Design, synthesis, and biological evaluation of 5-((4-(pyridin-3-yl)pyrimidin-2-yl)amino)-1<i>H</i>-Indole-2-Carbohydrazide derivatives: the methuosis inducer 12A as a Novel and selective anticancer agent

This study describes the synthesis and vacuole-inducing activity of 5-((4-(pyridin-3-yl)pyrimidin-2-yl)amino)-1H-indole-2-carbohydrazide derivatives, including five potent derivatives 12c, 12 g, 12i, 12n, 12A that exhibit excellent activity. Remarkably, effectively induces methuosis in tested cancer cells but not human normal cells. In addition, exhibits high pan-cytotoxicity against different cell lines is hardly toxic to It found 12A-induced vacuoles are derived from macropinosomes autophagosomes. The cytoplasmic may originate endoplasmic reticulum (ER) be accompanied by ER stress. MAPK/JNK signalling pathway involved methuotic death. Moreover, significant inhibition tumour growth MDA-MB-231 xenograft mouse model. potency selectivity prompt us select it as a good lead compound for further development inducers investigation molecular cellular mechanisms underlying methuosis.