Synthesis and Carbonic Anhydrase Isoenzymes I, II, IX, and XII Inhibitory Effects of Dimethoxybromophenol Derivatives Incorporating Cyclopropane Moieties

Cyclopropylcarboxylic acids and esters and cyclopropylmethanols incorporating bromophenol moieties were investigated as inhibitors of the carbonic anhydrase enzyme (CA; EC 4.2.1.1). The cis- and trans-esters <bold>5</bold> and <bold>6</bold> were obtained from the reaction of 4-allyl-1,2-dimethoxybenzene (<bold>4</bold>) with ethyl diazoacetate, which after bromination with Br-2 gave two isomeric monobromides (<bold>11</bold> and <bold>15</bold>), four isomeric dibromides (<bold>12</bold>, <bold>13</bold>, <bold>16</bold>, and <bold>17</bold>), and two isomeric tribromides (<bold>14</bold> and <bold>18</bold>). The carboxylic acids <bold>7</bold>, <bold>8</bold>, and <bold>1926</bold> were thereafter obtained by hydrolysis of the synthesized esters. All these bromophenol derivatives were tested against human (h) CA isoenzymes I and II (cytosolic, ubiquitous isoforms) and hCA IX and XII (transmembrane, tumor-associated enzymes). All tested bromophenols exhibited excellent inhibitory effects, in the low nanomolar range, with K-i values in the range of 0.5459 nM against hCA I and in the range of 0.97-12.14 nM against hCA II, whereas they were low micromolar inhibitors against hCA IX and XII. The best hCA I inhibition was observed in new bromophenol derivative <bold>20</bold> (Ki = 0.54 nM). On the other hand, new bromophenol derivative <bold>12</bold> showed a powerful inhibition effect against hCA II (K-i = 0.97 nM).