Design and synthesis of 3-(azepan-1-ylsulfonyl)-N-aryl benzamide derivatives as potent carbonic anhydrase IX inhibitors with anticancer activities
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Mohammad A. Khanfar
and
Mohammad Saleh
Abstract
Carbonic anhydrase IX (CAIX) is known to be overexpressed in various tumors and plays a significant role in tumor development and progression. A series of 3-sulfonamide benzoate derivatives with a 7-membered azepane ring were synthesized and evaluated for their CAIX inhibitory activities. Most of the synthesized compounds successfully inhibited CAIX activities, exhibiting IC50 values in the low nanomolar range. The most potent CAIX inhibitor was compound 26, with an IC50 of 19 nM. A structure-activity relationship analysis of the synthesized compounds was conducted, and molecular docking revealed strong coordination with the catalytic Zn2+ metal, hydrophobic interactions of the azepane ring with a hydrophobic pocket, and π-stacking interactions of the aryl ring with an aromatic surface. The three most active analogues (8, 16, and 26) were further tested for their antiproliferative activities in the NCI-60 human tumor cell lines screen. Notably, compound 16 (CAIX, IC50 = 310 nM) demonstrated potent growth inhibitory effects against several cancer cell lines.
Acknowledgments
Authors thank the College of Pharmacy and Office of Research and Innovation (ORI) (grant # 23520) at Alfaisal University for their generous support and funds.
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Research ethics: Not applicable.
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Informed consent: Not applicable.
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Author contributions: All authors have accepted responsibility for the entire content of this manuscript and approved its submission.
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Use of Large Language Models, AI and Machine Learning Tools: None declared.
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Conflict of interest: The author states no conflict of interest.
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Research funding: Alfaisal University, grant # 23520.
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Data availability: The raw data can be obtained on request from the corresponding author.
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Supplementary Material
This article contains supplementary material (https://doi.org/10.1515/znc-2024-0224).
© 2025 Walter de Gruyter GmbH, Berlin/Boston
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Articles in the same Issue
- Frontmatter
- Review Articles
- Cutting-edge developments in agro-waste derived carbon nanomaterials and their multifaceted applications in agriculture: enhancing crop imaging, nutrient efficiency, and plant health
- Emerging silk sericin-based formulation fortified with therapeutics in the management of diabetic wound and skin tissue regeneration
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- Enhancing vaginal drug delivery: the nanoemulsion gel strategy
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- Exploring the therapeutic potential of leriodenine and nuciferine from Nelumbo nucifera for renal fibrosis: an In-silico analysis
- Antidiabetic activities of aerial part of Asparagus racemosus Willd. extract: an in vitro, in vivo, and in silico approach
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- Design and synthesis of new 1,3,4-thiadiazoles as antimicrobial and antibiofilm agents
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- Biotransformation of vinblastine into vincristine using a fungal endophyte Fusarium equiseti along with the assessment of its antiangiogenic properties
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