TY  - JOUR
AU  - Zakšauskas, Audrius
AU  - Čapkauskaitė, Edita
AU  - Jezepčikas, Linas
AU  - Linkuvienė, Vaida
AU  - Paketurytė, Vaida
AU  - Smirnov, Alexey
AU  - Leitans, Janis
AU  - Kazaks, Andris
AU  - Dvinskis, Elviss
AU  - Manakova, Elena
AU  - Gražulis, Saulius
AU  - Tars, Kaspars
AU  - Matulis, Daumantas
TI  - Halogenated and di-substituted benzenesulfonamides as selective inhibitors of carbonic anhydrase isoforms
JO  - European journal of medicinal chemistry
VL  - 185
SN  - 0223-5234
CY  - Amsterdam [u.a.]
PB  - Elsevier10887
M1  - PUBDB-2020-03220
SP  - 111825
PY  - 2020
AB  - By applying an approach of a “ring with two tails”, a series of novel inhibitors possessing high-affinity and significant selectivity towards selected carbonic anhydrase (CA) isoforms has been designed. The “ring” consists of 2-chloro/bromo-benzenesulfonamide, where the sulfonamide group is as an anchor coordinating the Zn(II) in the active site of CAs, and halogen atom orients the ring affecting the affinity and selectivity. First “tail” is a substituent containing carbonyl, carboxyl, hydroxyl, ether groups or hydrophilic amide linkage. The second “tail” contains aryl- or alkyl-substituents attached through a sulfanyl or sulfonyl group. Both “tails” are connected to the benzene ring and play a crucial role in selectivity. Varying the substituents, we designed compounds selective for CA VII, CA IX, CA XII, or CA XIV.Since due to binding-linked protonation reactions the binding-ready fractions of the compound and protein are much lower than one, the “intrinsic” affinities were calculated that should be used to study correlations between crystal structures and the thermodynamics of binding for rational drug design. The “intrinsic” affinities together with the intrinsic enthalpies and entropies of binding together with co-crystal structures were used demonstrate structural factors determining major contributions for compound affinity and selectivity.
LB  - PUB:(DE-HGF)16
C6  - pmid:31740053
UR  - <Go to ISI:>//WOS:000503099900056
DO  - DOI:10.1016/j.ejmech.2019.111825
UR  - https://bib-pubdb1.desy.de/record/442800
ER  -