Development of new disulfiram analogues as ALDH1a1-selective inhibitors

Disulfiram is an FDA-approved drug used to treat chronic alcoholism. This drug works by blocking the second step of ethanol metabolism by inhibiting aldehyde dehydrogenase-2 (ALDH2), the enzyme responsible for acetaldehyde oxidation into acetic acid. This leads to the accumulation of acetaldehyde in the blood following alcohol ingestion and to highly unpleasant symptoms known as acetaldehyde syndrome. Disulfiram also inhibits ALDH1a1, another member of the aldehyde dehydrogenases that catalyzes the oxidation of retinal into retinoic acid. ALDH1a1 represents a key therapeutic target for the treatment of important diseases such as cancer and obesity. The substrate tunnel is larger in ALDH1a1 than in ALDH2; therefore. Thus, replacing disulfiram ethyl groups with larger groups will yield selective ALDH1a1 inhibitors. In this work, we successfully synthesized derivative 2b, in which two ethyl groups were replaced by two para fluorobenzyl groups. The 2b derivative showed a comparable activity to disulfiram against ALDH1a1; however, it was completely devoid of inhibitory activity against ALDH2.