Benzenesulfonamides with benzimidazole moieties as inhibitors of carbonic anhydrases I, II, VII, XII and XIII

Zubrienė, Asta; Čapkauskaitė, Edita; Gylytė, Joana; Kišonaitė, Miglė; Tumkevičius, Sigitas; Matulis, Daumantas

doi:10.3109/14756366.2012.757223

Cited by 28 publications

(22 citation statements)

References 33 publications

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“…All observed K d s are listed in Table . The K d values of the compound binding to six CA isoforms have been previously published in ,. Here we determine the K d s of remaining 6 CAs and thus compare them among all 12 human catalytically active CAs.…”

Section: Resultssupporting

confidence: 81%

“…The standard deviation of the FTSA measurements is ±1.6‐fold in K d . The K d for compounds 1–4(a–j) binding to CA I, II, VII, XII, and XIII are taken from our previously published data ,…”

Section: Resultsmentioning

confidence: 99%

“…Compounds of series 4 which differ from series 3 only in the additional chlorine‐substituent on the benzene ring, showed increased affinity for all CAs (with the exception of decrease in binding to CA I and CA IX). However, it was completely unexpected to observe the subnanomolar affinity of 4 a to CA VA ( K d 0.25 nM) and also high selectivity.…”

Section: Resultsmentioning

confidence: 99%

“…Here we describe an interesting result when compounds with similar chemical structures, varied in their sulfonamide headgroup or substituted tailgroup position, even the ones with identical composition, but different arrangement of substituents, exhibited significant selectivities towards desired CA isoforms. Despite that the synthesis of N ‐alkylated benzimidazoles as structural analogues of drug indapamide and their observed affinities to several CA isoforms has been previously described in our studies,, the determination of intrinsic affinities to the complete set of human CAs revealed unexpectedly significant selectivities of compounds towards particular CA isoforms. Especially strong and selective inhibitor of CA VA was discovered that could be developed for therapeutic applications.…”

Section: Introductionmentioning

confidence: 99%

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Combinatorial Design of Isoform-Selective N-Alkylated Benzimidazole-Based Inhibitors of Carbonic Anhydrases

et al. 2017

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Human carbonic anhydrases comprise a family of isoforms that form structurally similar active site and thus it is difficult to design inhibitors that would selectively inhibit the targeted isoform and leave uninhibited all remaining ones. Most common inhibitors are aromatic sulfonamides that strongly bind and inhibit CAs, but usually with limited selectivity towards a targeted isoform. However, sometimes seemingly minor changes in the inhibitor structure may cause significant increase or decrease in affinity towards a CA isoform. Here, the affinities of previously designed N‐alkylated benzimidazoles were determined to all active human CA isoforms. This combinatorial approach yielded several compounds that were highly selective for CA VA. Intrinsic affinities were determined by subtraction of the binding‐linked protonation reactions that, together with the X‐ray crystallographic structures revealing the arrangement of the inhibitors in the active site, help in the design of inhibitors exhibiting subnanomolar affinities and improved selectivities towards a particular CA isoform.

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Section: Resultssupporting

confidence: 81%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Combinatorial Design of Isoform-Selective N-Alkylated Benzimidazole-Based Inhibitors of Carbonic Anhydrases

et al. 2017

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“…The most studied class of CA inhibitors is aromatic sulfonamides [12] , [20] , [21] . Although about 30 CA inhibitors are currently used as drugs, the challenge of developing compounds that are selective for a specific isoform still remains [22] , [23] .…”

Section: Introductionmentioning

confidence: 99%

Intrinsic Thermodynamics and Structure Correlation of Benzenesulfonamides with a Pyrimidine Moiety Binding to Carbonic Anhydrases I, II, VII, XII, and XIII

et al. 2014

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The early stage of drug discovery is often based on selecting the highest affinity lead compound. To this end the structural and energetic characterization of the binding reaction is important. The binding energetics can be resolved into enthalpic and entropic contributions to the binding Gibbs free energy. Most compound binding reactions are coupled to the absorption or release of protons by the protein or the compound. A distinction between the observed and intrinsic parameters of the binding energetics requires the dissection of the protonation/deprotonation processes. Since only the intrinsic parameters can be correlated with molecular structural perturbations associated with complex formation, it is these parameters that are required for rational drug design. Carbonic anhydrase (CA) isoforms are important therapeutic targets to treat a range of disorders including glaucoma, obesity, epilepsy, and cancer. For effective treatment isoform-specific inhibitors are needed. In this work we investigated the binding and protonation energetics of sixteen [(2-pyrimidinylthio)acetyl]benzenesulfonamide CA inhibitors using isothermal titration calorimetry and fluorescent thermal shift assay. The compounds were built by combining four sulfonamide headgroups with four tailgroups yielding 16 compounds. Their intrinsic binding thermodynamics showed the limitations of the functional group energetic additivity approach used in fragment-based drug design, especially at the level of enthalpies and entropies of binding. Combined with high resolution crystal structural data correlations were drawn between the chemical functional groups on selected inhibitors and intrinsic thermodynamic parameters of CA-inhibitor complex formation.

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Aqueous acidities of primary benzenesulfonamides: Quantum chemical predictions based on density functional theory and SMD

Aidas

Lanevskij²,

Kubilius³

et al. 2015

J Comput Chem

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Aqueous pK(a) of selected primary benzenesulfonamides are predicted in a systematic manner using density functional theory methods and the SMD solvent model together with direct and proton exchange thermodynamic cycles. Some test calculations were also performed using high-level composite CBS-QB3 approach. The direct scheme generally does not yield a satisfactory agreement between calculated and measured acidities due to a severe overestimation of the Gibbs free energy changes of the gas-phase deprotonation reaction by the used exchange-correlation functionals. The relative pK(a) values calculated using proton exchange method compare to experimental data very well in both qualitative and quantitative terms, with a mean absolute error of about 0.4 pK(a) units. To achieve this accuracy, we find it mandatory to perform geometry optimization of the neutral and anionic species in the gas and solution phases separately, because different conformations are stabilized in these two cases. We have attempted to evaluate the effect of the conformer-averaged free energies in the pK(a) predictions, and the general conclusion is that this procedure is highly too costly as compared with the very small improvement we have gained.

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Benzenesulfonamides with benzimidazole moieties as inhibitors of carbonic anhydrases I, II, VII, XII and XIII

Cited by 28 publications

References 33 publications

Combinatorial Design of Isoform-Selective N-Alkylated Benzimidazole-Based Inhibitors of Carbonic Anhydrases

Combinatorial Design of Isoform-Selective N-Alkylated Benzimidazole-Based Inhibitors of Carbonic Anhydrases

Intrinsic Thermodynamics and Structure Correlation of Benzenesulfonamides with a Pyrimidine Moiety Binding to Carbonic Anhydrases I, II, VII, XII, and XIII

Aqueous acidities of primary benzenesulfonamides: Quantum chemical predictions based on density functional theory and SMD

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