Synthesis, molecular docking, and QSAR study of bis-sulfonamide derivatives as potential aromatase inhibitors. Issue 19 (1st October 2019)

• Record Type: Journal Article
• Authors: Leechaisit, Ronnakorn; Pingaew, Ratchanok; Prachayasittikul, Veda; Worachartcheewan, Apilak; Prachayasittikul, Supaluk; Ruchirawat, Somsak; Prachayasittikul, Virapong
• Is Part Of: Bioorganic & medicinal chemistry. Volume 27:Issue 19(2019)
• Publication Date: 2019-10-01
• Subjects: Sulfonamide -- Bis-sulfonamide -- Xylylenediamine -- Aromatase inhibitor -- Molecular docking -- QSAR; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; Biochemistry -- Periodicals; Chemistry, Clinical -- Periodicals; Chemistry, Organic -- Periodicals; Chimie bio-organique -- Périodiques; Chimie pharmaceutique -- Périodiques; 615.19
• DOI: 10.1016/j.bmc.2019.08.001
• Languages: English
• ISSNs: 0968-0896

Abstract

Graphical abstract: Highlights: Eighteen bis-sulfonamides were synthesized. Seventeen bis-sulfonamides displayed aromatase inhibitory activity (IC50 = 0.05–11.6 μM). Chloro (15, IC50 = 50 nM) and bromo (16, IC50 = 60 nM) analogs are promising inhibitors with high safety index. Molecular docking and QSAR were studied. Abstract: A library of bis-sulfonamides (9 –26 ) were synthesized and tested for their aromatase inhibitory activities. Interestingly, all bis-sulfonamide derivatives inhibited the aromatase with IC50 range of 0.05–11.6 μM except for compound 23 . The analogs 15 and 16 bearing hydrophobic chloro and bromo groups exhibited the potent aromatase inhibitory activity in sub-micromolar IC50 values (i.e., 50 and 60 nM, respectively) with high safety index. Molecular docking revealed that the chloro and bromo benzenesulfonamides (15 and 16 ) may play role in the hydrophobic interaction with Leu477 of the aromatase to mimic steroidal backbone of the natural substrate, androstenedione. QSAR study also revealed that the most potent activity of compounds was governed by van der Waals volume (GATS6v) and mass (Mor03m) descriptors. Finally, the two compounds (15 and 16 ) were highlighted as promising compounds to be further developed as novel aromatase inhibitors.