Next Article in Journal
Halogen Bonds Formed between Substituted Imidazoliums and N Bases of Varying N-Hybridization
Previous Article in Journal
N-(4-bromophenethyl) Caffeamide Protects Skin from UVB-Induced Inflammation Through MAPK/IL-6/NF-κB-Dependent Signaling in Human Skin Fibroblasts and Hairless Mouse Skin
Previous Article in Special Issue
Optimization and Comparison of Synthetic Procedures for a Group of Triazinyl-Substituted Benzene-Sulfonamide Conjugates with Amino Acids
Article Menu
Issue 10 (October) cover image

Export Article

Molecules 2017, 22(10), 1642; doi:10.3390/molecules22101642

Editorial
Special Issue: Sulfonamides
Claudiu T. Supuran
Dipartimento Neurofarba, Sezione di Scienze Farmaceutiche e Nutraceutiche, Università degli Studi di Firenze, Via Ugo Schiff 6, I-50019 Sesto Fiorentino (Florence), Italy
Received: 28 September 2017 / Accepted: 29 September 2017 / Published: 29 September 2017
The sulfonamides and their structurally related derivatives, such as the sulfamates and sulfamides, possess the general formula A-SO2NHR, in which the functional group is either directly bound to an aromatic, heterocyclic, aliphatic, or sugar scaffold (of type A), or appended to such a scaffold via a heteroatom, most frequently oxygen or nitrogen (leading thus to sulfamates and sulfamides, respectively) [1,2,3,4]. The nature of the R moiety may also be quite variable, starting with hydrogen, case in which primary sulfonamides/sulfamates/sulfamides are being considered [5], and ranging to a variety of moieties incorporating heteroatoms (OH, NH2, etc.) as well as organic scaffolds of the types mentioned above for A [6,7]. As thus, this class of compounds may lead to a huge range of derivatives, which are generally easily available through classical synthetic methodologies [5,6,7], and in addition, possess drug-like properties, well-known for decades [8,9,10,11,12,13,14,15].
Indeed, the sulfonamides constitute an important class of drugs, with many types of pharmacological agents possessing antibacterial [4], anti-carbonic anhydrase [2,8,9,10,11,12], anti-obesity [13], diuretic [14,15], hypoglycemic [16], antithyroid [17], antitumor [18,19,20], and anti-neuropathic pain [21] activities, among others. The common chemical motifs present in the aromatic/heterocyclic/sugar/amino acid sulfonamides endowed with such properties is thus associated with a multitude of biological activities, and many others are being constantly reported, such as, among others: matrix metalloproteinase and bacterial protease inhibitors [22,23], HIV protease inhibitors [24], non nucleoside HIV reverse transcriptase or HIV integrase inhibitors [25,26], etc. This is probably due to the particular features of the -SO2NH- (or -OSO2NH-, -NHSO2NH-) moieties, which can participate in multiple interactions with metal ions, amino acid residues, DNA or RNA moieties present in various biomolecules acting as drug targets [27,28,29,30]. Furthermore, sulfonamides and their isosteres are generally stable, easy to prepare and bioavailable, which may explain the huge number of drugs incorporating these motifs [7,8,9,10,11,12,13,14,15,16,17,18,19,20,21,22,23,24,25,26].
The following special issue of Molecules is in fact a nice example of this multitude of possible applications of the sulfonamides, with the wide range of targets to which they bind, diverse synthetic procedures and pharmacological applications, some of which highly innovative, for many representatives of this interesting class of pharmacologic agents. The first contribution is a nice review article [31] from Silvestri’s group, dealing with N-pyrrylarylsulfones, a class of pharmacological agents discovered using the sulfonamides as leads, through a simplification of the functional group. The extensive review presents both the many synthetic procedures for obtaining representatives of this class, as well as many relevant examples of their biological activity as antiviral, anticancer and SNC drugs [31].
Considering the fact that the sulfonamides were the first antibacterials [4,32], due to their interfering with dihydropteroate synthase and dihydrofolate reductase enzymes from bacteria (and protozoa) [32,33] the next two papers from the special issue deal with this type of applications of sulfonamides incorporating sulfa drugs in their molecules, such as sulfadiazine [34] or sulfamethoxazole [35]. The first paper describes hybrids incorporating sulfonamides (such as sulfadiazine) to which other chemotypes have been attached, e.g., ciprofloxacin (an antibacterial agent [36]) or amantadine (an antiviral [3]). These hybrids were tested as inhibitors of jack bean urease, some of them showing low nanomolar activity. Both kinetic and computational studies were performed in order to investigate the inhibition mechanisms of these new sulfonamides [34]. The paper by Krátký et al. [35] describes another interesting hybrid drug approach in the search of new anti-mycobacterial agents. Thus, sulfamethoxazole has been derivatized at its primary amino moiety by using alkyl isocyanates, with the formation of a large series of ureas. Other derivatives were synthesized by reacting sulfamethoxazole with oxalyl chloride. These sulfonamides were tested as inhibitors of the growth of several Mycobacterium species, such as M. avium, M. kansassii, some of them showing remarkable activity [35].
The next three papers in the special issue [37,38,39] deal with targeting carbonic anhydrases (CAs) from various organisms [1,2,8,9,10,11,12]. Indeed, these metalloenzymes are potently inhibited by various classes of sulfonamides, many of which show pharmacologic applications as antiglaucoma [8,10], antiobesity [13], antitumor [8,9,11,18], or diuretic [15] drugs. The first contribution by Vullo et al. [37] presents an interesting work on the cloning and purification of β- and γ-class CAs from the pathogenic bacterium Burkholderia pseudomallei, and the inhibition of these enzymes with a range of more than 40 sulfonamides and sulfamates. Indeed, due to the relevant problem of drug resistance to commonly used antibiotics, the inhibition of CAs from pathogenic organisms started to be considered as an alternative, innovative approach for finding new such pharmacologic agents [40,41].
The next paper [38] presents an optimization for the synthesis of sulfonamide CA inhibitors derived from 1,3,5-triazine, aromatic sulfonamides and amino acid derivatives. This class of CA inhibitors was reported earlier to represent highly efficient and isoform-selective compounds for the tumor-associated CA isoforms IX and XII over the cytosolic, widespread CA I and II [42,43,44]. In the present paper, the authors present and alternative synthesis in which the base used earlier (a tertiary amine) [42,43] was replaced by sodium carbonate in aqueous medium, leading to a better yield in the desired sulfonamide [38].
In the paper by Berrino et al. [39] a new series of benzenesulfamide derivatives (-NH-SO2NH2) which incorporate a 1-benzhydrylpiperazine tail, connected to the sulfonamide scaffolf by means of β-alanyl or nipecotyl spacers was reported and investigated for the inhibition of CAs of human (h) origin, such as hCA I, II, IV and IX. Some of these isoforms are established drug targets, but many sulfonamide or sulfamide inhibitors show little selectivity when inhibiting them. Some of the new sulfamides reported in this paper did show some selective inhibitory profile, mainly against hCA I, which has been rationalized by using computational methods [39].
The next paper in the special issue [45] investigates another enzyme, lactoperoxidase, for its interaction with sulfonamides incorporating (poly)acetoxybenzamide and/or (poly)hydroxybenzamide scaffolds. These secondary sulfonamides were effective-medium potency lactoperoxidase inhibitors, with inhibition constants varying between the nano- to the micromolar range [45].
Marciniec et al. [46] present on the other hand a highly interesting paper in which acetylenic quinolone sulfonamides are prepared by an innovative synthetic approach, followed by testing of their antiproliferative activity against several breast cancer cell lines. Many of these derivatives showed potent antitumor activity, comparable to that of cisplatin, and are thought to bind to some cytochrome P450 isoforms, for two of which computational studies were presented [46].
In the paper by Lin et al. [47] sulfadiazine is again used as the main scaffold, to which gallic acid moieties were introduced in order to obtain agents with pro-chondrogenic effects for the treatment of cartilage diseases. Gallic acid was thus derivatized with the sulfonamide moiety present in the sulfa drug sulfadiazine in order to increase the hydrophobicity and the bioavailability of this agent. Although the mechanism of action of this agent is not clearly understood so far, it seems that it interferes with the activity of a disintegrin and metalloproteinase with thrombospondin motifs 5 (ADAMTS-5) [47].
In conclusion, the present special issue presents an interesting collection of high quality papers which underline the many potential applications of the simple, sulfonamide structural motif, a highly used, almost magic moiety in the tool kit of medicinal chemists.

Conflicts of Interest

The author declares no conflict of interest.

References

  1. Supuran, C.T. Advances in structure-based drug discovery of carbonic anhydrase inhibitors. Expert Opin. Drug Discov. 2017, 12, 61–88. [Google Scholar] [CrossRef] [PubMed]
  2. Carta, F.; Supuran, C.T.; Scozzafava, A. Sulfonamides and their isosters as carbonic anhydrase inhibitors. Future Med. Chem. 2014, 6, 1149–1165. [Google Scholar] [CrossRef] [PubMed]
  3. Scozzafava, A.; Owa, T.; Mastrolorenzo, A.; Supuran, C.T. Anticancer and antiviral sulfonamides. Curr. Med. Chem. 2003, 10, 925–953. [Google Scholar] [CrossRef] [PubMed]
  4. Capasso, C.; Supuran, C.T. Sulfa and trimethoprim-like drugs-antimetabolites acting as carbonic anhydrase, dihydropteroate synthase and dihydrofolate reductase inhibitors. J. Enzym. Inhib. Med. Chem. 2014, 29, 379–387. [Google Scholar] [CrossRef] [PubMed]
  5. Carta, F.; Scozzafava, A.; Supuran, C.T. Sulfonamides: A patent review (2008–2012). Expert Opin. Ther. Pat. 2012, 22, 747–758. [Google Scholar] [CrossRef] [PubMed]
  6. Scozzafava, A.; Carta, F.; Supuran, C.T. Secondary and tertiary sulfonamides: A patent review (2008–2012). Expert Opin. Ther. Pat. 2013, 23, 203–213. [Google Scholar] [CrossRef] [PubMed]
  7. Winum, J.Y.; Scozzafava, A.; Montero, J.L.; Supuran, C.T. The sulfamide motif in the design of enzyme inhibitors. Expert Opin. Ther. Pat. 2006, 16, 27–47. [Google Scholar] [CrossRef] [PubMed]
  8. Supuran, C.T. Carbonic anhydrases: Novel therapeutic applications for inhibitors and activators. Nat. Rev. Drug Discov. 2008, 7, 168–181. [Google Scholar] [CrossRef] [PubMed]
  9. Neri, D.; Supuran, C.T. Interfering with pH regulation in tumours as a therapeutic strategy. Nat. Rev. Drug Discov. 2011, 10, 767–777. [Google Scholar] [CrossRef] [PubMed]
  10. Masini, E.; Carta, F.; Scozzafava, A.; Supuran, C.T. Antiglaucoma carbonic anhydrase inhibitors: A patent review. Expert Opin. Ther. Pat. 2013, 23, 705–716. [Google Scholar] [CrossRef] [PubMed]
  11. Monti, S.M.; Supuran, C.T.; De Simone, G. Anticancer carbonic anhydrase inhibitors: A patent review (2008–2013). Expert Opin. Ther. Pat. 2013, 23, 737–749. [Google Scholar] [CrossRef] [PubMed]
  12. Supuran, C.T. Structure-based drug discovery of carbonic anhydrase inhibitors. J. Enzym. Inhib. Med. Chem. 2012, 27, 759–772. [Google Scholar] [CrossRef] [PubMed]
  13. Scozzafava, A.; Supuran, C.T.; Carta, F. Antiobesity carbonic anhydrase inhibitors: A literature and patent review. Expert Opin. Ther. Pat. 2013, 23, 725–735. [Google Scholar] [CrossRef] [PubMed]
  14. Supuran, C.T. How many carbonic anhydrase inhibition mechanisms exist? J. Enzym. Inhib. Med. Chem. 2016, 31, 345–360. [Google Scholar] [CrossRef] [PubMed]
  15. Carta, F.; Supuran, C.T. Diuretics with carbonic anhydrase inhibitory action: A patent and literature review (2005–2013). Expert Opin. Ther. Pat. 2013, 23, 681–691. [Google Scholar] [CrossRef] [PubMed]
  16. Boyd, A.E. Sulfonylurea receptors, ion channels and fruit flies. Diabetes 1988, 37, 847–850. [Google Scholar] [CrossRef] [PubMed]
  17. Maren, T.H. Relations between structure and biological activity of sulfonamides. Annu. Rev. Pharmacol. Toxicol. 1976, 16, 309–327. [Google Scholar] [CrossRef] [PubMed]
  18. Supuran, C.T. Carbonic Anhydrase Inhibition and the Management of Hypoxic Tumors. Metabolites 2017, 7, 48. [Google Scholar] [CrossRef] [PubMed]
  19. Abbate, F.; Winum, J.Y.; Potter, B.V.; Casini, A.; Montero, J.L.; Scozzafava, A.; Supuran, C.T. Carbonic anhydrase inhibitors: X-ray crystallographic structure of the adduct of human isozyme II with EMATE, a dual inhibitor of carbonic anhydrases and steroid sulfatase. Bioorg. Med. Chem. Lett. 2004, 14, 231–234. [Google Scholar] [CrossRef] [PubMed]
  20. Puccetti, L.; Fasolis, G.; Vullo, D.; Chohan, Z.H.; Scozzafava, A.; Supuran, C.T. Carbonic anhydrase inhibitors. Inhibition of cytosolic/tumor-associated carbonic anhydrase isozymes I, II, IX and XII with Schiff's bases incorporating chromone and aromatic sulfonamide moieties, and their zinc complexes. Bioorg. Med. Chem. Lett. 2005, 15, 3096–3101. [Google Scholar] [CrossRef] [PubMed]
  21. Carta, F.; Di Cesare Mannelli, L.; Pinard, M.; Ghelardini, C.; Scozzafava, A.; McKenna, R.; Supuran, C.T. A class of sulfonamide carbonic anhydrase inhibitors with neuropathic pain modulating effects. Bioorg. Med. Chem. 2015, 23, 1828–1840. [Google Scholar] [CrossRef] [PubMed]
  22. Scozzafava, A.; Supuran, C.T. Carbonic anhydrase and matrix metalloproteinase inhibitors. Sulfonylated amino acid hydroxamates with MMP inhibitory properties act as efficient inhibitors of carbonic anhydrase isozymes I, II and IV, and N-hydroxysulfonamides inhibit both these zinc enzymes. J. Med. Chem. 2000, 43, 3677–3687. [Google Scholar] [PubMed]
  23. Scozzafava, A.; Supuran, C.T. Protease inhibitors. Synthesis of potent matrix metalloproteinase and bacterial collagenase inhibitors incorporating N-4-nitrobenzylsulfonyl glycine hydroxamate moieties. J. Med. Chem. 2000, 43, 1858–1865. [Google Scholar] [CrossRef] [PubMed]
  24. Turner, S.R.; Strohbach, J.W.; Tommasi, R.A.; Aristoff, P.A.; Johnson, P.D.; Skulnick, H.I.; Dolak, L.A.; Seest, E.P.; Tomich, P.K.; Bohanon, M.J.; et al. Tipranavir (PNU-140690): A potent, orally bioavailable nonpeptidic HIV protease inhibitor of the 5,6-dihydro-4-hydroxy-2-pyrone sulfonamide class. J. Med. Chem. 1998, 41, 3467–3476. [Google Scholar] [CrossRef] [PubMed]
  25. Aranz, E.; Dìaz, J.A.; Ingate, S.T.; Witvrouw, M.; Pannecouque, C.; Balzarini, J.; De Clercq, E.; Vega, S. Synthesis and anti-HIV activity of 1,1,3-trioxo-2H,4H-thieno[3,4-e][1,2,4]thiadiazines (TTDs): A new family of HIV-1 specific non-nucleoside reverse transcriptase inhibitors. Bioorg. Med. Chem. 1999, 7, 2811–2822. [Google Scholar] [CrossRef]
  26. Neamati, N.; Mazumder, A.; Sunder, S.; Owen, J.M.; Schultz, R.J.; Pommier, Y. 2-Mertcaptobenzenesulphonamides as novel inhibitors of human immunodeficiency virus type 1 integrase and replication. Antivir. Chem. Chemother. 1997, 8, 485–495. [Google Scholar] [CrossRef]
  27. Scozzafava, A.; Menabuoni, L.; Mincione, F.; Briganti, F.; Mincione, G.; Supuran, C.T. Carbonic anhydrase inhibitors: Perfluoroalkyl/aryl-substituted derivatives of aromatic/heterocyclic sulfonamides as topical intraocular pressure-lowering agents with prolonged duration of action. J. Med. Chem. 2000, 43, 4542–4551. [Google Scholar] [CrossRef] [PubMed]
  28. Scozzafava, A.; Menabuoni, L.; Mincione, F.; Supuran, C.T. Carbonic Anhydrase Inhibitors. A General Approach for the Preparation of Water-Soluble Sulfonamides Incorporating Polyamino—Polycarboxylate Tails and of Their Metal Complexes Possessing Long-Lasting, Topical Intraocular Pressure-Lowering Properties. J. Med. Chem. 2002, 45, 1466–1476. [Google Scholar] [CrossRef] [PubMed]
  29. Supuran, C.T.; Nicolae, A.; Popescu, A. Carbonic anhydrase inhibitors. Part 35. Synthesis of Schiff bases derived from sulfanilamide and aromatic aldehydes: The first inhibitors with equally high affinity towards cytosolic and membrane-bound isozymes. Eur. J. Med. Chem. 1996, 31, 431–438. [Google Scholar] [CrossRef]
  30. Pacchiano, F.; Aggarwal, M.; Avvaru, B.S.; Robbins, A.H.; Scozzafava, A.; McKenna, R.; Supuran, C.T. Selective hydrophobic pocket binding observed within the carbonic anhydrase II active site accommodate different 4-substituted-ureido-benzenesulfonamides and correlate to inhibitor potency. Chem. Commun. 2010, 46, 8371–8373. [Google Scholar] [CrossRef] [PubMed]
  31. Famiglini, V.; Castellano, S.; Silvestri, R. N-Pyrrylarylsulfones with High Therapeutic Potential. Molecules 2017, 22, 434. [Google Scholar] [CrossRef] [PubMed]
  32. Capasso, C.; Supuran, C.T. An overview of the alpha-, beta-and gamma-carbonic anhydrases from Bacteria: Can bacterial carbonic anhydrases shed new light on evolution of bacteria? J. Enzym. Inhib. Med. Chem. 2015, 30, 325–332. [Google Scholar] [CrossRef] [PubMed]
  33. Capasso, C.; Supuran, C.T. Bacterial, fungal and protozoan carbonic anhydrases as drug targets. Expert Opin. Ther. Targets 2015, 19, 1689–1704. [Google Scholar] [CrossRef] [PubMed]
  34. Channar, P.A.; Saeed, A.; Albericio, F.; Larik, F.A.; Abbas, Q.; Hassan, M.; Raza, H.; Seo, S.Y. Sulfonamide-Linked Ciprofloxacin, Sulfadiazine and Amantadine Derivatives as a Novel Class of Inhibitors of Jack Bean Urease; Synthesis, Kinetic Mechanism and Molecular Docking. Molecules 2017, 22, 1352. [Google Scholar] [CrossRef] [PubMed]
  35. Krátký, M.; Stolaříková, J.; Vinšová, J. Novel Sulfamethoxazole Ureas and Oxalamide as Potential Antimycobacterial Agents. Molecules 2017, 22, 535. [Google Scholar] [CrossRef] [PubMed]
  36. Chohan, Z.H.; Supuran, C.T.; Scozzafava, A. Metal binding and antibacterial activity of ciprofloxacin complexes. J. Enzym. Inhib. Med. Chem. 2005, 20, 303–307. [Google Scholar] [CrossRef] [PubMed]
  37. Vullo, D.; Del Prete, S.; Di Fonzo, P.; Carginale, V.; Donald, W.A.; Supuran, C.T.; Capasso, C. Comparison of the Sulfonamide Inhibition Profiles of the β- and γ-Carbonic Anhydrases from the Pathogenic Bacterium Burkholderia pseudomallei. Molecules 2017, 22, 421. [Google Scholar] [CrossRef] [PubMed]
  38. Krajčiová, D.; Pecher, D.; Garaj, V.; Mikuš, P. Optimization and Comparison of Synthetic Procedures for a Group of Triazinyl-Substituted Benzene-Sulfonamide Conjugates with Amino Acids. Molecules 2017, 22, 1533. [Google Scholar] [CrossRef] [PubMed]
  39. Berrino, E.; Bua, S.; Mori, M.; Botta, M.; Murthy, V.S.; Vijayakumar, V.; Tamboli, Y.; Bartolucci, G.; Mugelli, A.; Cerbai, E.; Supuran, C.T.; Carta, F. Novel Sulfamide-Containing Compounds as Selective Carbonic Anhydrase I Inhibitors. Molecules 2017, 22, 1049. [Google Scholar] [CrossRef] [PubMed]
  40. Zimmerman, S.A.; Ferry, J.G.; Supuran, C.T. Inhibition of the archaeal β-class (Cab) and γ-class (Cam) carbonic anhydrases. Curr. Top. Med. Chem. 2007, 7, 901–908. [Google Scholar] [CrossRef] [PubMed]
  41. Supuran, C.T. Structure and function of carbonic anhydrases. Biochem. J. 2016, 473, 2023–2032. [Google Scholar] [CrossRef] [PubMed]
  42. Garaj, V.; Puccetti, L.; Fasolis, G.; Winum, J.Y.; Montero, J.L.; Scozzafava, A.; Vullo, D.; Innocenti, A.; Supuran, C.T. Carbonic anhydrase inhibitors: Synthesis and inhibition of cytosolic/tumor-associated carbonic anhydrase isozymes I, II and IX with sulfonamides incorporating 1,2,4-triazine moieties. Bioorg. Med. Chem. Lett. 2004, 14, 5427–5433. [Google Scholar] [CrossRef] [PubMed]
  43. Garaj, V.; Puccetti, L.; Fasolis, G.; Winum, J.Y.; Montero, J.L.; Scozzafava, A.; Vullo, D.; Innocenti, A.; Supuran, C.T. Carbonic anhydrase inhibitors: Novel sulfonamides incorporating 1,3,5-triazine moieties as inhibitors of the cytosolic and tumour-associated carbonic anhydrase isozymes I, II and IX. Bioorg. Med. Chem. Lett. 2005, 15, 3102–3108. [Google Scholar] [CrossRef] [PubMed]
  44. Carta, F.; Garaj, V.; Maresca, A.; Wagner, J.; Avvaru, B.S.; Robbins, A.H.; Scozzafava, A.; McKenna, R.; Supuran, C.T. Sulfonamides incorporating 1,3,5-triazine moieties selectively and potently inhibit carbonic anhydrase transmembrane isoforms IX, XII and XIV over cytosolic isoforms I and II: Solution and X-ray crystallographic studies. Bioorg. Med. Chem. 2011, 19, 3105–3119. [Google Scholar] [CrossRef] [PubMed]
  45. Köksal, Z.; Kalin, R.; Camadan, Y.; Usanmaz, H.; Almaz, Z.; Gülçin, İ.; Gokcen, T.; Gören, A.C.; Ozdemir, H. Secondary Sulfonamides as Effective Lactoperoxidase Inhibitors. Molecules 2017, 22, 793. [Google Scholar] [CrossRef] [PubMed]
  46. Marciniec, K.; Pawełczak, B.; Latocha, M.; Skrzypek, L.; Maciążek-Jurczyk, M.; Boryczka, S. Synthesis, Anti-Breast Cancer Activity, and Molecular Docking Study of a New Group of Acetylenic Quinolinesulfonamide Derivatives. Molecules 2017, 22, 300. [Google Scholar] [CrossRef] [PubMed]
  47. Lin, X.; Chai, L.; Liu, B.; Chen, H.; Zheng, L.; Liu, Q.; Lin, C. Synthesis, Biological Evaluation, and Docking Studies of a Novel Sulfonamido-Based Gallate as Pro-Chondrogenic Agent for the Treatment of Cartilage. Molecules 2017, 22, 3. [Google Scholar] [CrossRef] [PubMed]
Molecules EISSN 1420-3049 Published by MDPI AG, Basel, Switzerland RSS E-Mail Table of Contents Alert
Back to Top