Identification of benzothiazole derived monosaccharides as potent, selective, and orally bioavailable inhibitors of human and mouse galectin-3; a rare example of using a S ···O binding interaction for drug design

Bioorg Med Chem. 2024 Feb 11;101:117638. doi: 10.1016/j.bmc.2024.117638. Online ahead of print.ABSTRACTAs a result of our continued efforts to pursue Gal-3 inhibitors that could be used to fully evaluate the potential of Gal-3 as a therapeutic target, two novel series of benzothiazole derived monosaccharides as potent (against both human and mouse Gal-3) and orally bioavailable Gal-3 inhibitors, represented by 4 and 5, respectively, were identified. These discoveries were made based on proposals that the benzothiazole sulfur atom could interact with the carbonyl oxygen of G182/G196 in h/mGal-3, and that the anomeric triazole moiety could be modified into an N-methyl carboxamide functionality. The interaction between the benzothiazole sulfur and the carbonyl oxygen of G196 in mGal-3 was confirmed by an X-ray co-crystal structure of early lead 9, providing a rare example of using a S···O binding interaction for drug design. It was found that for both the series, methylation of 3-OH in the monosaccharides caused no loss in h & mGal-3 potencies but significantly improved permeability of the molecules.PMID:38394996 | DOI:10.1016/j.bmc.2024.117638

Source: Bioorganic and Medicinal Chemistry - February 23, 2024 Category: Chemistry Authors: Chunjian Liu Wei Wang Jianxin Feng Brett Beno Thiruvenkadam Raja Jacob Swidorski Raju K V L P Manepalli Muthalagu Vetrichelvan Prasada Rao Jalagam Satheesh K Nair Anuradha Gupta Manoranjan Panda Kaushik Ghosh Jinal Kaushikkumar Shukla Harinath Sale Devang Source Type: research