Department of Chemistry, Kurukshetra University, Kurukshetra 136119, India.
Università degli Studi di Firenze, Laboratorio di Chimica Bioinorganica, Rm 188, and Neurofarba Department, Sezione di Scienze Farmaceutiche, Via U. Schiff 6, I-50019 Sesto Fiorentino, Firenze, Italy.
Bioorg Chem. 2019 Apr;85:198-208. doi: 10.1016/j.bioorg.2019.01.002. Epub 2019 Jan 3.
A series of twenty four hydroxy-trifluoromethylpyrazoline-carbonyl-1,2,3-triazoles and four hydrazones bearing benzenesulfonamide moieties was obtained by condensation of carboxyhydrazides with substituted 1,3-diketones. All the newly synthesized compounds were investigated as inhibitors of physiologically and pharmacologically relevant human (h) carbonic anhydrsae (CA, EC 4.2.1.1) cytosolic isoforms hCA I and II, as well as transmembrane tumor-assosciated isoforms hCA IX and XII. These compounds exhibited excellent CA inhibitory potency against the four CA isoenzymes as compared to clinically used reference drug acetazolamide (AAZ). Some compounds bearing bulkier group at C-5' position of 1,2,3-triazoles ring were weaker inhibitors of hCA I. Inhibition assay against hCA II indicates, that several derivatives exhibited upto 27-fold more effective inhibitory activity compared to AAZ. Five of the assayed compounds displayed low nanomolar potency (K ≤ 10 nM) against hCA IX, whereas five compounds were found to be endowed with excellent inhibitory potencies (K ≤ 5 nM) against hCA XII. The biological activity profile presented herein will be useful for designing new leads and provide candidates for preclinical investigations.
通过将羧基酰肼与取代的 1,3-二酮缩合，得到了一系列二十四羟三氟甲基吡唑啉羰基-1,2,3-三唑和四个带有苯磺酰胺部分的腙。所有新合成的化合物均被用作生理和药理学相关的人（h）碳酸酐酶（CA，EC 4.2.1.1）细胞溶质同工酶 hCA I 和 II 以及跨膜肿瘤相关同工酶 hCA IX 和 XII 的抑制剂进行了研究。与临床使用的参考药物乙酰唑胺（AAZ）相比，这些化合物对四种 CA 同工酶表现出优异的 CA 抑制效力。在 1,2,3-三唑环的 C-5'位置带有更大基团的一些化合物对 hCA I 的抑制作用较弱。对 hCA II 的抑制测定表明，与 AAZ 相比，几种衍生物的抑制活性高达 27 倍。在所测定的五种化合物中，有五种对 hCA IX 表现出低纳摩尔效力（K≤10 nM），而有五种化合物对 hCA XII 表现出极好的抑制效力（K≤5 nM）。本文呈现的生物学活性谱将有助于设计新的先导化合物，并为临床前研究提供候选药物。
