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

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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(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[1,2b]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.

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Authors and Affiliations

  1. Department of Chemistry, Faculty of Art and Sciences, Sakarya University, Sakarya, 54147, Turkey

    Nurcan Berber & Mustafa Arslan

  2. Department of Chemistry, Faculty of Art and Sciences, Balikesir University, Balikesir, 10145, Turkey

    Çiğdem Bilen, Zübeyde Sackes, Nahit Gençer & Oktay Arslan

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  1. Nurcan Berber
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  2. Mustafa Arslan
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  3. Çiğdem Bilen
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  4. Zübeyde Sackes
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  5. Nahit Gençer
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Correspondence to Nahit Gençer.

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Berber, N., Arslan, M., Bilen, Ç. et al. Synthesis and evaluation of new phthalazine substituted β-lactam derivatives as carbonic anhydrase inhibitors. Russ J Bioorg Chem 41, 414–420 (2015). https://doi.org/10.1134/S1068162015040111

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