Abstract
Four groups of novel sulfonamide derivatives: (i) acetoxybenzamide, (ii) triacetoxybenzamide, (iii) hydroxybenzamide and (iv) trihydroxybenzamide, all having thiazole, pyrimidine, pyridine, isoxazole and thiadiazole moieties were prepared and their inhibitory effects were studied on two metalloenzymes, i.e. carbonic anhydrase isozymes (hCA I and II), purified from human erythrocyte cells by Sepharose-4B-l-tyrosine-sulfanilamide affinity chromatography. These enzymes are present in almost all living organisms to catalyse the synthesis of bicarbonate ion (HCO3−) from carbon dioxide and water. The sulfonamide derivatives were found to be active against hCA I and II in the range of 2.62–136.54 and 5.74–210.58 nM, respectively.
Introduction
Carbonic anhydrases (CAs, EC 4.2.1.1) are zinc-containing metalloenzymes that catalyse the reversible reaction of carbon dioxide and water to produce bicarbonate (HCO3−) and proton (H+)Citation1–5. CAs play crucial pathophysiological roles including pH regulation, CO2 homeostasis and biosynthetic reactions such as gluconeogenesis, respiration, transport of CO2 and HCO3− among metabolizing tissues, lung electrolyte secretion, bone resorption, ureagenesis, lipogenesis, production of biological fluids, tumorigenicity, cell adhesion, proliferation, calcification, and in the growth and virulence of various fungal and bacterial pathogensCitation6–9.
CA appears to be almost ubiquitously expressed in living organisms. Thus far, six genetically distinct CA families are known, including the α-, β-, γ-, δ-, ζ- and η-class enzymesCitation10–13. Currently, there are 16 known human CA isoforms, which differ in their cellular localization and rate of enzymatic activityCitation14. The mammalian enzymes belong to the α-CA family and have different functions, kinetic parameters, inhibitory properties and cell and tissue localizationsCitation14–18. Humans encode 12 catalytically active α-CA isozymes, many of which have been studied both functionally and structurally. These CAs comprise CA I, II, III, IV, VA, VB, VI, VII, IX, XII, XIII and XIVCitation19. CAs I, II, III, VII and XIII are cytosolic isozymesCitation20–23, CAs VA and VB are localized in mitochondriaCitation24,Citation25, CA VI is a unique secreted isozymeCitation25, CAs IX, XII and XIV are transmembrane proteinsCitation26,Citation27, and CAs IV and XV are glycosylphosphatidylinositol-anchored to the cell membraneCitation28.
The CA isozymes have an increasing attention as important targets for designing inhibitors or activators for biomedical applications including treatments of epilepsy, glaucoma, idiopathic intracranial hypertension and altitude sicknessCitation29–31. Sulfonamides (R-SO2NH2) have found widespread applications in design of CA inhibitors as they are among the most important groups for zinc ion (Zn2+) binding and most of the clinically used CA inhibitors contain sulfonamide moietiesCitation32. Since the first evidence of their CA inhibition, their physiological, pharmacological and kinetic properties were largely investigatedCitation32–36. Crystallographic studies of their adducts with several CA isozymes elucidate the key factors responsible for the binding of the sulfonamide moiety to the CA active site and provide a rationale for the unique tailored properties of this anchoring groupCitation32,Citation37,Citation38. Although binding of the sulfonamide derivatives was indicated to be driven by coordination of the deprotonated sulfonamide nitrogen to the catalytic zinc ion (Zn2+), additional interactions with the hydrophilic and/or hydrophobic region of the active site may take place, depending on the nature of the substituent groupCitation32,39–41. These studies demonstrated that sulfonamide is an ideal ligand of the CA active site as it combines the negative charge of the deprotonated nitrogen with the zinc ion, and the presence of a proton on the coordinated nitrogen atom provides Thr199 atom with a strong H-bondCitation32.
Sulfonamides, which are the basis of several groups of drugs, were reported to have significant inhibitory activity against many CA classes. These studies are widely related with inhibition of mammalian isoformsCitation42,Citation43. It was reported that the discovery of isoform-selective CA inhibitors or at least organ-specific targeting inhibitors would represent one of the most important aims of the CA research, which has been very intense recentlyCitation44. However, there are critical barriers need to be addressed on design of CAI as therapeutic agent such as high number of CA isoforms in human body, their rather diffuse localization in many tissues and organs, and lack of isozyme selectivity of the currently available inhibitors of sulfonamide/sulfamatesCitation45,Citation46.
The natural phenolic acids, gallic (3,4,5-trihydroxybenzoic) acid and p-hydroxybenzoic acid, found in many plants and used as preservatives in food, possess antibacterial, anticarcinogenic, antioxidant, antifungal and antimutagenic activities, and cytotoxicity toward tumor cellsCitation47–49. Innocenti et al. showed that p-hydroxybenzoic acid had better inhibition properties on hCA I and hCA II compared with the natural products, polyphenols and phenolic acidsCitation42. Caffeic acid phenethyl ester which is also a polyphenolic compound, was derived from natural products. It possesses a range of biological activitiesCitation50 against such as hCA I, hCA II, hCA IX, hCA XII and comprises potent activities toward HIV-1. Wang et al. showed that designed inhibitors, mimicing caffeic acid phenethyl ester as bearing polyphenols at one side, sulphonamide moieties in the middle and various phenyl groups at the other side can be effective integrase inhibitorsCitation51. The study presented herein targets zinc ion (Zn2+) instead of Mg2+ or Mn2+ and replaced catechol with gallic acid and p-hydroxyphenolic acid. In place of sulfonamide linker and phenyl group, sulfonamide drugs having thiazole, pyrimidine, pyridine, isoxazole and thiadiazole moieties were introduced. Although, it was believed that amine group of sulfonamide should be a primary agent acting as a CA inhibitor, recent studies indicated that secondary and even tertiary sulfonamides can act as affective CA inhibitors and they can be selectiveCitation52–55. In this study, four groups of novel sulfonamide derivatives: (i) acetoxybenzamide, (ii) triacetoxybenzamide (iii) hydroxybenzamide and (iv) trihydroxybenzamide, all having thiazole, pyrimidine, pyridine, isoxazole and thiadiazole moieties are disclosed. In addition to their hydroxyl forms, we decided to investigate their acetylated derivatives since it is a general application in medicinal chemistry to esterify polar hydroxyl groups to convert them into prodrugs to promote physicochemical, biopharmaceutical and pharmacokinetic properties, membrane permeability and oral absorptionCitation56–59. In this study, we focus on inhibition of two metalloenzymes, CA isozymes (hCA I and II), purified from human erythrocyte cells by Sepharose-4B-L-tyrosine-sulphanilamide affinity chromatography.
Methods
Syntheses of the sulfonamide derivatives were conducted starting from 4-hydroxy 1a and 3,4,5-trihydroxy 1b benzoic acids (Scheme 1), which are naturally occurring compounds in many plants and fruitsCitation60–63. Their reaction with acetic anhydride selectively produced 4-acetoxy 2a and 3,4,5-triacetoxy 2b benzoic acids, reactions of which with thionyl chloride yielded the benzoyl chlorides 3a,b. Then, sulfonamides 4, possessing thiazole, pyrimidine, pyridine, isoxazole and thiadiazole moieties, were reacted with the benzoyl chlorides 3a,b to obtain first two classes of sulfonamide derivatives: (i) acetoxybenzamides 5a–h and (ii) triacetoxybenzamides 6a–h. Acid treatment of the first sulfonamide derivatives gave the second two classes of the derivatives 7a–h and 8a–h. Compounds 5gCitation64, 6cCitation65, 8aCitation65, 8cCitation66 and 8hCitation51 are listed in literature but no CA inhibition activity was reported before.
Scheme 1. Synthesis of the compounds.
Chemistry
All starting materials and the reagents were purchased from commercial suppliers. Progress of the reaction was monitored by TLC using silica gel-60 F254 plates with detection by short wave UV fluorescence (λ = 254 nm) and staining with cerium sulphate. Silica gel flash chromatography was performed using silica gel 60 Å (230–400 mesh). 1H and 13C NMR spectra were recorded on a Varian 600 MHz spectrometer at 25 °C. Chemical shifts for 1H and 13C NMR spectra obtained in DMSO-d6 are reported in ppm relative to residual solvent proton (δ = 2.50 ppm) and carbon (δ = 39.52 ppm) signals, respectively. Multiplicity is indicated as follows: s (singlet); d (doublet); t (triplet); m (multiplet). Coupling constants are reported in hertz (Hz). High-resolution mass spectra (HRMS) were recorded on BrukerMicroTOF-Q at positive electro spray ionization (ESI+) mode. 1H and 13C NMR, and HRMS spectra of compounds are provided in Supporting Information. Melting points were determined by Barnstead Electrothermal IA9200. Purities of compounds determined by C, H, N analysis by Thermo Finnigan Flash 1112 EA Series and also by HPLC-UV at 270 nm and >95%.
General procedure for acetylation of hydroxyl substituted benzoic acids 1a,b
To the stirred solution of benzoic acid 1 (20 mmol) in acetic anhydride (120 mmol), few drops of concentrated H2SO4 was addedCitation67. A fast temperature rise was observed and after all the solid was dissolved, the stirring was continued for an hour. Then, water (100 mL) was added and the solution was stirred for further 2.5 h to remove any excess acetic anhydride left. The solid precipitate was filtered, washed with water (2 × 50 mL) and dried on filter by air suction for 10 min and under vacuum for overnight.
p-Acetoxybenzoic acid (2a). White solid, yield 90%. 1H NMR (DMSO-d6, 600 MHz) δ (ppm): 7.99 (d, J = 8.6 Hz, 2H), 7.26 (d, J = 8.6 Hz, 2H), 2.28 (s, 3H).
3,4,5-Triacetoxybenzoic acid (2b). White solid, yield 85%. 1H NMR (DMSO-d6, 600 MHz) δ (ppm): 7.72 (s, 2H), 2.30 (s, 3H), 2.27 (s, 6H).
General procedure for preparation of acyl chlorides 3
A mixture of acetyl protected benzoic acid 2 (20 mmol) and thionyl chloride (300 mmol) was heated at 80 °C for 5 h. Excess of thionyl chloride was then evaporated under reduced pressure at 50 °C. To the residue was added acetone (20 mL) and the solution was used for the next step without further purificationCitation51.
General procedure for preparation of N-(sulfonamide)-acetoxybenzamide (5 and 6)
To a mixture of sulfonamide 4 (20 mmol) and pyridine (20 mmol) in acetone (50 mL) was added dropwise acyl chloride 3 (20 mmol) in acetone (20 mL) with stirring at 0 °C, after which stirring was continued at room temperature for overnightCitation51. Progress of the reaction was monitored by TLC, staining with ceric sulphate. The precipitated products were filtered. Otherwise, the solvent was evaporated under reduced pressure. The crude product was purified by re-crystallization from ethanol or flash column chromatography using ethyl acetate/hexane (1:1) mixture as an eluent.
N-(sulfathiazole)-p-acetoxybenzamide (5a)
Off white powder, yield 58%. m.p. 267–268 °C. 1H NMR (600 MHz, DMSO-d6) δ (ppm): 10.57 (s, 1H), 8.00 (d, J = 8.7 Hz, 2H), 7.93 (d, J = 8.8 Hz, 2H), 7.79 (d, J = 8.8 Hz, 2H), 7.31 (d, J = 8.6 Hz, 2H), 7.25 (d, J = 4.6 Hz, 1H), 6.82 (d, J = 4.6 Hz, 1H), 2.31 (s, 3H). 13C NMR (150 MHz, DMSO-d6) δ (ppm): 169.27, 169.16, 165.61, 153.57, 142.79, 137.21, 132.46, 129.79, 127.23, 124.83, 122.36, 120.18, 108.55, 21.33. HRMS (ESI+): m/z calculated for C18H16N3O5S2 [M + H+]: 418.0526, found 418.0526.
N-(sulfadiazine)-p-acetoxybenzamide (5b)
White powder, yield 55%. m.p. 269–270 °C. 1H NMR (600 MHz, DMSO-d6) δ (ppm): 11.71 (s, 1H), 10.61 (s, 1H), 8.51 (d, J = 4.8 Hz, 2H), 7.98 (m, 6H), 7.31 (d, J = 8.7 Hz, 2H), 7.05 (t, J = 4.8 Hz, 1H), 2.31 (s, 3H). 13C NMR (150 MHz, DMSO-d6) δ (ppm): 169.38, 165.74, 158.79, 157.37, 153.62, 143.55, 134.94, 132.41, 129.82, 129.14, 122.37, 119.95, 116.23, 21.32. HRMS (ESI+): m/z calculated for C19H16N4O5S1Na1 [M + Na+]: 435.0734, found 435.0738.
N-(sulfamethazine)-p-acetoxybenzamide (5c)
Off white powder, yield 62%. m.p. 245–246 °C. 1H NMR (600 MHz, DMSO-d6) δ (ppm): 10.58 (s, 1H), 8.00 (d, J = 8.7 Hz, 2H), 7.98 (d, J = 8.9 Hz, 2H), 7.94 (d, J = 8.9 Hz, 2H), 7.31 (d, J = 8.6 Hz, 2H), 6.77 (s, 1H), 2.31 (s, 3H), 2.26 (s, 6H). 13C NMR (150 MHz, DMSO-d6) δ (ppm): 169.37, 167.72, 165.66, 157.08, 153.29, 132.41, 130.72, 129.79, 129.54, 122.35, 119.60, 114.19, 112.26, 23.54, 21.31. HRMS (ESI+): m/z calculated for C21H21N4O5S1 [M + H+]: 441.1227, found 441.1214.
N-(sulfapyridine)-p-acetoxybenzamide (5d)
White powder, yield 65%. m.p. 259–260 °C. 1H NMR (600 MHz, DMSO-d6) δ (ppm): 10.57 (s, 1H), 8.03 (d, J = 3.6 Hz, 1H), 7.99 (d, J = 8.6 Hz, 2H), 7.92 (d, J = 8.8 Hz, 2H), 7.87 (d, J = 8.7 Hz, 2H), 7.75–7.68 (m, 1H), 7.31 (d, J = 8.6 Hz, 2H), 7.15 (d, J = 8.6 Hz, 1H), 6.88 (t, J = 5.9 Hz, 1H), 2.31 (s, 3H). 13C NMR (150 MHz, DMSO-d6) δ (ppm): 168.94, 165.23, 153.15, 152.96, 142.55, 140.11, 136.07, 132.00, 129.38, 127.64, 126.63, 121.91, 119.75, 115.78, 113.53, 20.88. HRMS (ESI+): m/z calculated for C20H18N3O5S1 [M + H+]: 412.0962, found 412.0963.
N-(sulfisoxazole)-p-acetoxybenzamide (5e)
Off white powder, yield 47%. m.p. 221–222 °C. 1H NMR (600 MHz, DMSO-d6) δ (ppm): 10.68 (s, 1H), 8.02 (d, J = 8.7 Hz, 2H), 8.00 (d, J = 8.9 Hz, 2H), 7.76 (d, J = 8.9 Hz, 2H), 7.32 (d, J = 8.7 Hz, 2H), 2.31 (s, 3H), 2.09 (s, 3H), 1.66 (s, 3H). 13C NMR (150 MHz, DMSO-d6) δ (ppm): 169.39, 165.81, 161.86, 155.94, 153.65, 143.95, 134.53, 132.34, 129.86, 128.20, 122.39, 120.42, 105.58, 21.33, 10.77, 6.33. HRMS (ESI+): m/z calculated for C20H20N3O6S1 [M + H+]: 430.1067, found 430.1066.
N-(sulfamethizole)-p-acetoxybenzamide (5f)
White powder, yield 58%. m.p. 244.5–246 °C. 1H NMR (600 MHz, DMSO-d6) δ (ppm): 10.60 (s, 1H), 8.01 (d, J = 8.7 Hz, 2H), 7.95 (d, J = 8.8 Hz, 2H), 7.78 (d, J = 8.8 Hz, 2H), 7.31 (d, J = 8.7 Hz, 2H), 2.47 (s, 3H), 2.31 (s, 3H). 13C NMR (150 MHz, DMSO-d6) δ (ppm): 169.37, 168.24, 165.65, 154.88, 153.60, 143.11, 136.74, 132.40, 129.80, 127.20, 122.36, 120.30, 21.32, 16.50. HRMS (ESI+): m/z calculated for C18H17N4O5S2 [M + H+]: 433.0635, found 433.0636.
N-(sulfamerazine)-p-acetoxybenzamide (5g)
Off white powder, yield 62%. m.p. 260–261 °C. 1H NMR (600 MHz, DMSO-d6) δ (ppm): 11.61 (s, 1H), 10.60 (s, 1H), 8.33 (d, J = 5.1 Hz, 1H), 8.00 (d, J = 8.6 Hz, 2H), 7.98 (d, J = 9.0 Hz, 2H), 7.95 (d, J = 9.0 Hz, 2H), 7.31 (d, J = 8.6 Hz, 2H), 6.91 (d, J = 5.1 Hz, 1H), 2.33 (s, 3H), 2.31 (s, 3H). 13C NMR (150 MHz, DMSO-d6) δ (ppm): 169.39, 168.80, 165.71, 158.10, 156.98, 153.61, 143.43, 135.12, 132.41, 129.81, 129.34, 122.36, 119.80, 115.28, 23.69, 21.30. HRMS (ESI+): m/z calculated for C19H19N3O8S1 [M + H+]: 449.0887, found 449.0890.
N-(sulfanilamide)-p-acetoxybenzamide (5h)
White powder, yield 55%. m.p. 251–252 °C. 1H NMR (600 MHz, DMSO-d6) δ (ppm): 10.58 (s, 1H), 8.03 (d, J = 8.6 Hz, 2H), 7.95 (d, J = 8.8 Hz, 2H), 7.82 (d, J = 8.8 Hz, 2H), 7.32 (d, J = 8.6 Hz, 2H), 7.28 (s, 2H), 2.32 (s, 3H). 13C NMR (150 MHz, DMSO-d6) δ (ppm): 169.38, 165.61, 153.58, 142.51, 139.20, 132.44, 129.79, 126.96, 122.36, 120.22, 21.32. HRMS (ESI+): m/z calculated for C15H15N2O5S1 [M + H+]: 335.0696, found 335.0694.
N-(sulfathiazole)-3,4,5-triacetoxybenzamide (6a)
Yellowish powder, yield 50%. m.p. 177–178 °C. 1H NMR (600 MHz, DMSO-d6) δ (ppm): 10.63 (s, 1H), 7.90 (d, J = 8.9 Hz, 2H), 7.82 (s, 2H), 7.80 (d, J = 8.8 Hz, 2H), 7.24 (d, J = 4.6 Hz, 1H), 6.82 (d, J = 4.6 Hz, 1H), 2.34 (s, 3H), 2.33 (s, 6H). 13C NMR (150 MHz, DMSO-d6) δ (ppm): 168.77, 167.99, 166.94, 163.50, 143.14, 141.91, 137.55, 137.20, 132.46, 126.81, 124.59, 120.69, 119.95, 108.10, 20.31, 19.87. HRMS (ESI+): m/z calculated for C22H20N3O9S2 [M + H+]: 534.0635, found 534.0641.
N-(sulfadiazine)-3,4,5-triacetoxybenzamide (6b)
Off white powder, yield 40%. m.p. 207–208 °C. 1H NMR (600 MHz, DMSO-d6) δ (ppm): 10.64 (s, 1H), 8.48 (d, J = 4.8 Hz, 2H), 7.95 (d, J = 8.9 Hz, 2H), 7.90 (d, J = 8.9 Hz, 2H), 7.79 (s, 2H), 7.02 (t, J = 4.9 Hz, 1H), 2.31 (s, 3H), 2.29 (s, 6H). 13C NMR (150 MHz, DMSO-d6) δ (ppm): 168.43, 167.37, 164.08, 158.79, 157.33, 143.58, 143.13, 138.03, 135.30, 132.84, 129.13, 121.15, 120.16, 116.23, 20.73, 20.29. HRMS (ESI+): m/z calculated for C23H21N4O9S1 [M + H+]: 529.1024, found 529.1015.
N-(sulfamethazine)-3,4,5-triacetoxybenzamide (6c)
White powder, yield 48%. m.p. 236–238 °C. 1H NMR (600 MHz, DMSO-d6) δ (ppm): 10.64 (s, 1H), 7.99 (d, J = 8.7 Hz, 2H), 7.91 (d, J = 8.8 Hz, 2H), 7.82 (s, 2H), 6.76 (s, 1H), 2.34 (s, 3H), 2.33 (s, 6H), 2.26 (s, 6H). 13C NMR (150 MHz, DMSO-d6) δ (ppm) 169.16, 168.43, 167.38, 164.01, 156.60, 143.58, 142.81, 139.52, 138.01, 135.80, 132.86, 129.55, 121.14, 119.80, 23.27, 21.45, 20.28. HRMS (ESI+): m/z calculated for C25H25N4O9S1 [M + H+]: 557.1337, found 557.1336.
N-(sulfapyridine)-3,4,5-triacetoxybenzamide (6d)
White powder, yield 62%. m.p. 213–214 °C. 1H NMR (600 MHz, DMSO-d6) δ (ppm): 10.61 (s, 1H), 8.00 (s, 1H), 7.90–7.82 (m, 4H), 7.79 (s, 2H), 7.70 (t, J = 8.0 Hz, 1H), 7.13 (d, J = 8.6 Hz, 1H), 6.85 (t, J = 6.3 Hz, 1H), 2.32 (s, 3H), 2.30 (s, 6H). 13C NMR (150 MHz, DMSO-d6) δ (ppm): 168.44, 167.38, 164.01, 153.47, 143.89, 143.58, 142.53, 140.66, 138.00, 136.94, 132.89, 128.07, 121.13, 120.38, 116.14, 114.04, 20.73, 20.28. HRMS (ESI+): m/z calculated for C24H22N3O9S1 [M + H+]: 528.1071, found 528.1068.
N-(sulfisoxazole)-3,4,5-triacetoxybenzamide (6e)
White powder, yield 54%. m.p. 147–148 °C. 1H NMR (600 MHz, DMSO-d6) δ (ppm): 10.72 (s, 1H), 7.95 (d, J = 8.8 Hz, 2H), 7.82 (s, 2H), 7.75 (d, J = 8.8 Hz, 2H), 2.33 (s, 3H), 2.31 (s, 6H), 2.07 (s, 3H), 1.63 (s, 3H). 13C NMR (150 MHz, DMSO-d6) δ (ppm): 168.02, 166.96, 163.74, 161.43, 155.51, 143.17, 143.13, 137.65, 134.48, 132.38, 127.80, 120.79, 120.21, 105.14, 20.33, 19.89, 10.35, 5.90. HRMS (ESI+): m/z calculated for C24H23N3O10S1Na [M + Na+]: 568.0996, found 568.0997.
N-(sulfamethizole)-3,4,5-triacetoxybenzamide (6f)
Yellowish powder, yield 40%. m.p. 225–226 °C. 1H NMR (600 MHz, DMSO-d6) δ (ppm): 10.68 (s, 1H), 7.94 (d, J = 8.7 Hz, 2H), 7.84 (s, 2H), 7.80 (d, J = 8.7 Hz, 2H), 2.47 (s, 3H), 2.35 (s, 3H), 2.33 (s, 6H). 13C NMR (150 MHz, DMSO-d6) δ (ppm): 167.83 (d, J = 22.4 Hz), 167.75–167.27 (m), 166.84 (s), 163.46 (s), 154.39 (s), 143.06 (s), 142.19 (s), 137.49 (s), 136.56 (s), 132.30 (s), 126.69 (s), 120.63 (s), 120.01 (s), 20.21 (s), 19.77 (s), 15.97 (s). HRMS (ESI+): m/z calculated for C22H20N4O9S2Na [M + Na+]: 571.0564, found 571.0564.
N-(sulfamerazine)-3,4,5-triacetoxybenzamide (6g)
Yellowish powder, yield 42%. m.p. 234–236 °C. 1H NMR (DMSO-d6, 600 MHz) δ (ppm): 10.66 (s, 1H), 8.33 (d, J = 5.1 Hz, 1H), 7.99 (d, J = 8.9 Hz, 2H), 7.93 (d, J = 8.9 Hz, 2H), 7.82 (s, 2H), 6.91 (d, J = 5.1 Hz, 1H), 2.34 (s, 3H), 2.33 (s, 6H), 2.32 (s, 3H). 13C NMR (150 MHz, DMSO-d6) δ (ppm): 168.26, 168.00, 166.95, 163.63, 157.53, 156.56, 143.17, 142.61, 137.61, 135.08, 132.45, 128.93, 120.75, 119.58, 114.85, 23.25, 20.31, 19.87. HRMS (ESI+): m/z calculated for C24H23N4O9S1 [M + H+]: 543.1180, found 543.1180.
N-(sulfanilamide)-3,4,5-triacetoxybenzamide (6h)
White powder, yield 54%. m.p. 222–223 °C. 1H NMR (DMSO-d6, 600 MHz) δ (ppm): 10.61 (s, 1H), 7.89 (d, J = 8.8 Hz, 2H), 7.81 (s, 2H), 7.79 (d, J = 8.8 Hz, 2H), 7.26 (s, 2H), 2.32 (s, 3H), 2.30 (s, 6H). 13C NMR (150 MHz, DMSO-d6) δ (ppm): 168.02, 166.96, 163.53, 143.17, 141.69, 139.09, 137.57, 132.45, 126.57, 120.71, 120.02, 20.33, 19.88. HRMS (ESI+): m/z calculated for C19H18N2O9S1Na [M + Na+]: 473.0625, found 473.0625.
General procedure for N-(sulfonamide)- hydroxybenzamide (7 and 8)
N-(sulfonamide)-acetoxybenzamide 5 or 6 (1 g) was added to a solution of tetrahydrofuran (10 mL), methanol (10 mL) and concentrated hydrochloric acid (5 mL)Citation53. The mixture stirred at 60 °C for one hour. The solvent was evaporated under reduced pressure and the crude product was purified by re-crystallization from ethanol or by flash column chromatography using ethyl acetate/hexane (1:1).
N-(sulfathiazole)-p-hydroxybenzamide (7a)
Off white powder, yield 48%. m.p. 293–294 °C. 1H NMR (600 MHz, DMSO-d6) δ (ppm): 12.68 (s, 1H), 10.28 (s, 1H), 10.16 (s, 1H), 7.91 (d, J = 8.8 Hz, 2H), 7.86 (d, J = 8.7 Hz, 2H), 7.76 (d, J = 8.8 Hz, 2H), 7.24 (d, J = 4.6 Hz, 1H), 6.87 (d, J = 8.7 Hz, 2H), 6.81 (d, J = 4.6 Hz, 1H). 13C NMR (150 MHz, DMSO-d6) δ (ppm): 169.16, 165.85, 161.30, 143.19, 136.75, 130.35, 127.15, 125.33, 124.77, 120.02, 115.42, 108.48. HRMS (ESI+): m/z calculated for C16H14N3O4S2 [M + H+]: 376.0420, found 376.0419.
N-(sulfadiazine)-p-hydroxybenzamide (7b)
White powder, yield 44%. m.p. 298–299 °C. 1H NMR (600 MHz, DMSO-d6) δ (ppm): 10.33 (s, 1H), 8.51 (d, J = 4.9 Hz, 2H), 7.94 (s, 4H), 7.85 (d, J = 8.7 Hz, 2H), 7.04 (t, J = 4.9 Hz, 1H), 6.87 (d, J = 8.7 Hz, 2H). 13C NMR (150 MHz, DMSO-d6) δ (ppm): 165.96, 161.37, 158.77, 157.38, 143.96, 134.42, 130.39, 129.05, 125.24, 119.79, 116.21, 115.43. HRMS (ESI+): m/z calculated for C17H15N4O4S1 [M + H+]: 371.0809, found 371.0817.
N-(sulfamethazine)-p-hydroxybenzamide (7c)
Off white powder, yield 48%. m.p. 162–163 °C. 1H NMR (600 MHz, DMSO-d6) δ (ppm): 10.31 (s, 1H), 10.17 (s, 1H), 7.95 (q, J = 9.0 Hz, 4H), 7.87 (d, J = 8.7 Hz, 2H), 6.88 (d, J = 8.7 Hz, 2H), 6.76 (s, 1H), 2.26 (s, 6H). 13C NMR (150 MHz, DMSO-d6) δ (ppm): 167.79, 165.90, 161.34, 156.67, 143.66, 134.84, 130.36, 129.46, 125.25, 119.45, 115.42, 114.01, 23.33. HRMS (ESI+): m/z calculated for C19H19N4O4S1 [M + H+]: 399.1122, found 399.1123.
N-(sulfapyridine)-p-hydroxybenzamide (7d)
White powder, yield 50%. m.p. 282–283 °C. 1H NMR (600 MHz, DMSO-d6) δ (ppm): 10.29 (s, 1H), 8.03 (s, 1H), 7.91 (d, J = 8.7 Hz, 2H), 7.84 (two doublets, 4H), 7.71 (d, 1H), 7.14 (d, J = 8.5 Hz, 1H), 6.87 (3H). 13C NMR (150 MHz, DMSO-d6) δ (ppm): 165.45, 160.93, 152.85, 143.94, 142.98, 140.02, 135.45, 129.91, 127.54, 124.76, 119.57, 115.42, 114.96, 113.43. HRMS (ESI+): m/z calculated for C18H16N3O4S1 [M + H+]: 370.0856, found 370.0856.
N-(sulfisoxazole)-p-hydroxybenzamide (7e)
Off white powder, yield 41%. m.p. 235–236 °C. 1H NMR (600 MHz, DMSO-d6) δ (ppm): 10.92 (s, 1H), 10.39 (s, 1H), 10.19 (s, 1H), 7.99 (d, J = 8.8 Hz, 2H), 7.87 (d, J = 8.6 Hz, 2H), 7.73 (d, J = 8.8 Hz, 2H), 6.88 (d, J = 8.6 Hz, 2H), 2.09 (s, 3H), 1.65 (s, 3H). 13C NMR (150 MHz, DMSO-d6) δ (ppm): 166.02, 161.84, 161.42, 156.01, 144.37, 134.05, 130.44, 128.12, 125.19, 120.25, 115.46, 105.52, 10.77, 6.32. HRMS (ESI+): m/z calculated for C18H17N3O5S1Na [M + Na+]: 410.0781, found 410.0781.
N-(sulfamethizole)-p-hydroxybenzamide (7f)
Off white powder, yield 39%. m.p. 272–273 °C. 1H NMR (600 MHz, DMSO-d6) δ (ppm): 10.29 (s, 1H), 10.14 (s, 1H), 7.91 (d, J = 8.9 Hz, 2H), 7.84 (d, J = 8.7 Hz, 2H), 7.73 (d, J = 8.8 Hz, 2H), 6.85 (d, J = 8.7 Hz, 2H), 2.45 (s, 3H). 13C NMR (150 MHz, DMSO-d6) δ (ppm): 168.20, 165.89, 161.34, 154.85, 143.54, 136.26, 130.38, 127.13, 125.27, 120.14, 115.43, 16.51. HRMS (ESI+): m/z calculated for C16H15N4O4S2 [M + H+]: 391.0529, found 391.0530.
N-(sulfamerazine)-p-hydroxybenzamide (7g)
Off white powder, yield 50%. m.p. 271–272 °C. 1H NMR (600 MHz, DMSO-d6) δ (ppm): 10.36 (s, 1H), 8.33 (d, J = 5.1 Hz, 1H), 7.95 (s, 4H), 7.89–7.86 (m, 2H), 6.91 (d, J = 5.2 Hz, 1H), 6.90–6.87 (m, 2H), 2.32 (s, 3H). 13C NMR (150 MHz, DMSO-d6) δ (ppm): 168.65, 165.93, 161.40, 157.96, 157.00, 143.86, 134.56, 130.38, 129.22, 125.17, 119.65, 115.44, 115.35, 23.70. HRMS (ESI+): m/z calculated for C18H17N4O4S1 [M + H+]: 385.0965, found 385.0965.
N-(sulfanilamide)-p-hydroxybenzamide (7h)
White powder, yield 47%. m.p. 308–309 °C. 1H NMR (600 MHz, DMSO-d6) δ (ppm): 10.30 (s, 1H), 10.18 (s, 1H), 7.95 (d, J = 8.9 Hz, 2H), 7.89 (d, J = 8.7 Hz, 2H), 7.80 (d, J = 8.8 Hz, 2H), 7.26 (s, 2H), 6.89 (d, J = 8.7 Hz, 2H). 13C NMR (150 MHz, DMSO-d6) δ (ppm): 165.52, 160.93, 142.56, 138.34, 129.99, 126.54, 124.96, 119.73, 115.08. HRMS (ESI+): m/z calculated for C13H13N2O4S1 [M + H+]: 293.0591, found 293.0594.
N-(sulfathiazole)-3,4,5-trihydroxybenzamide (8a)
Off white powder, yield 50%. m.p. 289–290 °C. 1H NMR (600 MHz, DMSO-d6) δ (ppm): 10.19 (s, 1H), 7.88 (d, J = 8.8 Hz, 2H), 7.72 (d, J = 8.8 Hz, 2H), 7.22 (d, J = 4.6 Hz, 1H), 6.94 (s, 2H), 6.79 (d, J = 4.6 Hz, 1H). 13C NMR (150 MHz, DMSO-d6) δ (ppm): 169.07, 166.31, 145.96, 143.30, 137.59, 136.54, 127.09, 124.84, 124,87, 119.95, 108.50, 107.85. HRMS (ESI+): m/z calculated for C16H14N3O6S2 [M + H+]: 408.0319, found 408.0315.
N-(sulfadiazine)-3,4,5-trihydroxybenzamide (8b)
Off white powder, yield 43%. m.p. 244–245 °C. 1H NMR (600 MHz, DMSO-d6) δ (ppm): 10.26 (s, 1H), 8.50 (d, J = 4.9 Hz, 2H), 7.96–7.89 (m, 4H), 7.04 (t, J = 4.9 Hz, 1H), 6.96 (s, 2H). 13C NMR (150 MHz, DMSO-d6) δ (ppm): 166.41, 158.77, 157.36, 145.97, 144.06, 137.67, 134.25, 128.98, 124.77, 119.72, 116.21, 107.89. HRMS (ESI+): m/z calculated for C17H15N4O6S1 [M + H+]: 403.0707, found 403.0707.
N-(sulfamethazine)-3,4,5-trihydroxybenzamide (8c)
Off white powder, yield 35%. m.p. 270.5–271.5 °C. 1H NMR (600 MHz, DMSO-d6) δ (ppm): 10.23 (s, 1H), 7.96–7.89 (m, 4H), 6.96 (s, 2H), 6.75 (s, 1H), 2.25 (s, 6H). 13C NMR (150 MHz, DMSO-d6) δ (ppm): 167.47, 166.02, 156.29, 145.63, 143.43, 137.30, 134.30, 129.07, 124.45, 119.03, 113.68, 107.52, 22.99. HRMS (ESI+): m/z calculated for C19H19N4O6S1 [M + H+]: 431.1020, found 431.1026.
N-(sulfapyridine)-3,4,5-trihydroxybenzamide (8d)
White powder, yield 48%. m.p. 268–269 °C. 1H NMR (600 MHz, DMSO-d6) δ (ppm): 10.21 (s, 1H), 8.04 (d, J = 4.5 Hz, 1H), 7.92–7.88 (m, 2H), 7.85–7.80 (m, 2H), 7.71 (ddd, J = 8.9, 7.3, 1.9 Hz, 1H), 7.15 (d, J = 8.6 Hz, 1H), 6.96 (s, 2H), 6.91–6.86 (m, 1H). 13C NMR (150 MHz, DMSO-d6) δ (ppm): 166.35, 153.26, 145.97, 143.53, 140.47, 137.63, 135.73, 129.22, 127.98, 124.83, 119.92, 116.40, 113.86, 107.83. HRMS (ESI+): m/z calculated for C18H16N3O6S1 [M + H+]: 402.0754, found 402.0754.
N-(sulfisoxazole)-3,4,5-triacetoxybenzamide (8e)
White powder, yield 57%. m.p. 252–253 °C. 1H NMR (600 MHz, DMSO-d6) δ (ppm): 10.93 (s, 1H), 10.32 (s, 1H), 7.98 (d, J = 8.9 Hz, 2H), 7.71 (d, J = 8.9 Hz, 2H), 6.99 (s, 2H), 2.09 (s, 3H), 1.66 (s, 3H). 13C NMR (150 MHz, DMSO-d6) δ (ppm): 166.45, 161.84, 156.01, 145.98, 144.48, 137.75, 133.90, 128.07, 124.68, 120.15, 107.85, 105.49, 10.77, 6.32. HRMS (ESI+): m/z calculated for C18H17N3O7S1Na [M + Na+]: 442.0679, found 442.0675.
N-(sulfamethizole)-3,4,5-trihydroxybenzamide (8f)
Off white powder, yield 62%. m.p. 177–178 °C. 1H NMR (600 MHz, DMSO-d6) δ (ppm): 10.23 (s, 1H), 7.92 (d, J = 8.9 Hz, 2H), 7.73 (d, J = 8.9 Hz, 2H), 6.96 (s, 2H), 2.46 (s, 3H). 13C NMR (150 MHz, DMSO-d6) δ (ppm): 167.82, 165.98, 154.49, 145.57, 143.26, 137.27, 135.69, 126.71, 124.40, 119.69, 107.41, 16.13. HRMS (ESI+): m/z calculated for C16H14N4O6S2Na [M + Na+]: 445.0247, found 445.0249.
N-(sulfamerazine)-3,4,5-trihydroxybenzamide (8g)
White powder, yield 54%. m.p. 214–215 °C. 1H NMR (600 MHz, DMSO-d6) δ 8 ppm): 10.24 (s, 1H), 8.31 (d, J = 5.1 Hz, 1H), 7.92 (s, 4H), 6.97 (s, 2H), 6.89 (d, J = 5.2 Hz, 1H), 2.31 (s, 3H). 13C NMR (150 MHz, DMSO-d6) δ (ppm): 168.39, 166.09, 157.63, 156.66, 145.67, 143.63, 137.36, 134.09, 128.89, 124.46, 119.28, 114.99, 107.58, 23.40. HRMS (ESI+): m/z calculated for C18H17N4O6S1 [M + H+]: 417.0863, found 417.0862.
N-(sulfanilamide)-3,4,5-trihydroxybenzamide (8h)
White powder, yield 40%. m.p. 307–308 °C. 1H NMR (600 MHz, DMSO-d6) δ (ppm): 10.22 (s, 1H), 7.93 (d, J = 8.8 Hz, 2H), 7.77 (d, J = 8.8 Hz, 2H), 7.25 (s, 2H), 6.99 (s, 2H). 13C NMR (150 MHz, DMSO-d6) δ (ppm): 166.00, 145.63, 142.69, 138.22, 137.27, 126.52, 124.53, 119.66, 107.48. HRMS (ESI+): m/z calculated for C13H13N2O6S1 [M + H+]: 325.0489, found 325.0477.
Carbonic anhydrase inhibition
CA isozymes (hCA I and II) were purified by Sepharose-4B-L-tyrosine-sulfanilamide affinity chromatography in a single purification step2. The column material, Sepharose-4B-L-tyrosine-sulfanilamide, was prepared according to a reported methodCitation22,Citation25. Thus, pH of the solution was adjusted to 8.7, using solid Tris. Subsequently, the supernatant was transferred to the previously prepared Sepharose-4B-L-tyrosine-sulfanilamide affinity columnCitation68. The proteins from the column were spectrophotometrically determined at 280 nm. For determination of the purity of the isozymes, sodium dodecyl sulphate-polyacrylamide gel electrophoresis (SDS-PAGE), having 10% and 3% acrylamide as an eluent and packing gel, respectively, with 0.1% SDS, was performed, through which a single band was observed for each isozyme.
CA isozyme activities were determined following to the methods described by Verpoorte et al.Citation69 and the methods reported previously. Absorbance change at 348 nm from p-nitrophenylacetate (NPA) to p-nitrophenolate (NP) was recorded by 3 min intervals at the room temperature (25 °C) using a spectrophotometer (Shimadzu, UV-VIS Spectrophotometer, UVmini-1240, Kyoto, Japan). Quantity of the protein was measured spectrophotometrically at 595 nm during the purification steps according to the Bradford method. As reported previously, bovine serum albumin (BSA) was used as a standard proteinCitation14. An activity (%)–[Sulfonamide] graph was depicted to determine the inhibition effect of each sulfonamide derivative. For Ki values, three different sulfonamide derivatives were tested. NPA was used as a substrate at five different concentrations and Lineweaver–Burk curves were drawn as described previouselyCitation11.
Results and discussion
The isozymes CA I and CA II, examined in this study, have different activities. In mammals, CA II, which generally exists in red blood cells in lower concentrations, has approximately 10 times higher activity compared with CA I30. Cytosolic isozyme hCA I is ubiquitously expressed in body and available in high concentrations in blood and gastrointestinal tract. As it was demonstrated that this isozyme is involved in retinal and cerebral edema, its inhibition could be a valuable tool for fighting the condition. It is generally accepted that if Ki value of a tested compound is less than 50 μM (Ki >50 μM), that compound is considered to be inactive against hCA I55. The results presented in indicate that the new sulfonamide derivatives had effective inhibition profile against slow cytosolic isoform hCA I, and cytosolic dominant rapid isozymes hCA II. The cytosolic isozyme hCA I was inhibited by all the synthesized sulfonamide derivatives in nanomolar level, the Ki of which varied between 2.62 ± 0.05 and 136.54 ± 24.21 nM. On the other hand, acetazolamide (AZA), considered being a broad-specificity CA inhibitor owing to its widespread inhibition of CAs, showed Ki value of 19.92 ± 0.16 nM against hCA I. Among the inhibitors, sulfonamide derivative 7d (N-(sulfapyridine)-p-hydroxybenzamide) was found to be the best hCA I inhibitor with Ki of 2.62 ± 0.05 nM. The inhibition effects of the sulfonamide derivatives (6a–8h) were found to be the same or lower than that of acetazolamide. Comparison of hydroxyl groups with their acetylated derivatives, in terms of hCA I inhibition, no clear trend was observed. Compound 5c showed the best hCA I inhibition selectivity over hCA II inhibition.
Table 1. IC50, Ki and the selectivity values of the compounds.
The cytosolic hCA II is not only a very effective catalyst for interconversion between CO2 and HCO3−, it also shows some catalytic versatility, participating in several other hydrolytic processes, which presumably involve nonphysiological substratesCitation32,Citation70,Citation71. Against the physiologically dominant isoform hCA II, sulfonamide derivatives showed Kis varying from 5.74 ± 1.17 to 210.58 ± 75.36 nM (), among which the compound 6c, (N-(sulfamethazine)-3,4,5-triacetoxybenzamide), was the best hCA II inhibitor (Ki: 5.74 ± 1.17 nM). Thus, the new sulfonamide derivatives (6a–8h) had high inhibition affinity toward hCA II. On the other hand, AZA, which may interact with the distinct hydrophobic and hydrophilic halves of the CA II active site, showed Ki of 9.76 ± 0.03 nM. Comparison of hydroxyl groups with their acetylated derivatives, in terms of hCA II inhibition, generally acetylated groups showed better hCA II inhibition activity. Compound 6c showed the best hCA II inhibition selectivity over hCA I inhibition.
Conclusions
Four groups of sulfonamide derivatives, having thiazole, pyrimidine, pyridine, isoxazole and thiadiazole, groups, were synthesized and their inhibition activities toward hCA I and II isozymes purified from human erythrocyte cells by affinity chromatography were evaluated, which indicated that they are sufficiently active compared to clinically used drug AZA (acetazolamide). The most active inhibitors in the both series were found to be the compound 7d (N-(sulfapyridine)-p-hydroxybenzamide), which had Ki value of 2.62 ± 0.05 nM for hCA I, and compound 6c (N-(sulfamethazine)-3,4,5-triacetoxybenzamide) with Ki value of 5.74 ± 1.17 nM for hCA II. Although almost all the synthesized sulfonamides showed good inhibition activities compared with the used standard, AZA (acetazolamide), as a structure–activity relationship (SAR) there is no clear cut evidence on the individual effects of the introduced groups on the activities of the sulfonamides.
Declaration of interest
The authors have declared no conflict of interest.
Supplementary material available online
IENZ_1198900_Supplementary_Material.pdf
Download PDF (2.4 MB)Acknowledgements
We thank Prof. Ramazan Altundas of Ataturk University for his useful discussions, F. Melike Al of University of Applied Sciences (BeuthHS) for her support for the synthetic studies, Dr. Meryem Topal for carbonic anhydrase inhibition activity studies, Dr. Ilker Un and Muhiddin Cergel for NMR spectrums and Gokhan Bilsel for HRMS spectrums.
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