4 research outputs found
Dithiocarbamates Strongly Inhibit Carbonic Anhydrases and Show Antiglaucoma Action in Vivo
A series of dithiocarbamates were prepared by reaction
of primary/secondary amines with carbon disulfide in the presence
of bases. These compounds were tested for the inhibition of four human
(h) isoforms of the zinc enzyme carbonic anhydrase, CA (EC 4.2.1.1),
hCA I, II, IX, and XII, involved in pathologies such as glaucoma (CA
II and XII) or cancer (CA IX). Several low nanomolar inhibitors targeting
these CAs were detected. The X-ray crystal structure of the hCA II
adduct with morpholine dithiocarbamate evidenced the inhibition mechanism
of these compounds, which coordinate to the metal ion through a sulfur
atom from the dithiocarbamate zinc-binding function. Some dithiocarbamates
showed an effective intraocular pressure lowering activity in an animal
model of glucoma
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
Monothiocarbamates Strongly Inhibit Carbonic Anhydrases in Vitro and Possess Intraocular Pressure Lowering Activity in an Animal Model of Glaucoma
A series
of monothiocarbamates (MTCs) were prepared from primary/secondary
amines and COS as potential carbonic anhydrase (CA, EC 4.2.1.1) inhibitors,
using the dithiocarbamates, the xanthates, and the trithiocarbonates
as lead compounds. The MTCs effectively inhibited the pharmacologically
relevant human (h) hCAs isoforms I, II, IX, and XII in vitro and showed <i>K</i><sub>I</sub>s spanning between the low and medium nanomolar
range. By means of a computational study, the MTC moiety binding mode
on the CAs was explained. Furthermore, a selection of MTCs were evaluated
in a normotensive glaucoma rabbit model for their intraocular pressure
(IOP) lowering effects and showed interesting activity
Discovery of β‑Adrenergic Receptors Blocker–Carbonic Anhydrase Inhibitor Hybrids for Multitargeted Antiglaucoma Therapy
The
combination of a β-adrenergic receptors (AR) blocker
and a carbonic anhydrase (CA, EC 4.2.1.1) inhibitor in eye drops formulations
is one of the most clinically used treatment for glaucoma. A novel
approach consisting of single-molecule, multitargeted compounds for
the treatment of glaucoma is proposed here by designing compounds
which concomitantly interact with the β-adrenergic and CA targets.
Most derivatives of the two series of benzenesulfonamides incorporating
2-hydroxypropylamine moieties reported here exhibited striking efficacy
against the target hCA II and XII, whereas a subset of compounds also
showed significant modulation of β<sub>1</sub>- and β<sub>2</sub>-ARs. X-ray crystallography studies provided rationale for
the observed hCA inhibition. The best dual-agents decreased IOP more
effectively than clinically used dorzolamide, timolol, and the combination
of them in an animal model of glaucoma. The reported evidence supports
the proof-of-concept of β-ARs blocker–CAI hybrids for
antiglaucoma therapy with an innovative mechanism of action