5-Aryl-2-(naphtha-1-yl)sulfonamido-thiazol-4(5H)-ones as clathrin inhibitors?

Organic & Biomolecular Chemistry Pub Date: 2016-11-04 DOI: 10.1039/C6OB02308H

Abstract

The development of a (Z)-5-((6,8-dichloro-4-oxo-4H-chromen-3-yl)methylene)-2-thioxothiazolidin-4-one (2), rhodanine-based lead that led to the Pitstop? 2 family of clathrin inhibitors is described herein. Head group substitution and bioisosteric replacement of the rhodanine core with a 2-aminothiazol-4(5H)-one scaffold eliminated off target dynamin activity. A series of N-substituents gave first phenylglycine (20, IC50 ～ 20 μM) then phenyl (25, IC50 ～ 7.1 μM) and 1-napthyl sulfonamide (26, Pitstop? 2 compound, IC50 ～ 1.9 μM) analogues with good activity, validating this approach. A final library exploring the head group resulted in three analogues displaying either slight improvements or comparable activity (33, 38, and 29 with IC50 ～ 1.4, 1.6 and 1.8 μM respectively) and nine others with IC50 < 10 μM. These results were rationalized using in silico docking studies. Docking studies predicted enhanced Pitstop? 2 family binding, not a loss of binding, within the Pistop? groove of the reported clathrin mutant invalidating recent assumptions of poor selectivity for this family of clathrin inhibitors.

Graphical abstract: 5-Aryl-2-(naphtha-1-yl)sulfonamido-thiazol-4(5H)-ones as clathrin inhibitors
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