Several pyrazole-benzene sulfonamides were reported as human carbonic anhydrase inhibitors. In this research work, a design of Arylidine-extented 5-oxo-pyrazole benzenesulfonamides (4a-i), (8a-d) and (10a-e) were reported based on tail-approach design. Beside the reported synthetic procedures and confirmation by different analytical procedures, a DFT study was employed to confirm the Z- conformer of the synthesized compounds. In vitro biological assay against four different human carbonic anhydrases took place and based on the results, SAR study was illustrated and selectivity indexes were discussed. Compounds 4g and 8a exhibited the best inhibitory activity among the target compounds with values (hCAIX: K_I = 71.2 nM, hCAXII: K_I = 22.5 nM), (hCAIX: K_I = 34.3 nM, hCAXII: K_I = 74.3 nM); respectively. Both of them were subjected to cellular assay against two different cancer cell lines with expressing nature to hCA isoforms under both normoxic and hypoxic conditions. Compound 4g showed the highest cytotoxic activity against MCF-7 cancer cell line (IC₅₀ = 4.15 µM under hypoxic conditions and IC₅₀ = 8.59 µM under normoxic conditions) compared to the reference drug doxorubicin under normoxic, (IC₅₀ = 4.34 µM), and hypoxic, (IC₅₀ = 2.23 µM), conditions. Further cellular investigations were employed to study the effect of this compound on the cell cycle of the affected cell line. Finally, molecular docking supported by molecular dynamic simulation was utilized to understand the mechanism of the inhibitory activity of two of these compounds – as representative examples- based on the designed rational.

据报道，几种吡唑-苯磺酰胺可作为人类碳酸酐酶抑制剂。在这项研究工作中，基于尾部方法设计，报道了亚芳基扩展的 5-氧代-吡唑苯磺酰胺 ( 4a-i )、( 8a-d ) 和 ( 10a-e ) 的设计。除了报道的合成程序和通过不同分析程序的确认之外，还采用 DFT 研究来确认合成化合物的Z构象异构体。对四种不同的人碳酸酐酶进行了体外生物学测定，并根据结果阐述了SAR研究并讨论了选择性指标。化合物4g和8a在目标化合物中表现出最好的抑制活性，其值为 (hCAIX: K _I = 71.2 nM, hCAXII: K _I = 22.5 nM)，(hCAIX: K _I = 34.3 nM, hCAXII: K _I = 74.3 nM) ;分别。在常氧和低氧条件下，对两种具有 hCA 同种型表达性质的不同癌细胞系进行细胞测定。与常氧条件下的参考药物阿霉素（IC ₅₀ = 4.34 µM）相比，化合物4g对 MCF-7 癌细胞系表现出最高的细胞毒活性（低氧条件下 IC ₅₀ = 4.15 µM，常氧条件下 IC ₅₀ = 8.59 µM），和缺氧（IC ₅₀ = 2.23 µM）条件。采用进一步的细胞研究来研究该化合物对受影响细胞系的细胞周期的影响。 最后，基于设计原理，利用分子动力学模拟支持的分子对接来了解其中两种化合物（作为代表性实例）的抑制活性机制。