SYNTHESIS AND EVALUATION OF NEW PHTHALAZINE SUBSTITUTED β-LACTAM DERIVATIVES AS CARBONIC ANHYDRASE INHIBITORS
© 2015 Nurcan Berber*, Mustafa Arslan*, Çiğdem Bilen**, Zübeyde Sackes**, Nahit Gençer**, #, and Oktay Arslan**
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*Department of Chemistry, Faculty of Art and Sciences, Sakarya University, Sakarya, 54147 Turkey; **Department of Chemistry, Faculty of Art and Sciences, Balikesir University, Balikesir, 10145 Turkey
Received June 6, 2014; in final form February 12, 2015
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(13H)-trione with SnCl2 · 2H2O. 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 2H-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-1H-indazolo[1,2-b]phthalazin-13-yl)phenyl)-2-oxo-4-p-tolylazetidin-3-yl acetate (IC50 = 6.97 μM for hCA I and 8.48 μM for hCA II) had the most inhibitory effect.
Keywords: β-lactam, imine, carbonic anhydrase, enzyme inhibitor.