Design and Synthesis of Tetrazole- and Pyridine-Containing Itraconazole Analogs as Potent Angiogenesis Inhibitors

Itraconazole, a widely used Antifungal drug, was found to possess antiangiogenic activity and is currently undergoing multiple clinical trials for the treatment of different types of Cancer. However, it suffers from extremely low solubility and strong interactions with many drugs through inhibition of CYP3A4, limiting its potential as a new antiangiogenic and Anticancer drug. To address these issues, a series of analogs in which the phenyl group is replaced with pyridine or fluorine-substituted benzene was synthesized. Among them the pyridine- and tetrazole-containing compound 24 has significantly improved solubility and reduced CYP3A4 inhibition compared to itraconazole. Similar to itraconazole, compound 24 inhibited the AMPK/mTOR signaling axis and the glycosylation of VEGFR2/KDR/Flk-1. It also induced Cholesterol accumulation in the endolysosome and demonstrated binding to the sterol-sensing domain of NPC1 in a simulation study. These results suggested that compound 24 may serve as an attractive candidate for the development of a new generation of antiangiogenic drug.