Berber Nurcan, Arslan Mustafa, Bilen Çiğdem, Sackes Zübeyde, Gençer Nahit, Arslan Oktay
Bioorg Khim. 2015 Jul-Aug;41(4):468-74. doi: 10.7868/s0132342315040119.
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]phthala- zine-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 re- acted 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]phthala-zine-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- 1,6,1 1-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.
合成了一系列新的酞嗪取代的β-内酰胺衍生物，并评估了它们对纯化的人碳酸酐酶（hCA I和II）活性的抑制作用。在DMF中，于TFA存在下，用4-硝基苯甲醛、达米酮和邻苯二甲酰肼制备了2H-吲唑并[2,1-b]酞嗪-三酮衍生物，然后用SnCl₂·2H₂O将硝基还原为13-(4-氨基苯基)-3,3-二甲基-3,4-二氢-2H-吲唑并[1,2-b]酞嗪-1,6,11(13H)-三酮。将还原后的化合物与不同的芳香醛反应，合成了酞嗪取代的亚胺。亚胺化合物与烯酮发生(2+2)环加成反应，生成2H-吲唑并[2,1-b]酞嗪-三酮取代的β-内酰胺衍生物。测试了β-内酰胺化合物作为CA同工酶活性抑制剂的效果。结果表明，所有合成的化合物均抑制CA同工酶活性。1-(4-(3,3-二甲基-1,6,11-三氧代-2,3,4,6,11,13-六氢-1H-吲唑并[1,2-b]酞嗪-13-基)phenyl)-2-氧代-4-对甲苯基氮杂环丁烷-3-基乙酸酯（对hCA I的IC₅₀ = 6.97 μM，对hCA II的IC₅₀ = 8.48 μM）具有最强的抑制作用。
