4Z1N: Carbonic Anhydrase Inhibitors: Design And Synthesis Of New Heteroaryl- N-carbonylbenzenesulfonamides Targeting Druggable Human Carbonic Anhydrase Isoforms (hca Vii, Hca Ix, And Hca Xiv)

A set of heteroaryl-N-carbonylbenzenesulfonamides has been designed, synthesized, and screened as inhibitors of human carbonic anhydrases (hCAs). The new sulfonamide derivatives were tested against hCA I, hCA II, hCA VII, hCA IX, and hCA XII isoforms using acetazolamide (AAZ, 1) and topiramate (TPM, 2) as reference compounds. Six compounds were low nanomolar inhibitors of tumor-associated hCA IX isoform (Ki values < 10 nM); among them we identified three arylsulfonamides showing unexpected inefficacy over brain distributed hCA VII isoform (hCA IX/hCA VII selectivity ratio > 1500 for compound 5c). Thus, these compounds can offer the opportunity to highlight the interactions preventing the inhibition of hCA VII mainly expressed in central nervous system. Thereby, we used structural and computational techniques to study in depth the interaction with hCAs. In an effort to confirm the inhibitory action we determined crystal structures of five selected heteroaryl-N-carbonylbenzenesulfonamides (4a, 4b, 4e, 5c, and 5e) in complex with hCA II. Moreover, to explore the lack of inhibitory effects of selected compounds (e.g.4b and 5c) we also performed docking studies into hCA VII catalytic site.
PDB ID: 4Z1NDownload
MMDB ID: 132047
PDB Deposition Date: 2015/3/27
Updated in MMDB: 2015/08
Experimental Method:
x-ray diffraction
Resolution: 1.47  Å
Source Organism:
Similar Structures:
Biological Unit for 4Z1N: monomeric; determined by author and by software (PISA)
Molecular Components in 4Z1N
Label Count Molecule
Protein (1 molecule)
Carbonic Anhydrase 2(Gene symbol: CA2)
Molecule annotation
Chemicals (2 molecules)
* Click molecule labels to explore molecular sequence information.

Citing MMDB