Abstract
A series of novel N-substituted-β-d-glucosamine derivatives that incorporate benzenesulfonamides were designed using a fragment-based drug design strategy. Each derivative was synthesized and evaluated in vitro for its inhibitory activity against human carbonic anhydrase (hCA) IX; several derivatives displayed desirable potency profiles against this enzyme. The molecular docking studies provided the design rationale and predicted potential binding modes for carbonic anhydrase (CA) IX and three target compounds, including the most potent inhibitor, compound 7f (IC50 = 10.01 nM). Moreover, the calculated Log P (cLog P) values showed that all the compounds tended to be hydrophilic. In addition, topological polar surface area (TPSA) value-based predictions highlighted the selectivity of these carbohydrate-based inhibitors for membrane-associated CA IX.
Highlights
Carbonic anhydrases (CAs) are ubiquitous zinc metalloenzymes that catalyze the reversible hydration of carbon dioxide and water to a bicarbonate ion and proton [1,2,3,4,5,6]
The results indicate that it is possible for the designed compounds to exhibit hydrophilic properties, limited membrane permeabilities, and target CA IX
We report a novel series of N-substituted-β-D-glucosamines derivatives incorporating benzenesulfonamides by utilizing a fragment-based drug design
Summary
Carbonic anhydrases (CAs) are ubiquitous zinc metalloenzymes that catalyze the reversible hydration of carbon dioxide and water to a bicarbonate ion and proton [1,2,3,4,5,6]. Human cells express twelve catalytically active CA isoforms belonging to the α family These isoforms have been classified into four different subclasses based on the subcellular localization: cytosolic isoforms (CA I, CA II, CA III, CA VII, and CA XIII) and membrane-bound (CA IV, CA IX, CA XII, and CA XIV), secreted (CA VI), and mitochondrial (CA VA and CA VB) forms [1,2,7]. Apart from this difference, they have variable organ and tissue distributions and catalytic activities. The role of the zinc cation is to bind to and activate the substrate H2 O in the process of hydration of CO2 [1,2]
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