From random to rational: A discovery approach to selective subnanomolar inhibitors of human carbonic anhydrase IV based on the Castagnoli-Cushman multicomponent reaction

Abstract

By exploiting the power of multicomponent chemistry, a relatively small, diverse set of primary sulfonamides was synthesized and screened against a panel of human carbonic anhydrases to reveal a low-nanomolar, albeit non-selective hCA IV lead inhibitor. Investigation of the docking poses of this compound identified a hydrophilic pocket unique to hCA IV and conveniently positioned near the carboxylate functionality of the initial lead. Various residues capable of forming hydrogen bonds as well as salt bridges were placed in this pocket via a carboxamides linkage, which led to drastic improvement of potency and selectivity towards hCA IV. This improvement of the desired inhibitory profile was rationalized by the new contacts as had been envisioned. These new tool compounds were shown to possess selective, dose-dependent cytotoxicity against human glioma T98G cell line. The latter showed a substantially increased hCA IV mRNA expression under hypoxic conditions.

Sulfonamides incorporating ketene N,S‐acetal bioisosteres as potent carbonic anhydrase and acetylcholinesterase inhibitors

“…[ 82 ] Three‐dimensional ligand structures were prepared by the LigPrep tool [ 83 ] and implemented for their minimization states at neutral pH (7.0 ± 0.5) with Epik. [ 84 ] Extra precision Glide protocol [ 85 ] in Schrödinger Suite [ 86 ] was performed and bioactive compound structures were treated as flexible to obtain five poses for each ligand. The Prime MM–GBSA module [ 87 ] (Schrödinger Release 2019‐3) using the VSGB solvent model [ 88 ] and OPLS3e force field [ 89 ] was applied to calculate the binding free energy (ΔG Bind) of the synthesized derivatives ( 7a – o ) toward the receptors (5E2M, 6H29, and 4M0E).…”

Five-Membered Heterocyclic Sulfonamides as Carbonic Anhydrase Inhibitors

“…This consists of the application of a tail to a zinc-binding group in order to modulate the chemical-physical properties of the molecules and at the same time increase the interaction with the active site of the specific isoform of interest. The tail allows to interact with the residues of the middle and outer ridges of the binding pockets (areas with greater amino acid variability among the various isoforms) to improve the isoform specificity [ 70 , 71 , 72 , 73 ].…”

Sulfonamides with Heterocyclic Periphery as Antiviral Agents

“…Sulfonamides are of particular importance in the synthesis of carbonic anhydrase inhibitors, which are used, for example, in combined chemotherapy for cancer [22]. Heterocyclic sulfonamides acts as hCA IV (as drug targets) inhibitors [23]. Pyrrolidine-containing sulfonamides (hCA IV inhibitors) are promising drugs for the treatment of glioma [23].…”

“…Heterocyclic sulfonamides acts as hCA IV (as drug targets) inhibitors [23]. Pyrrolidine-containing sulfonamides (hCA IV inhibitors) are promising drugs for the treatment of glioma [23]. Sulfonamide hCA VII inhibitors are used in the complex therapy of HIV-infection.…”