Development of Second-Generation
Indole-Based Dynamin
GTPase Inhibitors
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Abstract
Focused library development of our lead 2-cyano-3-(1-(3-(dimethylamino)propyl)-2-methyl-1<i>H</i>-indol-3-yl)-<i>N</i>-octylacrylamide (<b>2</b>) confirmed the tertiary dimethylamino-propyl moiety as critical
for inhibition of dynamin GTPase. The cyanoamide moiety could be replaced
with a thiazole-4(5<i>H</i>)-one isostere (<b>19</b>, IC<sub>50(dyn I)</sub> = 7.7 μM), reduced under flow
chemistry conditions (<b>20</b>, IC<sub>50(dyn I)</sub> = 5.2 μM) or replaced by a simple amine. The latter provided
a basis for a high yield library of compounds via a reductive amination
by flow hydrogenation. Two compounds, <b>24</b> (IC<sub>50 (dyn I)</sub> = 0.56 μM) and <b>25</b> (IC<sub>50(dyn I)</sub> = 0.76 μM), stood out. Indole <b>24</b> is nontoxic
and showed increased potency against dynamin I and II in vitro and
in cells (IC<sub>50(CME)</sub> = 1.9 μM). It also showed 4.4-fold
selectivity for dynamin I. The indole <b>24</b> compound has
improved isoform selectivity and is the most active in-cell inhibitor
of clathrin-mediated endocytosis reported to date
