Editorial

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Open AccessEditorial

by Claudiu T. Supuran

Molecules 2017, 22(10), 1642; https://doi.org/10.3390/molecules22101642 - 29 Sep 2017

Cited by 73 | Viewed by 8485

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 [...] Read more.

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) [...] Full article

(This article belongs to the Special Issue Sulfonamides)

Research

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2359 KiB

Open AccessArticle

A Chemical Genetics Strategy That Identifies Small Molecules Which Induce the Triple Response in Arabidopsis

by Keimei Oh, Tomoki Hoshi, Sumiya Tomio, Kenji Ueda and Kojiro Hara

Molecules 2017, 22(12), 2270; https://doi.org/10.3390/molecules22122270 - 19 Dec 2017

Cited by 8 | Viewed by 5536

Abstract

To explore small molecules with ethylene-like biological activity, we conducted a triple response-based assay system for chemical library screening. Among 9600 compounds, we found N-[(1,3,5-trimethyl-1H-pyrazol-4-yl)methyl]-N-methyl-2-naphthalenesulfonamide (EH-1) displayed promising biological activity on inducing a triple response in [...] Read more.

To explore small molecules with ethylene-like biological activity, we conducted a triple response-based assay system for chemical library screening. Among 9600 compounds, we found N-[(1,3,5-trimethyl-1H-pyrazol-4-yl)methyl]-N-methyl-2-naphthalenesulfonamide (EH-1) displayed promising biological activity on inducing a triple response in Arabidopsis seedlings. Chemical synthesis and structure–activity relationship (SAR) analysis of EH-1 analogues with different substitution patterns on the phenyl ring structure of the sulfonamide group indicated that 3,4-dichloro-N-methyl-N-(1,3,5-trimethyl-1H-pyrazol-4-yl-methyl)benzenesulfonamide (8) exhibits the most potent biological activity. To determine the mechanism of action, we conducted RNA sequencing (RNA-Seq) analysis of the effect of EH-1 and 1-aminocyclopropane-1-carboxylate (ACC), the precursor of ethylene biosynthesis, following the quantitative real-time polymerase chain reaction (RT-PCR) confirmation. Data obtained from RNA-Seq analysis indicated that EH-1 and ACC significantly induced the expression of 39 and 48 genes, respectively (above 20 fold of control), among which five genes are up-regulated by EH-1 as well as by ACC. We also found 67 and 32 genes that are significantly down-regulated, respectively, among which seven genes are in common. For quantitative RT-PCR analysis. 12 up-regulated genes were selected from the data obtained from RNA-Seq analysis. We found a good correlation of quantitative RT-PCR analysis and RNA-Seq analysis. Based on these results, we conclude that the action mechanism of EH-1 on inducing triple response in Arabidopsis is different from that of ACC. Full article

(This article belongs to the Special Issue Sulfonamides)

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1356 KiB

Open AccessArticle

Optimization and Comparison of Synthetic Procedures for a Group of Triazinyl-Substituted Benzene-Sulfonamide Conjugates with Amino Acids

by Dominika Krajčiová, Daniel Pecher, Vladimír Garaj and Peter Mikuš

Molecules 2017, 22(9), 1533; https://doi.org/10.3390/molecules22091533 - 13 Sep 2017

Cited by 6 | Viewed by 4852

Abstract

Sulfonamides incorporating 1,3,5-triazine moieties can selectively and potently inhibit carbonic anhydrase transmembrane isoforms IX, XII, and XIV over cytosolic isoforms I and II. In the present work, a highly effective synthetic procedure was proposed for this group of potent cancerostatic drugs and compared [...] Read more.

Sulfonamides incorporating 1,3,5-triazine moieties can selectively and potently inhibit carbonic anhydrase transmembrane isoforms IX, XII, and XIV over cytosolic isoforms I and II. In the present work, a highly effective synthetic procedure was proposed for this group of potent cancerostatic drugs and compared with previously used methods. The synthesis of triazinyl-substituted benzene-sulfonamide conjugates with amino acids can be easily carried out using sodium carbonate-based water solution as a synthetic medium instead of N,N-Diisopropylethylamine/Dimethylformamide. The benefits of this synthetic procedure include: (i) high selectivity of the creation of disubstituted conjugates; (ii) several times higher yield (≥95%) than that achieved previously; (iii) elimination of organic solvents by the use of an environmental friendly water medium (green chemistry); (iv) simple and fast isolation of the product. The synthesis and resulting products were evaluated using TLC, IR, NMR, and MS methods. The present work demonstrates a significant advantage in providing shortened routes to target structures. Full article

(This article belongs to the Special Issue Sulfonamides)

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2023 KiB

Open AccessArticle

Sulfonamide-Linked Ciprofloxacin, Sulfadiazine and Amantadine Derivatives as a Novel Class of Inhibitors of Jack Bean Urease; Synthesis, Kinetic Mechanism and Molecular Docking

by Pervaiz Ali Channar, Aamer Saeed, Fernando Albericio, Fayaz Ali Larik, Qamar Abbas, Mubashir Hassan, Hussain Raza and Sung-Yum Seo

Molecules 2017, 22(8), 1352; https://doi.org/10.3390/molecules22081352 - 16 Aug 2017

Cited by 46 | Viewed by 9591

Abstract

Sulfonamide derivatives serve as an important building blocks in the drug design discovery and development (4D) process. Ciprofloxacin-, sulfadiazine- and amantadine-based sulfonamides were synthesized as potent inhibitors of jack bean urease and free radical scavengers. Molecular diversity was explored and electronic factors were [...] Read more.

Sulfonamide derivatives serve as an important building blocks in the drug design discovery and development (4D) process. Ciprofloxacin-, sulfadiazine- and amantadine-based sulfonamides were synthesized as potent inhibitors of jack bean urease and free radical scavengers. Molecular diversity was explored and electronic factors were also examined. All 24 synthesized compounds exhibited excellent potential against urease enzyme. Compound 3e (IC₅₀ = 0.081 ± 0.003 µM), 6a (IC₅₀ = 0.0022 ± 0.0002 µM), 9e (IC₅₀ = 0.0250 ± 0.0007 µM) and 12d (IC₅₀ = 0.0266 ± 0.0021 µM) were found to be the lead compounds compared to standard (thiourea, IC₅₀ = 17.814 ± 0.096 µM). Molecular docking studies were performed to delineate the binding affinity of the molecules and a kinetic mechanism of enzyme inhibition was propounded. Compounds 3e, 6a and 12d exhibited a mixed type of inhibition, while derivative 9e revealed a non-competitive mode of inhibition. Compounds 12a, 12b, 12d, 12e and 12f showed excellent radical scavenging potency in comparison to the reference drug vitamin C. Full article

(This article belongs to the Special Issue Sulfonamides)

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1333 KiB

Open AccessArticle

Novel Sulfamide-Containing Compounds as Selective Carbonic Anhydrase I Inhibitors

by Emanuela Berrino, Silvia Bua, Mattia Mori, Maurizio Botta, Vallabhaneni S. Murthy, Vijayaparthasarathi Vijayakumar, Yasinalli Tamboli, Gianluca Bartolucci, Alessandro Mugelli, Elisabetta Cerbai, Claudiu T. Supuran and Fabrizio Carta

Molecules 2017, 22(7), 1049; https://doi.org/10.3390/molecules22071049 - 24 Jun 2017

Cited by 25 | Viewed by 6243

Abstract

The development of isoform selective inhibitors of the carbonic anhydrase (CA; EC 4.2.1.1) enzymes represents the key approach for the successful development of druggable small molecules. Herein we report a series of new benzenesulfamide derivatives (-NH-SO₂NH₂) bearing the 1-benzhydrylpiperazine [...] Read more.

The development of isoform selective inhibitors of the carbonic anhydrase (CA; EC 4.2.1.1) enzymes represents the key approach for the successful development of druggable small molecules. Herein we report a series of new benzenesulfamide derivatives (-NH-SO₂NH₂) bearing the 1-benzhydrylpiperazine tail and connected by means of a β-alanyl or nipecotyl spacer. All compounds 6a–l were investigated in vitro for their ability to inhibit the physiological relevant human (h) CA isoforms such as I, II, IV and IX. Molecular modeling provided further structural support to enzyme inhibition data and structure-activity relationship. In conclusion the hCA I resulted the most inhibited isoform, whereas all the remaining ones showed different inhibition profiles. Full article

(This article belongs to the Special Issue Sulfonamides)

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702 KiB

Open AccessArticle

Secondary Sulfonamides as Effective Lactoperoxidase Inhibitors

by Zeynep Köksal, Ramazan Kalin, Yasemin Camadan, Hande Usanmaz, Züleyha Almaz, İlhami Gülçin, Taner Gokcen, Ahmet Ceyhan Gören and Hasan Ozdemir

Molecules 2017, 22(6), 793; https://doi.org/10.3390/molecules22060793 - 24 May 2017

Cited by 33 | Viewed by 5360

Abstract

Secondary sulfonamides (4a–8h) incorporating acetoxybenzamide, triacetoxybenzamide, hydroxybenzamide, and trihydroxybenzamide and possessing thiazole, pyrimidine, pyridine, isoxazole and thiadiazole groups were synthesized. Lactoperoxidase (LPO, E.C.1.11.1.7), as a natural antibacterial agent, is a peroxidase enzyme secreted from salivary, mammary, and other mucosal [...] Read more.

Secondary sulfonamides (4a–8h) incorporating acetoxybenzamide, triacetoxybenzamide, hydroxybenzamide, and trihydroxybenzamide and possessing thiazole, pyrimidine, pyridine, isoxazole and thiadiazole groups were synthesized. Lactoperoxidase (LPO, E.C.1.11.1.7), as a natural antibacterial agent, is a peroxidase enzyme secreted from salivary, mammary, and other mucosal glands. In the present study, the in vitro inhibitory effects of some secondary sulfonamide derivatives (4a–8h) were examined against LPO. The obtained results reveal that secondary sulfonamide derivatives (4a–8h) are effective LPO inhibitors. The K_i values of secondary sulfonamide derivatives (4a–8h) were found in the range of 1.096 × 10⁻³ to 1203.83 µM against LPO. However, the most effective inhibition was found for N-(sulfathiazole)-3,4,5-triacetoxybenzamide (6a), with K_i values of 1.096 × 10⁻³ ± 0.471 × 10⁻³ µM as non-competitive inhibition. Full article

(This article belongs to the Special Issue Sulfonamides)

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Open AccessArticle

Novel Sulfamethoxazole Ureas and Oxalamide as Potential Antimycobacterial Agents

by Martin Krátký, Jiřina Stolaříková and Jarmila Vinšová

Molecules 2017, 22(4), 535; https://doi.org/10.3390/molecules22040535 - 28 Mar 2017

Cited by 13 | Viewed by 5242

Abstract

Infections caused by Mycobacterium tuberculosis (Mtb.) and nontuberculous mycobacteria (NTM) are considered to be a global health problem; current therapeutic options are limited. Sulfonamides have exhibited a wide range of biological activities including those against mycobacteria. Based on the activity of [...] Read more.

Infections caused by Mycobacterium tuberculosis (Mtb.) and nontuberculous mycobacteria (NTM) are considered to be a global health problem; current therapeutic options are limited. Sulfonamides have exhibited a wide range of biological activities including those against mycobacteria. Based on the activity of 4-(3-heptylureido)-N-(5-methylisoxazol-3-yl)benzenesulfonamide against NTM, we designed a series of homologous sulfamethoxazole-based n-alkyl ureas (C₁–C₁₂), as well as several related ureas and an oxalamide. Fifteen ureas and one oxalamide were synthesized by five synthetic procedures and characterized. They were screened for their activity against Mtb. and three NTM strains (M. avium, M. kansasii). All of them share antimycobacterial properties with minimum inhibitory concentration (MIC) values starting from 2 µM. The highest activity showed 4,4′-[carbonylbis(azanediyl)]bis[N-(5-methylisoxazol-3-yl)benzenesulfonamide] with MIC of 2–62.5 µM (i.e., 1.07–33.28 µg/mL). Among n-alkyl ureas, methyl group is optimal for the inhibition of both Mtb. and NTM. Generally, longer alkyls led to increased MIC values, heptyl being an exception for NTM. Some of the novel derivatives are superior to parent sulfamethoxazole. Several urea and oxalamide derivatives are promising antimycobacterial agents with low micromolar MIC values. Full article

(This article belongs to the Special Issue Sulfonamides)

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Open AccessArticle

Comparison of the Sulfonamide Inhibition Profiles of the β- and γ-Carbonic Anhydrases from the Pathogenic Bacterium Burkholderia pseudomallei

by Daniela Vullo, Sonia Del Prete, Pietro Di Fonzo, Vincenzo Carginale, W. Alexander Donald, Claudiu T. Supuran and Clemente Capasso

Molecules 2017, 22(3), 421; https://doi.org/10.3390/molecules22030421 - 07 Mar 2017

Cited by 32 | Viewed by 4914

Abstract

We have cloned, purified, and characterized a β-carbonic anhydrase (CA, EC 4.2.1.1), BpsCAβ, from the pathogenic bacterium Burkholderia pseudomallei, responsible for the tropical disease melioidosis. The enzyme showed high catalytic activity for the physiologic CO₂ hydration reaction to bicarbonate and protons, [...] Read more.

We have cloned, purified, and characterized a β-carbonic anhydrase (CA, EC 4.2.1.1), BpsCAβ, from the pathogenic bacterium Burkholderia pseudomallei, responsible for the tropical disease melioidosis. The enzyme showed high catalytic activity for the physiologic CO₂ hydration reaction to bicarbonate and protons, with the following kinetic parameters: k_cat of 1.6 × 10⁵ s⁻¹ and k_cat/K_M of 3.4 × 10⁷ M⁻¹ s⁻¹. An inhibition study with a panel of 38 sulfonamides and one sulfamate—including 15 compounds that are used clinically—revealed an interesting structure–activity relationship for the interaction of this enzyme with these inhibitors. Many simple sulfonamides and clinically used agents such as topiramate, sulpiride, celecoxib, valdecoxib, and sulthiame were ineffective BpsCAβ inhibitors (K_I > 50 µM). Other drugs, such as ethoxzolamide, dorzolamide, brinzolamide, zonisamide, indisulam, and hydrochlorothiazide were moderately potent micromolar inhibitors. The best inhibition was observed with benzene-1,3-disulfonamides—benzolamide and its analogs acetazolamide and methazolamide—which showed K_I in the range of 185–745 nM. The inhibition profile of BpsCAβ is very different from that of the γ-class enzyme from the same pathogen, BpsCAγ. Thus, identifying compounds that would effectively interact with both enzymes is relatively challenging. However, benzolamide was one of the best inhibitors of both of these CAs with K_I of 653 and 185 nM, respectively, making it an interesting lead compound for the design of more effective agents, which may be useful tools for understanding the pathogenicity of this bacterium. Full article

(This article belongs to the Special Issue Sulfonamides)

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5209 KiB

Open AccessArticle

Synthesis, Anti-Breast Cancer Activity, and Molecular Docking Study of a New Group of Acetylenic Quinolinesulfonamide Derivatives

by Krzysztof Marciniec, Bartosz Pawełczak, Małgorzata Latocha, Leszek Skrzypek, Małgorzata Maciążek-Jurczyk and Stanisław Boryczka

Molecules 2017, 22(2), 300; https://doi.org/10.3390/molecules22020300 - 16 Feb 2017

Cited by 18 | Viewed by 6977

Abstract

In this study, a series of regioisomeric acetylenic sulfamoylquinolines are designed, synthesized, and tested in vitro for their antiproliferative activity against three human breast cacer cell lines (T47D, MCF-7, and MDA-MB-231) and a human normal fibroblast (HFF-1) by 4-[3-(4-iodophenyl)-2-(4-nitrophenyl)-2H-5-tetrazolio]-1,3-benzene disulfonate (WST-1) [...] Read more.

In this study, a series of regioisomeric acetylenic sulfamoylquinolines are designed, synthesized, and tested in vitro for their antiproliferative activity against three human breast cacer cell lines (T47D, MCF-7, and MDA-MB-231) and a human normal fibroblast (HFF-1) by 4-[3-(4-iodophenyl)-2-(4-nitrophenyl)-2H-5-tetrazolio]-1,3-benzene disulfonate (WST-1) assay. The antiproliferative activity of the tested acetylenic quinolinesulfonamides is comparable to that of cisplatin. The bioassay results demonstrate that most of the tested compounds show potent antitumor activities, and that some compounds exhibit better effects than the positive control cisplatin against various cancer cell lines. Among these compounds, 4-(3-propynylthio)-7-[N-methyl-N-(3-propynyl)sulfamoyl]quinoline shows significant antiprolierative activity against T47D cells with IC₅₀ values of 0.07 µM. In addition, 2-(3-Propynylthio)-6-[N-methyl-N-(3-propynyl)sulfa-moyl]quinoline and 2-(3-propynylseleno)-6-[N-methyl-N-(3-propynyl)sulfamoyl]quinoline display highly effective atitumor activity against MDA-MB-231 cells, with IC₅₀ values of 0.09 and 0.50 µM, respectively. Furthermore, most of the tested compounds show a weak cytotoxic effect against the normal HFF-1 cell line. Additionally, in order to suggest a mechanism of action for their activity, all compounds are docked into the binding site of two human cytochrome P450 (CYP) isoenzymes. These data indicate that some of the title compounds display significant cytotoxic activity, possibly targeting the CYPs pathways. Full article

(This article belongs to the Special Issue Sulfonamides)

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13546 KiB

Open AccessArticle

Synthesis, Biological Evaluation, and Docking Studies of a Novel Sulfonamido-Based Gallate as Pro-Chondrogenic Agent for the Treatment of Cartilage

by Xiao Lin, Ling Chai, Buming Liu, Hailan Chen, Li Zheng, Qin Liu and Cuiwu Lin

Molecules 2017, 22(1), 3; https://doi.org/10.3390/molecules22010003 - 23 Dec 2016

Cited by 11 | Viewed by 5679

Abstract

Gallic acid (GA) and its derivatives are anti-inflammatory agents and are reported to have potent effects on Osteoarthritis (OA) treatment. Nonetheless, it is generally accepted that the therapeutic effect and biocompatibility of GA is much weaker than its esters due to the high [...] Read more.

Gallic acid (GA) and its derivatives are anti-inflammatory agents and are reported to have potent effects on Osteoarthritis (OA) treatment. Nonetheless, it is generally accepted that the therapeutic effect and biocompatibility of GA is much weaker than its esters due to the high hydrophilicity. The therapeutic effect of GA on OA could be improved if certain structural modifications were made to increase its hydrophobicity. In this study, a novel sulfonamido-based gallate was synthesized by bonding sulfonamide with GA, and its biological evaluations on OA were investigated. Results show that 5-[4-(Pyrimidin-2-ylsulfamoylphenyl)]-carbamoyl-benzene-1,2,3-triyl triacetate (HAMDC) was able to reverse the effects induced by Interleukin-1 (IL-1) stimulation, and it also had a great effect on chondro-protection via promoting cell proliferation and maintaining the phenotype of articular chondrocytes, as well as enhancing synthesis of cartilage specific markers such as aggrecan, collagen II and Sox9. Furthermore, a docking study showed that HAMDC fits into the core of the active site of a disintegrin and metalloproteinase with thrombospondin motifs 5 (ADAMTS-5), which provides an explanation for its activity and selectivity. Full article

(This article belongs to the Special Issue Sulfonamides)

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Review

Jump to: Editorial, Research

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Open AccessReview

N-Pyrrylarylsulfones with High Therapeutic Potential

by Valeria Famiglini, Sabrina Castellano and Romano Silvestri

Molecules 2017, 22(3), 434; https://doi.org/10.3390/molecules22030434 - 09 Mar 2017

Cited by 7 | Viewed by 5389

Abstract

This review illustrates the various studies made to investigate the activity of N-pyrrylarylsulfone containing compounds as potential antiviral, anticancer and SNC drugs. A number of synthetic approaches to obtain tetracyclic, tricyclic and non-cyclic compounds, and their biological activity with regard to structure–activity [...] Read more.

This review illustrates the various studies made to investigate the activity of N-pyrrylarylsulfone containing compounds as potential antiviral, anticancer and SNC drugs. A number of synthetic approaches to obtain tetracyclic, tricyclic and non-cyclic compounds, and their biological activity with regard to structure–activity relationships (SARs) have been reviewed. The literature reviewed here may provide useful information on the potential of N-pyrrylarylsulfone pharmacophore as well as suggest concepts for the design and synthesis of new N-pyrrylarylsulfone based agents. Full article

(This article belongs to the Special Issue Sulfonamides)

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