Synthesis, Antimitotic and Antivascular Activity of 1‑(3′,4′,5′-Trimethoxybenzoyl)-3-arylamino-5-amino-1,2,4-triazoles

A new class of compounds that incorporated the structural motif of the 1-(3′,4′,5′-trimethoxtbenzoyl)-3-arylamino-5-amino-1,2,4-triazole molecular skeleton was synthesized and evaluated for their antiproliferative activity in vitro, interactions with tubulin, and cell cycle effects. The most active agent, <b>3c</b>, was evaluated for antitumor activity in vivo. Structure–activity relationships were elucidated with various substituents on the phenyl ring of the anilino moiety at the C-3 position of the 1,2,4-triazole ring. The best results for inhibition of cancer cell growth were obtained with the <i>p</i>-Me, <i>m</i>,<i>p</i>-diMe, and <i>p</i>-Et phenyl derivatives <b>3c</b>, <b>3e</b>, and <b>3f</b>, respectively, and overall, these compounds were more or less as active as CA-4. Their vascular disrupting activity was evaluated in HUVEC cells, with compound <b>3c</b> showing activity comparable with that of CA-4. Compound <b>3c</b> almost eliminated the growth of syngeneic hepatocellular carcinoma in Balb/c mice, suggesting that <b>3c</b> could be a new antimitotic agent with clinical potential