HDAC6 is a drug target correlated to several pathologies, such as autoimmune disorders, neurodegenerative diseases, and cancer. Importantly, HDAC6 KO mice are viable with no apparent phenotype and the selective inhibition of the enzyme does not show cytotoxic effects normally associated with the inhibition of Class I HDAC isoforms. Most of the selective inhibitors described in the literature are benzohydroxamic acids, a class of compounds that tends to show genotoxic and pharmacokinetic issues. We here report the identification of a new class of highly selective inhibitors, like ITF6475, that bear the difluoromethyl-1,3,4-oxadiazole as ZBG, do not show genotoxic liabilities and exhibit excellent in vitro stability and in vivo pharmacokinetic properties. These mols. selectively induce tubulin acetylation in several cell lines and are promising candidates for the development of novel drugs for the treatment of HDAC6-associated pathologies.