2. Academic Validation
  3. Synthesis, molecular docking, and QSAR study of sulfonamide-based indoles as aromatase inhibitors

Synthesis, molecular docking, and QSAR study of sulfonamide-based indoles as aromatase inhibitors

  • Eur J Med Chem. 2018 Jan 1:143:1604-1615. doi: 10.1016/j.ejmech.2017.10.057.
Ratchanok Pingaew 1,  Prasit Mandi 2,  Veda Prachayasittikul 3,  Supaluk Prachayasittikul 4,  Somsak Ruchirawat 5,  Virapong Prachayasittikul 6
Affiliations

Affiliations

  • 1 Department of Chemistry, Faculty of Science, Srinakharinwirot University, Bangkok 10110, Thailand. Electronic address: ratchanok@swu.ac.th.
  • 2 Department of Community Medical Technology, Faculty of Medical Technology, Mahidol University, Bangkok 10700, Thailand.
  • 3 Center of Data Mining and Biomedical Informatics, Faculty of Medical Technology, Mahidol University, Bangkok 10700, Thailand. Electronic address: veda.pra@mahidol.ac.th.
  • 4 Center of Data Mining and Biomedical Informatics, Faculty of Medical Technology, Mahidol University, Bangkok 10700, Thailand.
  • 5 Chulabhorn Research Institute, Bangkok 10210, Thailand; Program in Chemical Biology, Chulabhorn Graduate Institute, Bangkok 10210, Thailand; Center of Excellence on Environmental Health and Toxicology (EHT), CHE, Ministry of Education, Thailand.
  • 6 Department of Clinical Microbiology and Applied Technology, Faculty of Medical Technology, Mahidol University, Bangkok 10700, Thailand.
PMID: 29137864 DOI: 10.1016/j.ejmech.2017.10.057
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.

Keywords

Anti-aromatase activity; Indole; Molecular docking; QSAR; Sulfonamide.

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