Synthesis of Alkynylated Dihydrofuran-2(3H)-ones as Potent and Selective Inhibitors of Tissue Non-Specific Alkaline Phosphatase

The synthesis of new derivatives of 3-(3-arylprop-2-ynyl) dihydrofuran-2(3H)-ones by Sonogashira reactions and their screening as potent and selective inhibitors of b-TNAP is reported. Although a few derivatives exhibited non-selective inhibition of c-IAP, most of the derivatives were found to be potent and selective inhibitors of b-TNAP. The selective and potent inhibitors of b-TNAP might be useful for the treatment of vascular calcification. Among the derivatives studied, one compound was identified as the most potent inhibitor of b-TNAP with a high inhibitory value, exhibiting a 6 fold more selective activity towards b-TNAP as compared to c-IAP. The higher inhibitory activity of this compound towards b-TNAP is caused by the presence of two furan rings. Similarly, another derivative, having a furan ring, exhibited a lower inhibitory potential towards b-TNAP, but this compound was found to be the most potent inhibitor of c-IAP. Furthermore, molecular docking studies of these potent compounds were carried out to see the possible binding modes of potent inhibitors inside the active pocket of respective enzyme.