4 research outputs found
Carbonic Anhydrase Glycoinhibitors belonging to the Aminoxysulfonamide Series
A general
approach for the synthesis of carbonic anhydrases glycoinhibitors
belonging to an aminoxysulfonamide series is presented using a Ferrier
sulfonamidoglycosylation reaction on glycals. All the compounds showed
good <i>in vitro</i> inhibitory activity against four human
carbonic anhydrase isoforms, with selectivity against the cytosolic
(hCA II) vs the tumor associated (hCA IX and XII) enzymes
Development of Potent Carbonic Anhydrase Inhibitors Incorporating Both Sulfonamide and Sulfamide Groups
A series of compounds incorporating both sulfonamide
and sulfamide as zinc-binding groups (ZBGs) are reported as inhibitors
of the metalloenzyme carbonic anhydrase (CA, EC 4.2.1.1). Crystallographic
studies on the complex of hCA II with the lead compound of this series,
namely, 4-sulfamido-benzenesulfonamide, revealed the binding of two
molecules in the enzyme active site cavity, the first one canonically
coordinated to the zinc ion by means of the sulfonamide group and
the second one located at the entrance of the cavity. This observation
led to the design of elongated molecules incorporating these two ZBGs,
separated by a linker of proper length, to allow the simultaneous
binding to these different sites. The “long” inhibitors
indeed showed around 10 times better enzyme inhibitory properties
as compared to the shorter molecules against four physiologically
relevant human (h) isoforms, hCA I, II, IX, and XII
Benzoxaboroles as Efficient Inhibitors of the β‑Carbonic Anhydrases from Pathogenic Fungi: Activity and Modeling Study
A series
of 6-substituted benzoxaboroles were investigated as inhibitors
of the β-class carbonic anhydrase from three pathogenic fungi
(<i>Cryptococcus neoformans</i>, <i>Candida glabrata</i>, and <i>Malassezia globosa</i>). Independently from the
nature of the substituents on the phenyl of the urea/thiourea group,
all reported derivatives showed nanomolar inhibitory activities against
Can2 and CgNce103 vs micromolar inhibition against MgCA. Selectivity
over human CA I and CA II was noticed. The observed structure–activity
relationship trends have been rationalized by modeling study of selected
compounds into the active site of Can2 and MgCA. The present letter
demonstrates that benzoxaborole chemotype may offer interesting opportunities
for the inhibition of β-CA from pathogenic fungi and for the
development of antifungal agents with a new mechanism of action
Poly(amidoamine) Dendrimers with Carbonic Anhydrase Inhibitory Activity and Antiglaucoma Action
Four
generations of polyÂ(amidoamine) (PAMAM) dendrimers decorated with
benzenesulfonamide moieties were prepared by derivatizing the amino
groups of the dendrimer with 4-carboxy-benzenesulfonamide functionalities.
Compounds incorporating 4, 8, 16, and 32 sulfonamide moieties were
thus obtained, which showed an increasing carbonic anhydrase (CA,
EC 4.2.1.1) inhibitory action with the increase of the number of sulfamoyl
groups in the dendrimer. Best inhibitory activity (in the low nanomolar–subnanomolar
range) was observed for isoforms CA II and XII, involved among others
in glaucoma. In an animal model of this disease, the chronic administration
of such dendrimers for 5 days led to a much more efficient drop of
intraocular pressure compared to the standard drug dorzolamide