LAUSR

BACKGROUND The positively charged membrane impermeant sulfonamides were evaluated as a remarkable class of carbonic anhydrase inhibitors (CAIs) previously. Without affecting the cytosolic isoforms hCA I and II, inhibition of two membrane-associated isoforms hCA IX and XII especially over-expressed in hypoxic tumour cells, makes the pyridinium derivatives potent promising therapeutic agents. OBJECTIVE A novel series of tri, tetra, and cyclo-substituted pyridinium derivatives of the lead compound 2-(hydrazinocarbonyl)-3-phenyl-1H-indole-5-sulfonamide has been prepared by using sixteen different pyrylium salts, for the search of selective inhibitors of transmembrane tumour-associated human carbonic anhydrase hCA IX and XII. METHODS The compounds were tested against tumour-associated hCA IX/XII and off-targets hCA I/II with enzyme inhibition assays and molecular modelling studies were carried out to understand and rationalize the in vitro enzyme inhibition data. RESULTS Six of the new compounds have good inhibitory profiles with low nanomolar range (< 100 nM) against hCA IX/XII, and compound 5 showed excellent potency with Ki values lower than 10 nM. In addition, molecular modelling studies have presented the possible binding modes of the ligands. CONCLUSION Most of the compounds displayed potent inhibitory activity against the tumor-associated hCA IX and XII in the low nanomolar range and selectivity over the off-targeted isoforms hCA I and II. Due to their cationic structure and membrane-impermeant behavior, it is also expected maximizing the selectivity over cytosolic isoforms hCA I/II while inhibiting of tumor overexpressed isoforms hCA XI/XII of new compounds in in vivo conditions.