Human dihydroorotate dehydrogenase (hDHODH) catalyzes the rate-limiting step in the de novo pyrimidine biosynthesis where dihydroorotate (DHO) is converted to orotate (ORO). Being already validated as therapeutic target for the treatment of autoimmune diseases, as rheumatoid arthritis or multiple sclerosis, in the fall 2016 hDHODH was associated to acute myelogenous leukemia (AML), a disease that has not seen a new therapies in four decades being cytarabine still representing the last significant advance. This discovery opened a totally new perspective in hDHODH field. Starting from brequinar, one of the most potent known hDHODH inhibitors, and by applying innovative scaffold-hopping replacement, we recently designed a novel generation of potent and selective hDHODH inhibitors presenting, as the hydroxytriazole (1), nano-molar activity on the isolated hDHODH, just one digit from the lead brequinar. In this occasion, we move ahead presenting a second generation of inhibitors designed by using as hydroxyazole a novel fluorescent isostere of carboxylic acid. Compound 2 (see Figure), able to reach brequinar hDHODH potency levels although using a different scaffold, was found able to restore the myeloid differentiation in leukemia cell lines, in a range superior then brequinar itself. Theoretical design, modeling, synthesis, SAR, fluorescent properties, X-ray crystallographic poses, biological assays (cell viability, proliferation, cytotoxicity, immunosuppression, myeloid differentiation), ADME and in vivo toxicity are here presented and discussed.

Targeting myeloid differentiation using potent human dihydroorotate dehydrogenase (hDHODH) inhibitors designed by scaffold hopping using regio substituted hydroxyazole scaffolds

255th National Meeting (2018)

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