The indolylmaleimide (IM) derivative <b>IM-17</b> shows inhibitory activity against oxidative-stress-induced necrotic cell death and cardioprotective activity in rat ischemia-reperfusion injury models. In order to develop a more potent derivative, we conducted a detailed structure-activity relationship study of IM derivatives and identified <b>IM-93</b> as the most potent derivative with good water solubility. <b>IM-93</b> inhibited ferroptosis and NETosis, but not necroptosis or pyroptosis. In contrast, ferrostatin-1 (Fer-1), a ferroptosis inhibitor, did not inhibit NETosis, although the accompanying lipid peroxidation was partially inhibited by Fer-1, as well as by <b>IM-93</b>. Thus, IM derivatives have a unique activity profile and appear to be promising candidates for <i>in vivo</i> application.