Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Egyptian Russian University, Badr City, Cairo 11829, Egypt.
Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Kafrelsheikh University, Kafrelsheikh, P.O. Box 33516, Egypt.
Bioorg Chem. 2019 Jun;87:794-802. doi: 10.1016/j.bioorg.2019.04.002. Epub 2019 Apr 3.
In the presented work, we report the design and synthesis of novel SLC-0111 thiazole and thiadiazole analogues (11a-d, 12a-d, 16a-c and 17a-d). A bioisosteric replacement approach was adopted to replace the 4-fluorophenyl tail of SLC-0111 with thiazole and thiadiazole ones, which were thereafter extended with lipophilic un/substituted phenyl moieties. All the newly synthesized SLC-0111 analogues were evaluated in vitro for their inhibitory activity towards a panel of the metalloenzyme carbonic anhydrase (CA, EC 4.2.1.1) isoforms (hCA I, II, IX and XII), using a stopped-flow CO hydrase assay. All the examined isoforms were inhibited by the primary sulfonamide derivatives (11a-d and 12a-d) in variable degrees with the following K ranges: 162.6-7136 nM for hCA I, 9.0-833.6 nM for hCA II, 7.9-153.0 nM for hCA IX, and 9.4-94.0 nM for hCA XII. In particular, compounds 12b and 12d displayed 5.5-fold more potent inhibitory activity (Ks = 8.3 and 7.9 nM, respectively) than SLC-0111 (K = 45 nM) towards hCA IX. Molecular docking study was carried out for 12d within the hCA IX (PDB 3IAI) active site, to justify its inhibitory activity.
在本工作中，我们报告了新型 SLC-0111 噻唑和噻二唑类似物（11a-d、12a-d、16a-c 和 17a-d）的设计和合成。采用生物等排替代方法，用噻唑和噻二唑取代 SLC-0111 的 4-氟苯基尾部，并用亲脂性未取代的苯基部分进行扩展。所有新合成的 SLC-0111 类似物均通过停流 CO 水解测定法在体外评估其对一系列金属酶碳酸酐酶（CA，EC 4.2.1.1）同工酶（hCA I、II、IX 和 XII）的抑制活性。所有检查的同工酶均被主要磺酰胺衍生物（11a-d 和 12a-d）不同程度地抑制，其 K 值范围如下：hCA I 为 162.6-7136 nM，hCA II 为 9.0-833.6 nM，hCA IX 为 7.9-153.0 nM，hCA XII 为 9.4-94.0 nM。特别是，化合物 12b 和 12d 对 hCA IX 的抑制活性比 SLC-0111（K=45 nM）强 5.5 倍（Ks 分别为 8.3 和 7.9 nM）。对 12d 在 hCA IX（PDB 3IAI）活性部位内进行分子对接研究，以证明其抑制活性。
