Thermal and photoinduced copper-promoted C-Se bond formation: Synthesis of 2-alkyl-1,2-benzisoselenazol-3(2H)-ones and evaluation against Mycobacterium tuberculosis.

Research paper by Sandeep S Thanna, Christopher M CM Goins, Susan E SE Knudson, Richard A RA Slayden, Donald R DR Ronning, Steven J SJ Sucheck

Indexed on: 09 Mar '17Published on: 09 Mar '17Published in: Journal of Organic Chemistry


2-Alkyl-1,2-benzisoselenazol-3(2H)-ones, represented by the ebselen (1a), are being studied intensively for a range of medicinal applications. We describe both a new thermal and photoinduced copper-mediated cross-coupling between potassium selenocyanate (KSeCN) and N-substituted ortho-halobenzamides to form 2-alkyl-1,2-benzisoselenazol-3(2H)-ones containing a C-Se-N bond. The copper ligand (1,10-phenanthroline) facilitates C-Se bond formation during heating via a mechanism that likely involves atom transfer (AT); whereas, in the absence of ligand, photoinduced activation likely proceeds through a single electron transfer (SET) mechanism. A library of fifteen 2-alkyl-1,2-benzisoselenazol-3(2H)-ones was prepared. One member of the library was azide-containing derivative 1j that was competent to undergo a strain-promoted azide-alkyne cycloaddition. The library was evaluated for inhibition of Mycobacterium tuberculosis (Mtb) growth and Mtb Antigen 85C (Mtb Ag85C) activity. Compound 1f was most potent with a minimal inhibitory concentration (MIC) of 12.5 µg/mL and an Mtb Ag85C apparent IC50 of 8.8 µM.