Tail-approach based design, synthesis, and molecular modeling of benzenesulfonamides carrying thiadiazole and urea moieties as novel carbonic anhydrase inhibitors

被引:1
|
作者
Han, M. Ihsan [1 ]
Gunduz, Miyase Gozde [2 ]
Ammara, Andrea [3 ]
Supuran, Claudiu T. [3 ]
Dogan, Sengul Dilem [4 ]
机构
[1] Erciyes Univ, Fac Pharm, Dept Pharmaceut Chem, Kayseri, Turkiye
[2] Hacettepe Univ, Fac Pharm, Dept Pharmaceut Chem, Ankara, Turkiye
[3] Univ Florence, Dept NEUROFARBA, Sect Pharmaceut & Nutraceut Sci, Polo Sci, Via U Schiff 6, I-50019 Sesto Fiorentino, Firenze, Italy
[4] Erciyes Univ, Fac Pharm, Dept Basic Sci, TR-38039 Kayseri, Turkiye
关键词
1,3,4-thiadiazole; 3D pharmacophore; molecular docking; molecular dynamics; zinc binding; DISCOVERY; IX;
D O I
10.1002/ardp.202400439
中图分类号
R914 [药物化学];
学科分类号
100701 ;
摘要
We synthesized herein 16 compounds (SUT1-SUT16) as potential carbonic anhydrase (CA) inhibitors utilizing the tail-approach design. Based on this strategy, we connected benzenesulfonamide, the zinc-binding scaffold, to different urea moieties with the 1,3,4-thiadiazole ring as a linker. We obtained the target compounds by the reaction of 4-(5-amino-1,3,4-thiadiazol-2-yl)benzenesulfonamide with aryl isocyanates. Upon confirmation of their structures, the compounds were screened for their ability to inhibit the tumor-related human (h) isoforms human carbonic anhydrase (hCA) IX and XII, as well as the physiologically dominant hCA I and II. Most of the molecules demonstrated Ki values <= 10 nM with different selectivity profiles. The binding modes of SUT9, SUT10, and SUT5, the most effective inhibitors of hCA II, IX, and XII, respectively, were predicted by molecular docking. SUT16 (4-{5-[3-(naphthalen-1-yl)ureido]-1,3,4-thiadiazol-2-yl}benzenesulfonamide) was found to be the most selective inhibitor of the cancer-associated isoforms hCA IX and XII over the off-target isoforms, hCAI and II. The interaction dynamics and stability of SUT16 within hCA IX and XII were investigated by molecular dynamics simulations as well as dynophore analysis. Based on computational data, increased hydrophobic contacts and hydrogen bonds in the tail part of these molecules within hCA IX and XII were found as favorable interactions leading to effective inhibitors of cancer-related isoforms. To obtain novel carbonic anhydrase (CA) inhibitors, benzenesulfonamide, the zinc-binding scaffold, was connected to different urea moieties with the 1,3,4-thiadiazole ring as a linker, based on tail-approach design. Sixteen novel compounds (SUT1-SUT16) were tested for their human CA I, II, IX, and XII inhibitory activities. Molecular modeling studies supported the inhibition data. image
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页数:11
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