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 5 and 6 were obtained from the reaction of 4-allyl-1,2-dimethoxybenzene (4) with ethyl diazoacetate, which after bromination with Br2 gave two isomeric monobromides (11 and 15), four isomeric dibromides (12, 13, 16, and 17), and two isomeric tribromides (14 and 18). The carboxylic acids 7, 8, and 19-26 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 Ki values in the range of 0.54-59 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 20 (Ki = 0.54 nM). On the other hand, new bromophenol derivative 12 showed a powerful inhibition effect against hCA II (Ki = 0.97 nM).

Bromination of bis(3,4-dimethoxyphenyl)methanone (5) gave four products (6-9) with mono, di, tri, and tetra Br under different conditions. Reduction and demethylation reactions of product 9 with tetra Br were performed, consecutively and a natural product, 5,5'-methylene bis(3,4-dibrombenzene-1,2-diol) (1), was obtained with a 53% yield. Five derivatives, (13-17) (bromophenols), of 1 were also synthesised. The antioxidant and radical scavenging activities of bromophenols 1 and 13-17 were determined by employing various in vitro assays such as 1,1-diphenyl-2-picryl-hydrazyl free radical (DPPH(*)), 2,2'-azino-bis(3-ethylbenzthiazoline-6-sulphonic acid (ABTS(*+)), N,N-dimethyl-p-phenylenediamine dihydrochloride radical cation (DMPD(*+)), and superoxide anion radical (O(2)(*-)) scavenging, reducing ability determination by the Fe(3+)-Fe(2+) and Cu(2+)-Cu(+) cupric reducing antioxidant capacity (CUPRAC) transformation methods, hydrogen peroxide scavenging, and ferrous ion (Fe(2+)) chelating activities. Moreover, these activities were compared to those of synthetic standard antioxidant compounds such as butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), alpha-tocopherol, and trolox. The results showed that the synthesised bromophenols had effective antioxidant power.

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(3,4-Dihydroxyphenyl)(2,3,4-trihydroxyphenyl)methanone (5) and its two derivatives with bromine were synthesized from reactions such as bromination and demethylation of (3,4-dimethoxyphenyl)(2,3,4-trimethoxyphenyl)methanone (6). The Wolf-Kishner reduction product (9) of 6 and its three derivatives with bromine were obtained. 4-(3,4-Dihydroxybenzyl)benzene-1,2,3-triol and its dibromide derivative (16) were also synthesized from 9 and the corresponding dibromide derivative. The in vitro antioxidant activities of nine new compounds synthesized in these reactions were determined by analyzing the radical scavenging activities of bromophenols for 2,2'-azino-bis(3-ethylbenzthiazoline-6-sulfonic acid) (ABTS), 1,1-diphenyl-2-picryl-hydrazyl (DPPH), N,N-dimethyl-p-phenylenediamine (DMPD), and the superoxide anion radical (O(2)(·-)) and examining the total reducing power through Fe(3+)-Fe(2+) transformation, FRAP and CUPRAC assays and the ferrous ions (Fe(2+)) chelating activities. Moreover, the results of these activities were compared to those of standard antioxidant compounds such as butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), α-tocopherol, and trolox. The results showed that the synthesized bromophenols had effective antioxidant power. The phenol 5 with two phenolic rings and five phenolic hydroxyl groups was the most potent antioxidant and radical scavenger. In conclusion, the new compounds are promising molecules to be used owing to their potential antioxidant properties.