Efficient Synthesis of Novel Propargyl Sulfamate Derivatives and Their Potent Inhibitory Effects on Human Carbonic Anhydrase Isoenzymes

High Resolution Image Download MS PowerPoint Slide In the present study, a total of 21 novel propargyl sulfamate derivatives were designed and synthesized as potential inhibitors of human carbonic anhydrases I and II (hCA I and hCA II). An efficient and practical synthetic protocol was developed based on the reaction of propargyl alcohols with chlorosulfonyl isocyanate (CSI), affording the target sulfamate compounds in good yield. The inhibitory activities of all synthesized compounds against hCA I and hCA II isoenzymes were evaluated in vitro. The compounds exhibited potent inhibition with IC 50 values ranging from 8.97 to 161.16 nM for hCA I and from 3.89 to 177.69 nM for hCA II. Among the tested molecules, methyl (1-(2,5-dimethoxyphenyl)-3-phenylprop-2-yn-1-yl)sulfamate ( 2i ) emerged as the most active derivative, displaying superior inhibitory activity compared to the reference drug acetazolamide (AZA), with IC 50 values of 8.97 and 3.89 nM against hCA I and hCA II, respectively. Compound 2i is 7.72 times more active than the standard drug AZA in inhibiting the hCA I isoform and 15.35 times more active in inhibiting the hCA II isoform. Furthermore, selected compounds ( 2i, 2h, and 2b ) were evaluated against tumor-associated isoenzymes hCA IX and hCA XII, exhibiting strong inhibition with IC 50 values ranging from 5.12 to 26.85 nM. Notably, compound 2i demonstrated the highest activity with IC 50 values of 6.45 nM for hCA IX and 5.12 nM for hCA XII, surpassing the reference inhibitor AZA. These findings indicated that 2i, because of its strong carbonic anhydrase inhibition effect, represented a promising candidate for further drug development. This methodology may also serve as a convenient strategy for the generation of cinnamaldehyde derivatives.