study of sulfonamide-based indoles as aromatase inhibitors
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Issued Date
2018
Resource Type
File Type
application/pdf
ISSN
2235234
Other identifier(s)
2-s2.0-85033552512
Rights Holder(s)
Scopus
Bibliographic Citation
European Journal of Medicinal Chemistry. Vol 143, (2018), p.1604-1615
Suggested Citation
Pingaew R., Mandi P., Prachayasittikul V., Prachayasittikul S., Ruchirawat S., Prachayasittikul V. Synthesis, molecular docking, and QSAR study of sulfonamide-based indoles as aromatase inhibitors. European Journal of Medicinal Chemistry. Vol 143, (2018), p.1604-1615. doi:10.1016/j.ejmech.2017.10.057 Retrieved from: https://hdl.handle.net/20.500.14740/3907
Abstract
Thirty four of indoles bearing sulfonamides (11–44) were synthesized and evaluated for their anti-aromatase activities. Interestingly, all indole derivatives inhibited the aromatase with IC50 range of 0.7–15.3 μM. Indoles (27–36) exerted higher aromatase inhibitory activity than that of ketoconazole. The phenoxy analogs 28 and 34 with methoxy group were shown to be the most potent compounds with sub-micromolar IC50 values (i.e., 0.7 and 0.8 μM, respectively) without affecting to the normal cell line. Molecular docking demonstrated that the indoles 28, 30 and 34 could occupy the same binding site on the aromatase pocket and share several binding residues with those of the natural substrate (androstenedione), which suggested the competitive binding could be the mode of inhibition of the compounds. The most potent analog 28 could mimic H-bond interactions of the natural androstenedione with MET374 and ASP309 residues on the aromatase. QSAR model also revealed that the para-phenoxy indole (28) affords the higher value of electronegativity descriptor MATS6e as well as the higher inhibitory activity compared with that of the ortho-phenoxy compound (34). The study highlighted a series of promising indoles to be potentially developed as novel aromatase inhibitors for therapeutics. © 2017 Elsevier Masson SAS
Subject(s)
4 bromo n [2 (1h indol 3 yl)ethyl]benzenesulfonamide
4 fluoro n [2 (1h indol 3 yl)ethyl]benzenesulfonamide
4 trifluoromethyl n [2 (1h indol 3 yl)ethyl]benzenesulfonamide
Androstenedione
Aromatase
Aromatase inhibitor
Aspartic acid
Ellipticine
Indole derivative
Ketoconazole
Letrozole
Methionine
N,n' [(2,2' [(4 nitrophenyl)methylene]bis(1h indole 3,2 diyl)]bis(ethane 2,1 diyl)]bis(4 bromobenzenesulfonamide)
N,n' [(2,2' [(4 nitrophenyl)methylene]bis(1h indole 3,2 diyl)]bis(ethane 2,1 diyl)]bis(4 fluorobenzenesulfonamide)
N,n' [[2,2' [(4 bromophenyl)methylene]bis(1h indole 3,2 diyl)]bis(ethane 2,1 diyl)]bis(4 trifluoromethylbenzenesulfonamide)
N,n' [[2,2' [(4 cyanophenyl)methylene]bis(1h indole 3,2 diyl)]bis(ethane 2,1 diyl)]bis(4 chlorobenzenesulfonamide)
N,n' [[2,2' [(4 cyanophenyl)methylene]bis(1h indole 3,2 diyl)]bis(ethane 2,1 diyl)]bis(4 fluorobenzenesulfonamide)
N,n' [[2,2' [(4 cyanophenyl)methylene]bis(1h indole 3,2 diyl)]bis(ethane 2,1 diyl)]bis(4 trifluoromethylbenzenesulfonamide)
N,n' [[2,2' [(4 fluorophenyl)methylene]bis(1h indole 3,2 diyl)]bis(ethane 2,1 diyl)]bis(4 bromobenzenesulfonamide)
N,n' [[2,2' [(4 fluorophenyl)methylene]bis(1h indole 3,2 diyl)]bis(ethane 2,1 diyl)]bis(4 chlorobenzenesulfonamide)
N,n' [[2,2' [(4 fluorophenyl)methylene]bis(1h indole 3,2 diyl)]bis(ethane 2,1 diyl)]bis(4 trifluoromethylbenzenesulfonamide)
N,n' [[2,2' [(4 hydroxyphenyl)methylene]bis(1h indole 3,2 diyl)]bis(ethane 2,1 diyl)]bis(4 trifluoromethylbenzenesulfonamide)
N,n' [[2,2' [(4 nitrophenyl)methylene]bis(1h indole 3,2 diyl)]bis(ethane 2,1 diyl)]bis(4 trifluoromethylbenzenesulfonamide)
N,n' [[2,2' [(4 trifluoromethylphenyl)methylene]bis(1h indole 3,2 diyl)]bis(ethane 2,1 diyl)]bis(4 bromobenzenesulfonamide)
N,n' [[2,2' [(4 trifluoromethylphenyl)methylene]bis(1h indole 3,2 diyl)]bis(ethane 2,1 diyl)]bis(4 chlorobenzenesulfonamide)
N,n' [[2,2' [(4 trifluoromethylphenyl)methylene]bis(1h indole 3,2 diyl)]bis(ethane 2,1 diyl)]bis(4 trifluoromethylbenzenesulfonamide)
N,n' [[2,2' [(9 ethyl 9h carbazol 3 yl)methylene]bis(1h indole 3,2 diyl)]bis(ethane 2,1 diyl)]bis(4 chlorobenzenesulfonamide)
N,n' [[2,2' [(9h fluoren 2 yl)methylene]bis(1h indole 3,2 diyl)]bis(ethane 2,1 diyl)]bis(4 chlorobenzenesulfonamide)
Sulfonamide
Unclassified drug
Aromatase inhibitor
Indole derivative
Sulfonamide
Animal cell
Article
Binding competition
Controlled study
Drug binding site
Drug cytotoxicity
Drug mechanism
Drug potency
Drug protein binding
Drug screening
Drug synthesis
Enzyme active site
Enzyme inhibition
Hydrogen bond
IC50
Molecular docking
Nonhuman
Quantitative structure activity relation
Animal
Cell survival
Chemical structure
Chemistry
Chlorocebus aethiops
Dose response
Drug effects
Metabolism
Multivariate analysis
Synthesis
Vero cell line
Animals
Aromatase
Aromatase Inhibitors
Cell Survival
Cercopithecus aethiops
Dose-Response Relationship, Drug
Indoles
Molecular Docking Simulation
Molecular Structure
Multivariate Analysis
Quantitative Structure-Activity Relationship
Sulfonamides
Vero Cells
4 fluoro n [2 (1h indol 3 yl)ethyl]benzenesulfonamide
4 trifluoromethyl n [2 (1h indol 3 yl)ethyl]benzenesulfonamide
Androstenedione
Aromatase
Aromatase inhibitor
Aspartic acid
Ellipticine
Indole derivative
Ketoconazole
Letrozole
Methionine
N,n' [(2,2' [(4 nitrophenyl)methylene]bis(1h indole 3,2 diyl)]bis(ethane 2,1 diyl)]bis(4 bromobenzenesulfonamide)
N,n' [(2,2' [(4 nitrophenyl)methylene]bis(1h indole 3,2 diyl)]bis(ethane 2,1 diyl)]bis(4 fluorobenzenesulfonamide)
N,n' [[2,2' [(4 bromophenyl)methylene]bis(1h indole 3,2 diyl)]bis(ethane 2,1 diyl)]bis(4 trifluoromethylbenzenesulfonamide)
N,n' [[2,2' [(4 cyanophenyl)methylene]bis(1h indole 3,2 diyl)]bis(ethane 2,1 diyl)]bis(4 chlorobenzenesulfonamide)
N,n' [[2,2' [(4 cyanophenyl)methylene]bis(1h indole 3,2 diyl)]bis(ethane 2,1 diyl)]bis(4 fluorobenzenesulfonamide)
N,n' [[2,2' [(4 cyanophenyl)methylene]bis(1h indole 3,2 diyl)]bis(ethane 2,1 diyl)]bis(4 trifluoromethylbenzenesulfonamide)
N,n' [[2,2' [(4 fluorophenyl)methylene]bis(1h indole 3,2 diyl)]bis(ethane 2,1 diyl)]bis(4 bromobenzenesulfonamide)
N,n' [[2,2' [(4 fluorophenyl)methylene]bis(1h indole 3,2 diyl)]bis(ethane 2,1 diyl)]bis(4 chlorobenzenesulfonamide)
N,n' [[2,2' [(4 fluorophenyl)methylene]bis(1h indole 3,2 diyl)]bis(ethane 2,1 diyl)]bis(4 trifluoromethylbenzenesulfonamide)
N,n' [[2,2' [(4 hydroxyphenyl)methylene]bis(1h indole 3,2 diyl)]bis(ethane 2,1 diyl)]bis(4 trifluoromethylbenzenesulfonamide)
N,n' [[2,2' [(4 nitrophenyl)methylene]bis(1h indole 3,2 diyl)]bis(ethane 2,1 diyl)]bis(4 trifluoromethylbenzenesulfonamide)
N,n' [[2,2' [(4 trifluoromethylphenyl)methylene]bis(1h indole 3,2 diyl)]bis(ethane 2,1 diyl)]bis(4 bromobenzenesulfonamide)
N,n' [[2,2' [(4 trifluoromethylphenyl)methylene]bis(1h indole 3,2 diyl)]bis(ethane 2,1 diyl)]bis(4 chlorobenzenesulfonamide)
N,n' [[2,2' [(4 trifluoromethylphenyl)methylene]bis(1h indole 3,2 diyl)]bis(ethane 2,1 diyl)]bis(4 trifluoromethylbenzenesulfonamide)
N,n' [[2,2' [(9 ethyl 9h carbazol 3 yl)methylene]bis(1h indole 3,2 diyl)]bis(ethane 2,1 diyl)]bis(4 chlorobenzenesulfonamide)
N,n' [[2,2' [(9h fluoren 2 yl)methylene]bis(1h indole 3,2 diyl)]bis(ethane 2,1 diyl)]bis(4 chlorobenzenesulfonamide)
Sulfonamide
Unclassified drug
Aromatase inhibitor
Indole derivative
Sulfonamide
Animal cell
Article
Binding competition
Controlled study
Drug binding site
Drug cytotoxicity
Drug mechanism
Drug potency
Drug protein binding
Drug screening
Drug synthesis
Enzyme active site
Enzyme inhibition
Hydrogen bond
IC50
Molecular docking
Nonhuman
Quantitative structure activity relation
Animal
Cell survival
Chemical structure
Chemistry
Chlorocebus aethiops
Dose response
Drug effects
Metabolism
Multivariate analysis
Synthesis
Vero cell line
Animals
Aromatase
Aromatase Inhibitors
Cell Survival
Cercopithecus aethiops
Dose-Response Relationship, Drug
Indoles
Molecular Docking Simulation
Molecular Structure
Multivariate Analysis
Quantitative Structure-Activity Relationship
Sulfonamides
Vero Cells