Halogenated and di-substituted benzenesulfonamides as selective inhibitors of carbonic anhydrase isoforms

Zakšauskas, Audrius; Čapkauskaitė, Edita; Jezepčikas, Linas; Linkuvienė, Vaida; Paketurytė, Vaida; Smirnov, Alexander; Leitans, Janis; Kazāks, Andris; Dvinskis, Elviss; Manakova, E.; Gražulis, S.; Tars, K.; Matulis, Daumantas

doi:10.1016/j.ejmech.2019.111825

Cited by 13 publications

(29 citation statements)

References 45 publications

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“…Sulfa drugs are the oldest chemically synthesized antimicrobial agents, as they still are widely used today for treatment of various bacterial, protozoal, and fungal infections [10]. Sulfonamides have diverse biological activities, including antibacterial activities (by inhibition of dihydropteroate synthase (DHPS), thus inhibiting the biosynthesis of dihydro folic acid) [11], carbonic anhydrase inhibitors (CA) [12], EGFR inhibitors [13,14], insulin-release inducers [15], as well as antiviral [16], antifungal [17], anticancer [18,19], and anti-inflammatory activities [20].…”

Section: Introductionmentioning

confidence: 99%

Sulfaguanidine Hybrid with Some New Pyridine-2-One Derivatives: Design, Synthesis, and Antimicrobial Activity against Multidrug-Resistant Bacteria as Dual DNA Gyrase and DHFR Inhibitors

et al. 2021

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Herein, a series of novel hybrid sulfaguanidine moieties, bearing 2-cyanoacrylamide 2a–d, pyridine-2-one 3–10, and 2-imino-2H-chromene-3-carboxamide 11, 12 derivatives, were synthesized, and their structure confirmed by spectral data and elemental analysis. All the synthesized compounds showed moderate to good antimicrobial activity against eight pathogens. The most promising six derivatives, 2a, 2b, 2d, 3a, 8, and 11, revealed to be best in inhibiting bacterial and fungal growth, thus showing bactericidal and fungicidal activity. These derivatives exhibited moderate to potent inhibition against DNA gyrase and DHFR enzymes, with three derivatives 2d, 3a, and 2a demonstrating inhibition of DNA gyrase, with IC50 values of 18.17–23.87 µM, and of DHFR, with IC50 values of 4.33–5.54 µM; their potency is near to that of the positive controls. Further, the six derivatives exhibited immunomodulatory potential and three derivatives, 2d, 8, and 11, were selected for further study and displayed an increase in spleen and thymus weight and enhanced the activation of CD4+ and CD8+ T lymphocytes. Finally, molecular docking and some AMED studies were performed.

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Section: Introductionmentioning

confidence: 99%

Sulfaguanidine Hybrid with Some New Pyridine-2-One Derivatives: Design, Synthesis, and Antimicrobial Activity against Multidrug-Resistant Bacteria as Dual DNA Gyrase and DHFR Inhibitors

et al. 2021

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“…The second group of compounds included halogenated benzensulfonamides 23-34 that possess higher than ten-fold selectivity for anticancer target CA XII over off-target CA II (Figure 3 -7) and 30 (EA11-7) that were analogues to lead compound 26 (EA12-3). [36] We have measured binding affinities towards all 12 catalytically active CAs (Figure 5, Table S2) and showed that compound 29 (EA12-7) bound all CAs with decreased affinity compared to 26 (EA12-3), but significantly increased selectivity. In our previous study we showed that fluorinated compounds with bulky substituents on benzensulfonamide ring have greater affinity for CA XII than CA II.…”

Section: Ca Xii-selective Compoundsmentioning

confidence: 99%

“…The pK a of the zinc-bound water molecule at 25°C is 7.0-7.1. [33,34] A large body of work has resulted in the deposition of structural data for 24 crystal structures of chlorinated/ fluorinated mono-/di-substituted benzenesulfonamides bound to CA XII complexes [35][36][37][38][39][40][41][42] to the PDB. This forms a valuable resource for CA XII inhibitor design.…”

Section: Introductionmentioning

confidence: 99%

Switching the Inhibitor‐Enzyme Recognition Profile via Chimeric Carbonic Anhydrase XII

et al. 2021

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A key part of the optimization of small molecules in pharmaceutical inhibitor development is to vary the molecular design to enhance complementarity of chemical features of the compound with the positioning of amino acids in the active site of a target enzyme. Typically this involves iterations of synthesis, to modify the compound, and biophysical assay, to assess the outcomes. Selective targeting of the anti‐cancer carbonic anhydrase isoform XII (CA XII), this process is challenging because the overall fold is very similar across the twelve CA isoforms. To enhance drug development for CA XII we used a reverse engineering approach where mutation of the key six amino acids in the active site of human CA XII into the CA II isoform was performed to provide a protein chimera (chCA XII) which is amenable to structure‐based compound optimization. Through determination of structural detail and affinity measurement of the interaction with over 60 compounds we observed that the compounds that bound CA XII more strongly than CA II, switched their preference and bound more strongly to the engineered chimera, chCA XII, based on CA II, but containing the 6 key amino acids from CA XII, behaved as CA XII in its compound recognition profile. The structures of the compounds in the chimeric active site also resembled those determined for complexes with CA XII, hence validating this protein engineering approach in the development of new inhibitors.

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“…CAs, are the metalloenzymes, have a crucial role in many metabolic processes like bone resorption, [ 39 ] calcification, [ 40 ] carboxylation, [ 41 ] photosynthesis, [ 42 ] pH regulation, [ 43 ] respiration, [ 44 ] and ureagenesis, [ 45 ] etc and catalyzing the CO 2 hydration/dehydration biochemical reaction a reversible. [ 46,47 ] Although human CAs belong to the α‐class, they are classified into seven different families [ 48 ] : α‐, β‐, γ‐, δ‐, ζ‐, η‐, and θ‐CA.…”

Section: Introductionmentioning

confidence: 99%

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

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Türkeş

Arslan

et al. 2020

Archiv der Pharmazie

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In this study, 15 novel compounds in a series of sulfonamide-based ketenes (7a-o) were synthesized and characterized using Fourier-transform infrared spectroscopy, nuclear magnetic resonance spectroscopy, and mass spectrometry. All compounds were tested for their ability to inhibit the human carbonic anhydrase (hCA) isoforms I and II, and acetylcholinesterase (AChE). The halogen-appended compounds, 7g, 7o, and 7i, exhibited the highest hCA I/II and AChE inhibition, with the K I values in the low nanomolar range (K I = 9.01 ± 0.08, 7.41 ± 0.03, and 7.37 ± 0.31 nM, respectively), as compared with their corresponding parent 2-[2,2-dicyano-1-(phenylamino) vinylthio]-N-(4-sulfamoylphenyl)acetamide analogs 7a-o. Besides, derivatives 7c and 7e selectively inhibited the isoform hCA I, whereas compounds 7m and 7n selectively inhibited isoform hCA II. These findings indicated that all compounds can inhibit metabolic dysfunctions, such as edema, epilepsy, glaucoma, and Alzheimer's disease, by specifically targeting both the hCA isoforms and AChE expression.Herein, also the interactions between ligands and receptors were highlighted through in silico molecular docking studies. The molecular mechanics-generalized Born surface area method was utilized to compute the binding free energy and the energy contribution of the critical residues in the active site was estimated. All these results would help us to perfectly understand the relationship between activity and structural characteristics of derivatives and to further improve newly and highly effective analogs targeting hCA and AChE.

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Halogenated and di-substituted benzenesulfonamides as selective inhibitors of carbonic anhydrase isoforms

Cited by 13 publications

References 45 publications

Sulfaguanidine Hybrid with Some New Pyridine-2-One Derivatives: Design, Synthesis, and Antimicrobial Activity against Multidrug-Resistant Bacteria as Dual DNA Gyrase and DHFR Inhibitors

Sulfaguanidine Hybrid with Some New Pyridine-2-One Derivatives: Design, Synthesis, and Antimicrobial Activity against Multidrug-Resistant Bacteria as Dual DNA Gyrase and DHFR Inhibitors

Switching the Inhibitor‐Enzyme Recognition Profile via Chimeric Carbonic Anhydrase XII

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

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