Synthesis and molecular docking of 1,2,3-triazole-based sulfonamides as aromatase inhibitors.
A series of 1,4-disubstituted-1,2,3-triazoles (13-35) containing sulfonamide moiety were synthesized and evaluated for their aromatase inhibitory effects. Most triazoles with open-chain sulfonamide showed significant aromatase inhibitory activity (IC50=1.3-9.4μM). Interestingly, the meta analog of triazole-benzene-sulfonamide (34) bearing 6,7-dimethoxy substituents on the isoquinoline ring displayed the most potent aromatase inhibitory activity (IC50=0.2μM) without affecting normal cell. Molecular docking of these triazoles against aromatase revealed that the compounds could snugly occupy the active site of the enzyme through hydrophobic, π-π stacking, and hydrogen bonding interactions. The potent compound 34 was able to form hydrogen bonds with Met374 and Ser478 which were suggested to be the essential residues for the promising inhibition. The study provides compound 34 as a potential lead molecule of anti-aromatase agent for further development.
Department of Chemistry, Faculty of Science, Srinakharinwirot University, Bangkok 10110, Thailand. Electronic address: ratchanok@swu.ac.th.
Ratchanok
R
Pingaew
Department of Clinical Microbiology and Applied Technology, Faculty of Medical Technology, Mahidol University, Bangkok 10700, Thailand.
Veda
V
Prachayasittikul
Department of Clinical Microbiology and Applied Technology, Faculty of Medical Technology, Mahidol University, Bangkok 10700, Thailand; Center of Data Mining and Biomedical Informatics, Faculty of Medical Technology, Mahidol University, Bangkok 10700, Thailand.
Prasit
P
Mandi
Department of Clinical Microbiology and Applied Technology, Faculty of Medical Technology, Mahidol University, Bangkok 10700, Thailand; Center of Data Mining and Biomedical Informatics, Faculty of Medical Technology, Mahidol University, Bangkok 10700, Thailand.
Chanin
C
Nantasenamat
Center of Data Mining and Biomedical Informatics, Faculty of Medical Technology, Mahidol University, Bangkok 10700, Thailand.
Supaluk
S
Prachayasittikul
Laboratory of Medicinal Chemistry, Chulabhorn Research Institute, and Program in Chemical Biology, Chulabhorn Graduate Institute, Bangkok 10210, Thailand; Center of Excellence on Environmental Health and Toxicology, Commission on Higher Education (CHE), Ministry of Education, Thailand.
Somsak
S
Ruchirawat
Department of Clinical Microbiology and Applied Technology, Faculty of Medical Technology, Mahidol University, Bangkok 10700, Thailand. Electronic address: virapong.pra@mahidol.ac.th.
Virapong
V
Prachayasittikul
D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D001141:Aromatase / Q000737:chemistry*; D047072:Aromatase Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D020134:Catalytic Domain; D002470:Cell Survival / Q000187:drug effects; D002522:Chlorocebus aethiops; D006801:Humans; D006860:Hydrogen Bonding; D057927:Hydrophobic and Hydrophilic Interactions; D007546:Isoquinolines / Q000737:chemistry; D062105:Molecular Docking Simulation; D011485:Protein Binding; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000138:chemical synthesis* / Q000494:pharmacology; D014230:Triazoles / Q000138:chemical synthesis* / Q000494:pharmacology; D014709:Vero Cells
D000970:Antineoplastic Agents; D047072:Aromatase Inhibitors; D007546:Isoquinolines; D013449:Sulfonamides; D014230:Triazoles; D001141:Aromatase; C561410:CYP19A1 protein, human
Anti-aromatase activity; Molecular docking; Structure–activity relationships; Sulfonamide; Tetrahydroisoquinoline; Triazole