Synthesis and Inhibition Activity Study of Triazinyl-Substituted Amino(alkyl)-benzenesulfonamide Conjugates with Polar and Hydrophobic Amino Acids as Inhibitors of Human Carbonic Anhydrases I, II, IV, IX, and XII
Abstract
:1. Introduction
2. Results
2.1. Chemistry
2.2. hCA Inhibition Studies
2.3. Molecular Modelling
3. Materials and Methods
3.1. Materials and Instruments in the Synthetic, Purification and Analysis Methods
3.2. Synthetic Procedures and Pure Products Characterization
3.2.1. Methods for the Synthesis of 4-[((4′,6′-Dichloro-1′,3′,5′-triazine-2′-yl)amino)methyl/-2-amino)ethyl]benzenesulfonamide Derivatives 11–24
3.2.2. Pure Products Characterization
3.3. hCA Inhibition Assay
3.4. Molecular Docking
4. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
Abbreviations
AA | amino acid |
DAD | diode-array detector |
hCA | human carbonic anhydrase |
hCAi | human carbonic anhydrase inhibitors |
HILIC | hydrophilic interactions liquid chromatography |
HPLC | high performance liquid chromatography |
IR | infrared (spectroscopy) |
MP | mobile phase |
MS | mass spectrometry |
NMR | nuclear magnetic resonance |
Q-TOF | quadrupole–time-of-flight |
RP | reverse phase |
TEA | triethylamine |
T-SA | 1,3,5-triazinyl-aminobenzenesulfonamide derivative |
T-MSA | 1,3,5-triazinyl-aminomethylbenzenesulfonamide derivative |
T-ESA | 1,3,5-triazinyl-aminoethylbenzenesulfonamide derivative |
References
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Product (Mr in g/mol) | Reaction Conditions | Main Impurities in Crude Products before Purification (HPLC-DAD/MS) | Desired Products after Purification | |
---|---|---|---|---|
Yield [%] | Purity [%] | |||
4 T-SA-Ala2 (425.42) | A (reflux, 20 h) | OH + AA 1.2%; 438.0669 6.8% | 91.8 | 99.6 |
5 T-SA-Tyr2 (609.61) | C (reflux, 24 h) | OH + AA 32.2%; OH + OH 2.7% | 29.0 | 98.2 |
6 T-SA-Trp2 (655.68) | A (reflux, 24 h) | OH + AA 1.8%; Trp 1.6% | 87.2 | 98.4 |
7 T-SA-Ser2 (457.42) | B (reflux, 7 h) | OH + AA 2.3% | 71.0 | 98.1 |
8 T-SA-Thr2 (485.47) | B (reflux, 7 h) | OH + AA 1.4% | 87.2 | 99.3 |
9 T-SA-Asn2 (511.47) | B (reflux, 12 h) | OH + AA 0.4%; OH + OH 1.3% | 56.0 | 98.1 |
10 T-SA-Gln2 (539.52) | B (reflux, 12 h) | OH + AA 9.4%; AA + Cl 4.9% | 28.4 | 98.0 |
11 T-MSA-Ala2 (439.45) | A (reflux, 24 h) | OH + AA 1.1%; OH + OH 0.8% | 65.3 | 98.4 |
12 T-MSA-Tyr2 (623.64) | C (reflux, 22 h) | OH + AA 12.8%; OH + OH 2.3% | 31.3 | 97.0 |
13 T-MSA-Trp2 (669.71) | A (reflux, 24 h) | OH + OH 2.8% | 73.8 | 97.0 |
14 T-MSA-Ser2 (471.45) | B (reflux, 7 h) | OH + AA 1%; OH + OH 1% | 72.8 | 98.5 |
15 T-MSA-Thr2 (499.50) | B (reflux, 7 h) | OH + AA 5.4% | 59.8 | 98.9 |
16 T-MSA-Asn2 (525.50) | B (reflux, 7 h) | OH + AA 1.7%; OH + OH 1% | 76.5 | 98.1 |
17 T-MSA-Gln2 (553.55) | B (reflux, 8 h) | OH + AA 31.1%; OH + OH 1.8% | 31.6 | 97.9 |
18 T-ESA-Ala2 (453.47) | A (reflux, 24 h) | OH + AA 2.7% | 82.2 | 98.5 |
19 T-ESA-Tyr2 (637.66) | C (reflux, 22 h) | OH + AA 3.3%; OH + OH 1% | 20.6 | 97.8 |
20 T-ESA-Trp2 (683.74) | A (reflux, 24 h) | OH + OH 1% | 76.9 | 98.4 |
21 T-ESA-Ser2 (485.47) | B (reflux, 7 h) | OH + AA 1.3% | 72.9 | 97.5 |
22 T-ESA-Thr2 (513.53) | B (reflux, 7 h) | OH + AA 5.1% | 60.5 | 97.7 |
23 T-ESA-Asn2 (539.52) | B (reflux, 7 h) | OH + AA 5.1%; OH + OH 7.1% | 63.2 | 98.0 |
24 T-ESA-Gln2 (567.58) | B (reflux, 8 h) | OH + AA 43.2%; OH + OH 1.2% | 29.8 | 97.1 |
Ki (nM) | Selectivity | ||||||
---|---|---|---|---|---|---|---|
Product | hCA I | hCA II | hCA IV | hCA IX | hCA XII | II/IX | II/XII |
4 T-SA-Ala2 | 5545 | 782 | 88.1 | 515 | 8.88 | 1.52 | 88.10 |
5 T-SA-Tyr2 | 98.3 | 3.61 | 74.6 | 57.8 | 9.41 | 0.06 | 0.40 |
6 T-SA-Trp2 | 48.3 | 1.61 | 59.3 | 45.2 | 8.21 | 0.04 | 0.20 |
7 T-SA-Ser2 | 6562 | 523 | 8698 | 465 | 71.9 | 1.12 | 7.30 |
8 T-SA-Thr2 | 7273 | 904 | 4907 | 867 | 34.6 | 1.04 | 26.10 |
9 T-SA-Asn2 | >10,000 | 656 | 5328 | 895 | 38.4 | 0.73 | 17.10 |
10 T-SA-Gln2 | 9200 | 775 | 8411 | 625 | 68.3 | 1.24 | 11.30 |
11 T-MSA-Ala2 | 636 | 182 | 470 | 63.5 | 9.3 | 2.87 | 19.60 |
12 T-MSA-Tyr2 | 75.7 | 53.1 | 244 | 87.3 | 8.7 | 0.61 | 6.10 |
13 T-MSA-Trp2 | 30.5 | 6.22 | 93.6 | 66.4 | 8.6 | 0.09 | 0.70 |
14 T-MSA-Ser2 | 653 | 252 | 6098 | 263 | 81.5 | 0.96 | 3.10 |
15 T-MSA-Thr2 | 684 | 76.6 | >10,000 | 365 | 44.9 | 0.21 | 1.70 |
16 T-MSA-Asn2 | 834 | 251 | >10,000 | 95.3 | 44.0 | 2.63 | 5.70 |
17 T-MSA-Gln2 | 695 | 239 | >10,000 | 458 | 34.3 | 0.52 | 7.00 |
18 T-ESA-Ala2 | 787 | 169 | 3861 | 78.8 | 8.9 | 2.14 | 19.00 |
19 T-ESA-Tyr2 | 60.8 | 12.8 | 879 | 61.1 | 7.5 | 0.21 | 1.70 |
20 T-ESA-Trp2 | 41.4 | 3.54 | 542 | 308 | 8.4 | 0.01 | 0.40 |
21 T-ESA-Ser2 | 819 | 273 | >10,000 | 85.5 | 27.1 | 3.19 | 10.10 |
22 T-ESA-Thr2 | 829 | 259 | >10,000 | 89.5 | 62.7 | 2.89 | 4.10 |
23 T-ESA-Asn2 | 886 | 136 | >10,000 | 377 | 53.1 | 0.36 | 2.60 |
24 T-ESA-Gln2 | 684 | 191 | >10,000 | 480 | 57.0 | 0.40 | 3.40 |
Product | c (Mobile Phase A) [mmol/L] | Mobile Phase B | Flow Rate [mL/min] | Injected Volume [μL] |
---|---|---|---|---|
11 T-MSA-Ala2 | 100 | MeOH 10% | 20 | 1000 |
12 T-MSA-Tyr2 | 50 | MeOH 22.5% | 20 | 2500 |
13 T-MSA-Trp2 | 100 | MeOH 37% | 22.5 | 2000 |
14 T-MSA-Ser2 | 50 | MeOH 5% | 25 | 2000 |
15 T-MSA-Thr2 | 100 | MeOH 7.5% | 25 | 1000 |
16 T-MSA-Asn2 | 100 | MeOH 5% | 20 | 2500 |
17 T-MSA-Gln2 | 100 | MeCN 4% | 20 | 1000 |
18 T-ESA-Ala2 | 100 | MeOH 12.5% | 20 | 1000 |
19 T-ESA-Tyr2 | 50 | MeOH 25% | 20 | 2500 |
20 T-ESA-Trp2 | 100 | MeOH 40% | 20 | 2500 |
21 T-ESA-Ser2 | 50 | MeOH 5% | 25 | 2500 |
22 T-ESA-Thr2 | 100 | MeOH 12.5% | 15 | 1000 |
23 T-ESA-Asn2 | 50 | MeOH 5% | 25 | 2500 |
24 T-ESA-Gln2 | 50 | MeCN 5% | 20 | 2000 |
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Mikulová, M.B.; Kružlicová, D.; Pecher, D.; Petreni, A.; Supuran, C.T.; Mikuš, P. Synthesis and Inhibition Activity Study of Triazinyl-Substituted Amino(alkyl)-benzenesulfonamide Conjugates with Polar and Hydrophobic Amino Acids as Inhibitors of Human Carbonic Anhydrases I, II, IV, IX, and XII. Int. J. Mol. Sci. 2021, 22, 11283. https://doi.org/10.3390/ijms222011283
Mikulová MB, Kružlicová D, Pecher D, Petreni A, Supuran CT, Mikuš P. Synthesis and Inhibition Activity Study of Triazinyl-Substituted Amino(alkyl)-benzenesulfonamide Conjugates with Polar and Hydrophobic Amino Acids as Inhibitors of Human Carbonic Anhydrases I, II, IV, IX, and XII. International Journal of Molecular Sciences. 2021; 22(20):11283. https://doi.org/10.3390/ijms222011283
Chicago/Turabian StyleMikulová, Mária Bodnár, Dáša Kružlicová, Daniel Pecher, Andrea Petreni, Claudiu T. Supuran, and Peter Mikuš. 2021. "Synthesis and Inhibition Activity Study of Triazinyl-Substituted Amino(alkyl)-benzenesulfonamide Conjugates with Polar and Hydrophobic Amino Acids as Inhibitors of Human Carbonic Anhydrases I, II, IV, IX, and XII" International Journal of Molecular Sciences 22, no. 20: 11283. https://doi.org/10.3390/ijms222011283