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

Berber N., Arslan M., Bilen C., Sackes Z., Gencer N., Arslan O.

RUSSIAN JOURNAL OF BIOORGANIC CHEMISTRY, cilt.41, sa.4, ss.414-420, 2015 (SCI-Expanded) identifier identifier

  • Yayın Türü: Makale / Tam Makale
  • Cilt numarası: 41 Sayı: 4
  • Basım Tarihi: 2015
  • Doi Numarası: 10.1134/s1068162015040111
  • Dergi Adı: RUSSIAN JOURNAL OF BIOORGANIC CHEMISTRY
  • Derginin Tarandığı İndeksler: Science Citation Index Expanded (SCI-EXPANDED), Scopus
  • Sayfa Sayıları: ss.414-420
  • Anahtar Kelimeler: beta-lactam, imine, carbonic anhydrase, enzyme inhibitor, PYRIDAZINONE, MILLENNIUM, COUMARINS, MECHANISM
  • Yıldız Teknik Üniversitesi Adresli: Hayır

Özet

A new series of phthalazine substituted beta-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 center dot 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 2H-indazolo[2,1-b]phthalazine-trione substituted beta-lactam derivatives. The beta-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 A mu M for hCA I and 8.48 A mu M for hCA II) had the most inhibitory effect.