As histone deacetylases (HDACs) play an important role in cancer treatment, their selective inhibition has been subject of various studies. The continuous investigations have spawned a large collection of pan- and selective HDAC inhibitors, containing diverse FDA approved representatives. In former studies, a class of alkyne based inhibitors of HDACs was presented. We modified this scaffold in two previously neglected regions and compared cytotoxicity and affinity towards HDAC1, HDAC6 and HDAC8. We could show that (R)-configured propargylamines contribute increased selectivity on HDAC6, while the size of the substituents decreases their affinity. Docking studies on available HDAC crystal structures were carried out to rationalize the observed selectivity of the compounds. Substitution of the aromatic part by a thiophene derivative results in high affinity and low cytotoxicity, indicating an improved drug tolerance.