Alafeefy Ahmed M, Abdel-Aziz Hatem A, Vullo Daniela, Al-Tamimi Abdul-Malek S, Awaad Amani S, Mohamed Menshawy A, Capasso Clemente, Supuran Claudiu T
Department of Pharmaceutical Chemistry, College of Pharmacy, Salman bin Abdulaziz University , Alkharj , Saudi Arabia .
J Enzyme Inhib Med Chem. 2015 Feb;30(1):52-6. doi: 10.3109/14756366.2013.877897. Epub 2014 Mar 25.
A series of benzenesulfonamides incorporating aroylhydrazone, piperidinyl, sulfone, [1,2,4]triazolo[3,4-b][1,3,4]thiadiazinyl- or 2-(cyanophenyl-methylene)-1,3,4-thiadiazol-3(2H)-yl moieties was investigated as inhibitors of four α-carbonic anhydrases (CAs, EC 4.2.1.1), the human (h) isoforms hCA I, II (cytosolic, offtarget enzymes) and hCA IX and XII (transmembrane, tumor-associated isoforms). Low nanomolar activity was observed against hCA II (KIs of 0.56-17.1 nM) with these sulfonamides, whereas the slow cytosolic isoform hCA I was less inhibited by these compounds (KIs of 86.4 nM-32.8 µM). Most of these sulfonamides significantly inhibited CA IX, with KIs in the range of 4.5-47.0 nM, although some of the derivatives incorporating bulkier bicyclic moieties, as well as 2-thienyl fragments, showed a weaker activity against this isoform (KIs in the range 50.1-553 nM). All the investigated compounds also inhibited CA XII with KIs in the range 0.85-376 nM. The best inhibitors were those incorporating bulky [1,2,4]triazolo[3,4-b][1,3,4]thiadiazinyl moieties and 1,3,4-thiadiazol-3(2H)-yl groups.
研究了一系列含有芳酰腙、哌啶基、砜、[1,2,4]三唑并[3,4 - b][1,3,4]噻二嗪基或2 -（氰基苯基亚甲基）- 1,3,4 - 噻二唑 - 3(2H)-基部分的苯磺酰胺作为四种α - 碳酸酐酶（CAs，EC 4.2.1.1）的抑制剂，这四种酶分别是人（h）同工型hCA I、II（胞质，脱靶酶）以及hCA IX和XII（跨膜，肿瘤相关同工型）。这些磺酰胺对hCA II表现出低纳摩尔活性（KIs为0.56 - 17.1 nM），而胞质慢同工型hCA I受这些化合物的抑制作用较小（KIs为86.4 nM - 32.8 μM）。这些磺酰胺中的大多数对CA IX有显著抑制作用，KIs在4.5 - 47.0 nM范围内，不过一些含有较大双环部分以及2 - 噻吩基片段的衍生物对该同工型的活性较弱（KIs在50.1 - 553 nM范围内）。所有研究的化合物也抑制CA XII，KIs在0.85 - 376 nM范围内。最佳抑制剂是那些含有较大[1,2,4]三唑并[3,4 - b][1,3,4]噻二嗪基部分和1,3,4 - 噻二唑 - 3(2H)-基的化合物。
