An HPLC‐based screening of electrophilic compounds identified the etacrynic acid‐derived amide 106 and ester 107 as SARS‐CoV‐1 Mpro inhibitors with moderate potency. 175  Etacrynic carboxamide (105; K i, 35.3 µM) bound more strongly to SARS‐CoV‐1 Mpro than to papain protease, while etacrynic acid ester 104 was more active at papain protease (K i, 3.2 µM) than at SARS‐CoV‐1 Mpro (K i, 45.8 µM; Figure 28). SAR studies suggested that chloro substituents were necessary for protease inhibition. Docking studies of 105 to Mpro revealed that it forms hydrogen bonds with Gln189, Glu166, Thr190, and Gln192 with its terminal amino group. The Michael system carbonyl group interacts with Gly143, and the reactive double bond remained next to the Cys145 sulfur.