Design, Synthesis, Molecular Docking Analysis, and Carbonic Anhydrase IX Inhibitory Evaluations of Novel N-Substituted-β-d-Glucosamine Derivatives that Incorporate Benzenesulfonamides

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.

In silico evaluation of a new compound incorporating 4(3H)-quinazolinone and sulfonamide as a potential inhibitor of a human carbonic anhydrase

“…SSDC obtained a strong binding energy (− 12.19 kmol/cal) that is significantly higher than other prior findings, even than approved drugs. The binding energies for similar benzenesulfonamide compounds in earlier molecular docking studies ranged from − 6.16 to − 8.15 kcal/mol [ 39 ]. Acetazolamide (AZA), the known Carbonic Anhydrase inhibitor, was docked into the same target protein as a standard reference.…”

Discovery of non-sulfonamide carbonic anhydrase IX inhibitors through structure-based virtual screening

“…The enzyme activity level was indirectly measured by determining the absorbance value of the solution at 405 nm. 21,22 The spectrophotometric monitoring of the reaction rate was performed using a PerkinElmer Envision 2104 plate reader (PerkinElmer, Waltham, MA, USA). The buffer used consisted of 15 mmol L −1 4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid (HEPES) (pH = 7.40), 0.01% tetraethylene glycol monododecyl ether (Brij), and 100 mmol L −1 NaCl.…”

Novel Anthraquinone-Based Benzenesulfonamide Derivatives and Their Analogues as Potent Human Carbonic Anhydrase Inhibitors with Antitumor Activity: Synthesis, Biological Evaluation, and In Silico Analysis

“…The activity of CA is reflected by an increased absorbance value measured by an ultraviolet (UV)–visible spectrophotometer at a wavelength of 405 nm [ 33 ]. All compounds and the positive control AAZ were dissolved in DMSO at 25 °C and diluted to the indicated concentrations with 1× assay buffer (HEPES 7.2) [ 34 ]. Ten different compound and AAZ concentrations were utilized (30, 10, 3.3333, 1.1111, 0.3704, 0.1235, 0.0412, 0.0137, 0.0046, 0.0015, and 0 µM).…”