Novel synthesized SLC-0111 thiazole and thiadiazole analogues: Determination of their carbonic anhydrase inhibitory activity and molecular modeling studies

  • Bioorg Chem. 2019 Jun:87:794-802. doi: 10.1016/j.bioorg.2019.04.002.
Mahmoud F Abo-Ashour  1 ,  Wagdy M Eldehna  2 ,  Alessio Nocentini  3 ,  Hany S Ibrahim  1 ,  Silvia Bua  3 ,  Hatem A Abdel-Aziz  4 ,  Sahar M Abou-Seri  5 ,  Claudiu T Supuran  6
Affiliations
  • 1. Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Egyptian Russian University, Badr City, Cairo 11829, Egypt.
  • 2. Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Kafrelsheikh University, Kafrelsheikh, P.O. Box 33516, Egypt. Electronic address: [email protected].
  • 3. Department of NEUROFARBA, Section of Pharmaceutical and Nutraceutical Sciences, University of Florence, Polo Scientifico, Via U. Schiff 6, 50019, Sesto Fiorentino, Firenze, Italy.
  • 4. Department of Applied Organic Chemistry, National Research Center, Dokki, Cairo 12622, Egypt.
  • 5. Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Cairo University, Kasr El-Aini Street, Cairo, P.O. Box 11562, Egypt. Electronic address: [email protected].
  • 6. Department of NEUROFARBA, Section of Pharmaceutical and Nutraceutical Sciences, University of Florence, Polo Scientifico, Via U. Schiff 6, 50019, Sesto Fiorentino, Firenze, Italy. Electronic address: [email protected].
PMID: 30978604 DOI: 10.1016/j.bioorg.2019.04.002
Abstract

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 CO2 hydrase assay. All the examined isoforms were inhibited by the primary sulfonamide derivatives (11a-d and 12a-d) in variable degrees with the following KI 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 (KIs = 8.3 and 7.9 nM, respectively) than SLC-0111 (KI = 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.

Keywords
Carbonic anhydrase inhibitors; Molecular docking; SLC-0111 analogues; Thiazoles and thiadiazoles; Ureido-benzenesulfonamide.
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