Synthesis and comparative carbonic anhydrase inhibition of new Schiff’s bases incorporating benzenesulfonamide, methanesulfonamide, and methylsulfonylbenzene scaffolds

• Published in: Bioorganic chemistry 2019-11, Vol.92, p.103225-103225, Article 103225
• Main Authors: El-Azab, Adel S., Abdel-Aziz, Alaa A.-M., Bua, Silvia, Nocentini, Alessio, Alanazi, Mohammed M., AlSaif, Nawaf A., Al-Suwaidan, Ibrahim A., Hefnawy, Mohamed M., Supuran, Claudiu T.
• Format: Article
• Language: English
• Subjects: Acetazolamide; Benzenesulfonamide; Benzenesulfonamides; Carbonic anhydrase inhibition; Carbonic Anhydrase Inhibitors - chemical synthesis; Carbonic Anhydrase Inhibitors - chemistry; Carbonic Anhydrase Inhibitors - pharmacology; Carbonic Anhydrases - chemistry; Hydrogen Bonding; Molecular docking; Molecular Docking Simulation; Molecular Structure; Schiff Bases - chemistry; Schiff’s base; Structure-Activity Relationship; Sulfonamides - chemistry; Synthesis
• ISSN: 0045-2068; 1090-2120
• DOI: 10.1016/j.bioorg.2019.103225

Compounds 4a–8a exhibited potent inhibitory activity against human CA isoforms I, II, IX, and XII (KIs: 93.5–428.1, 18.2–133.3, 8.5–24.9, and 8.6–43.2 nM, respectively), compared to acetazolamide, a standard inhibitor (KIs: 250.0, 12.0, 25.0, and 5.7 nM respectively). Compound 5a acts as a selective inhibitor of the tumor associated isoenzymes CA IX/XII with KIs of 15.8 and 8.6, respectively. [Display omitted] •Synthesis of novel Schiff’s bases.•CA I, II, IX, and XII inhibition profiles were evaluated.•Compounds 4a–8a showed potent inhibition against hCA I with KIs ranging from 93.5 to 428.1 nM.•Compounds 4a–8a proved to be effective hCA II inhibitors, with KI = 18.2–133.3 nM.•Compounds 4a–8a proved to be potent hCA IX inhibitors (KI = 8.5–24.9 nM).•Compounds 4a–8a displayed effective hCA XII inhibitory activity with KI values ranging from 8.6 to 43.2 nM. Herein, we report the synthesis, characterization, and carbonic anhydrase (CA) inhibition of the newly synthesized Schiff’s bases 4–18 with benzenesulfonamide, methanesulfonamide, and methylsulfonylbenzene scaffolds. The compound inhibition profiles against human CA (hCA) isoforms I, II, IX, and XII were compared to those of the standard inhibitors, acetazolamide (AAZ) and SLC-0111 (a CA inhibitor in Phase II clinical trials for the treatment of hypoxic tumors). The hCA I was inhibited by compounds 4a–8a with inhibition constants (KI) in the range 93.5–428.1 nM (AAZ and SLC-0111: KI, 250.0 and 5080.0 nM, respectively). Compounds 4a–8a proved to be effective hCA II inhibitors, with KI ranging from 18.2 to 133.3 nM (AAZ and SLC-0111: KI, 12.0 and 960.0 nM, respectively). Compounds 4a–8a effectively inhibited hCA IX, with KI in the range 8.5–24.9 nM; these values are superior or equivalent to that of AAZ and SLC-0111 (KI, 25.0 and 45.0 nM, respectively). Compounds 4a–8a displayed effective hCA XII inhibitory activity with KI values ranging from 8.6 to 43.2 nM (AAZ and SLC-0111: KI, 5.7 and 4.5 nM, respectively). However, compounds 9b–13b and 14c–18c were found to be micromolar CA inhibitors. For molecular docking studies, compounds 5a, 6a, and 8a were selected.