Design of [(2-pyrimidinylthio)acetyl]benzenesulfonamides as inhibitors of human carbonic anhydrases

Čapkauskaitė, Edita; Zubrienė, Asta; Baranauskienė, Lina; Tamulaitiene, G.; Manakova, E.; Kairys, Visvaldas; Gražulis, S.; Tumkevičius, Sigitas; Matulis, Daumantas

doi:10.1016/j.ejmech.2012.02.050

Cited by 30 publications

(22 citation statements)

References 34 publications

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“…Therefore CAs are important therapeutic targets and some inhibitors are clinically approved drugs [19] . 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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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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“…Recently, we have investigated the interaction of several CA isozymes with pyrimidine derivatives such as [(2-pyrimidinylthio)acetyl]benzenesulfonamides 20 , 4-[N-(substituted 4-pyrimidinyl)amino]benzenesulfonamides 21 and thiadiazole derivatives 22 . We have also reported on the synthesis of 2-substituted benzimidazoles N-alkylated with 2-chloro-5-bromoacetylbenzenesulfonamide ( Figure 2, compounds 4(a-j)) and their binding to four CA isozymes, namely CA I, CA II, CA VII and CA XIII 23 .…”

Section: Introductionmentioning

confidence: 99%

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

Zubrienė

Čapkauskaitė

Gylytė

et al. 2013

Journal of Enzyme Inhibition and Medicinal Chemistry

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A series of benzenesulfonamide derivatives, bearing benzimidazole moieties, were designed and synthesized as inhibitors of carbonic anhydrases (CAs). Their binding affinities to recombinant human CA isozymes I, II, VII, XII and XIII were determined by the thermal shift assay. A group of compounds containing a benzimidazole substituent in the para position of the benzenesulfonamide ring was found to exhibit higher binding potency toward tested CAs than meta-substituted benzenesulfonamides. Some of these compounds exhibited nanomolar affinities and selectivity toward the CA isozymes tested.

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“…Compound 2 a has also two alternative locations in the active site of crystal structure of CA XII‐ 2 a . The binding mode of chlorobenzene ring is the same in the structures and similar to the binding mode of homologous compounds in the crystal structures published previously . The chlorobenzene ring is anchored by chlorine atom which is located in the hydrophobic cavity.…”

Section: Resultsmentioning

confidence: 99%

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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Design of [(2-pyrimidinylthio)acetyl]benzenesulfonamides as inhibitors of human carbonic anhydrases

Cited by 30 publications

References 34 publications

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

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

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

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

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