Carbonic anhydrase activators Part 24. High affinity isozymes I, II and IVactivators, derivatives of 4-(4-chlorophenylsulfonylureido-amino acyl)ethyl-1H-imidazole

N-1-Tritylsulfenyl histamine was synthesized by reaction of histamine (Hst) with tetrabromophthalic anhydride followed by protection of its imidazole moiety with tritylsulfenyl chloride. After hydrazinolysis, it afforded a ke y intermediate which was derivatized at the aminoethyl group in order to ob tain new types of activators of the zinc enzyme carbonic anhydrase (CA, EC 4.2.1.1). Reaction of the key intermediate with 4-chlorophenylsulfonylureid o amino acids (cpn-AA) in the presence of carbodiimides afforded, after dep rotection of the imidazolic nitrogen atom, a series of compounds with the g eneral formula cpu-AA-Hst (cpu, 4-ClC6H4SO2NHCO). Some structurally related dipeptide derivatives with the general formula cpu-AA1-AA2-Hst (AA, AA1 an d AA2 represent amino acyl moieties) were also prepared by a strategy simil ar to that applied for the amino acyl compounds mentioned above. The new de rivatives proved to be efficient activators of three CA isozymes. Best acti vity was detected against hCA I and bCA TV, for which some of the new compo unds showed affinities in the 1-10 nM range (h, human; b, bovine isozymes). hCA II, on the other hand, was less prone to activation by the new derivat ives, which possessed affinities around 20-50 nM for this isozyme. This new class of CA activators might lead to the development of drugs/diagnostic a gents for CA deficiency syndrome, a genetic disease of bone, brain and kidn eys. (C) 2000 Elsevier Science B.V. All rights reserved.