Synthesis and evaluation of new phthalazine substituted β-lactam derivatives as carbonic anhydrase inhibitors

Abstract

A new series of phthalazine substituted β-lactam derivatives were synthesized and their inhibitory effects on the activity of purified human carbonic anhydrase (hCA I and II) were evaluated. 2H -Indazolo[2,1- b ]phthalazine-trione derivative was prepared with 4-nitrobenzaldehyde, dimedone, and phthalhydrazide in the presence of TFA in DMF, and the nitro group was reduced to 13-(4-aminophenyl)-3,3-dimethyl-3,4-dihydro- 2H -indazolo[1,2- b ]phthalazine-1,6,11(13 H )-trione with SnCl 2 · 2H 2 O. The reduced compound was reacted with different aromatic aldehydes, and phthalazine substituted imines were synthesized. The imine compounds undergo (2+2) cycloaddition reactions with ketenes to produce 2 H -indazolo[2,1- b ]phthalazine-trione substituted β-lactam derivatives. The β-lactam compounds were tested as inhibitors of the CA isoenzyme activity. The results showed that all the synthesized compounds inhibited the CA isoenzyme activity. 1-(4-(3,3-dimethyl-1,6,11-trioxo-2,3,4,6,11,13-hexahydro-1 H -indazolo[1,2 b ]phthalazin-13-yl)phenyl)-2-oxo-4- p -tolylazetidin-3-yl acetate (IC 50 = 6.97 µM for hCA I and 8.48 µM for hCA II) had the most inhibitory effect.