Saccharin Derivatives Research Articles

Synthesis of Novel Saccharin Derivatives

The synthesis of saccharin (1,2-benzisothiazol-3-one-1,1-dioxide) derivatives substituted on the benzene ring has seen limited development despite the longevity of this compound’s use as an artificial sweetener. This type of saccharin derivative would however present attractive properties for the development of new bioactive, drug-like small molecule compounds. Here we report the derivatisation of the benzene ring of saccharin using Cu(I)-catalyzed azide alkyne cycloaddition (CuAAC) to synthesise a diverse library of novel saccharin-1,2,3-triazole conjugates. All library compounds retain the capability for interactions with biomolecules via the unmodified sulfonamide and lactam groups of the parent saccharin core heterocycle. The compounds also encompass alternate orientations of the 1,2,3-triazole heterocycle, thus further adding diversity to the potential hydrogen bonding interactions of these compounds with biomolecules of therapeutic interest. Our findings demonstrate that specifically functionalized derivatives of saccharin may be prepared from either saccharin azide or saccharin alkyne building blocks in high yield using CuAAC.

Open saccharin-based secondary sulfonamides as potent and selective inhibitors of cancer-related carbonic anhydrase IX and XII isoforms

A large number of novel secondary sulfonamides based on the open saccharin scaffold were synthesized and evaluated as selective inhibitors of four different isoforms of human carbonic anhydrase (hCA I, II, IX and XII, EC 4.2.1.1). They were obtained by reductive ring opening of the newly synthesized N-alkylated saccharin derivatives and were shown to be inactive against the two cytosolic off-target hCA I and II (Kis > 10 µM). Interestingly, these compounds inhibited hCA IX in the low nanomolar range with Kis ranging between 20 and 298 nM and were extremely potent inhibitors of hCA XII isoenzyme (Kis ranging between 4.3 and 432 nM). Since hCA IX and XII are the cancer-related isoforms recently validated as drug targets, these results represent an important goal in the development of new anticancer candidates. Finally, a computational approach has been performed to better correlate the biological data to the binding mode of these inhibitors.

Design, synthesis and biological evaluation of new phthalimide and saccharin derivatives with alicyclic amines targeting cholinesterases, beta-secretase and amyloid beta aggregation

The complexity of Alzheimer's disease (AD) calls for search of multifunctional compounds as potential candidates for effective therapy. A series of phthalimide and saccharin derivatives linked by different alicyclic fragments (piperazine, hexahydropyrimidine, 3-aminopyrrolidine or 3-aminopiperidine) with phenylalkyl moieties attached have been designed, synthesized, and evaluated as multifunctional anti-AD agents with cholinesterase, β-secretase and β-amyloid inhibitory activities. In vitro studies showed that the majority of saccharin derivatives with piperazine moiety and one phthalimide derivative with 3-aminopiperidine fragment exhibited inhibitory potency toward acetylcholinesterase (AChE) with EeAChE IC50 values ranging from 0.83 μM to 19.18 μM. The target compounds displayed inhibition of human β-secretase-1 (hBACE1) ranging from 26.71% to 61.42% at 50 μM concentration. Among these compounds, two multifunctional agents (26, [2-(2-(4-benzylpiperazin-1-yl)ethyl)benzo[d]isothiazol-3(2H)-one 1,1-dioxide] and 52, 2-(2-(3-(3,5-difluorobenzylamino)piperidin-1-yl)ethyl)isoindoline-1,3-dione) have been identified. Compound 26 exhibited the highest inhibitory potency against EeAChE (IC50 = 0.83 μM) and inhibitory activity against hBACE1 (33.61% at 50 μM). Compound 52 is a selective AChE inhibitor (IC50 AChE = 6.47 μM) with BACE1 inhibitory activity (26.3% at 50 μM) and it displays the most significant Aβ anti-aggregating properties among all the obtained compounds (39% at 10 μM). Kinetic and molecular modeling studies indicate that 26 may act as non-competitive AChE inhibitor able to interact with both catalytic and peripheral active site of the enzyme.

Saccharin Derivative Synthesis via [1,3] Thermal Sigmatropic Rearrangement: A Multistep Organic Chemistry Experiment for Undergraduate Students

Saccharin (1,2-benzisothiazole-3-one 1,1-dioxide) is an artificial sweetener used in the food industry. It is a cheap and easily available organic compound that may be used in organic chemistry laboratory classes for the synthesis of related heterocyclic compounds and as a derivatizing agent. In this work, saccharin is used as a starting material in a sequential synthesis designed for completion in three laboratory periods of 4 h each. This synthesis includes two nucleophilic substitutions, namely, the transformation of saccharin into saccharyl chloride and the addition of cinnamyl alcohol to saccharyl chloride (3-chloro-1,2-benzisothiazole 1,1-dioxide) to yield O-cinnamylsaccharin [(E)-3-(3-phenylprop-2-enoxy)-1,2-benzisothiazole 1,1-dioxide]. The third reaction is the isomerization of O-cinnamylsaccharin into N-cinnamylsaccharin [2-(3-phenyl-2(E)-propen-1-yl)]-1,2-benzisothiazole-3(2H)-one 1,1-dioxide], a [1,3] sigmatropic rearrangement. The products are characterized using melting point, IR, and 1H NMR...

ChemInform Abstract: Solvent‐Free Regioselective Synthesis of Novel Isoxazoline and Pyrazoline N‐Substituted Saccharin Derivatives under Microwave Irradiation.

AbstractRegioselective synthesis of novel isoxazoline and pyrazoline derivatives of N‐substituted saccharine of type (V) and (VII) are studied.

Synthesis, Molecular Modelling and Biological Evaluation of Novel Heterodimeric, Multiple Ligands Targeting Cholinesterases and Amyloid Beta.

Cholinesterases and amyloid beta are one of the major biological targets in the search for a new and efficacious treatment of Alzheimer’s disease. The study describes synthesis and pharmacological evaluation of new compounds designed as dual binding site acetylcholinesterase inhibitors. Among the synthesized compounds, two deserve special attention—compounds 42 and 13. The former is a saccharin derivative and the most potent and selective acetylcholinesterase inhibitor (EeAChE IC50 = 70 nM). Isoindoline-1,3-dione derivative 13 displays balanced inhibitory potency against acetyl- and butyrylcholinesterase (BuChE) (EeAChE IC50 = 0.76 μM, EqBuChE IC50 = 0.618 μM), and it inhibits amyloid beta aggregation (35.8% at 10 μM). Kinetic studies show that the developed compounds act as mixed or non-competitive acetylcholinesterase inhibitors. According to molecular modelling studies, they are able to interact with both catalytic and peripheral active sites of the acetylcholinesterase. Their ability to cross the blood-brain barrier (BBB) was confirmed in vitro in the parallel artificial membrane permeability BBB assay. These compounds can be used as a solid starting point for further development of novel multifunctional ligands as potential anti-Alzheimer’s agents.

Solvent-Free Regioselective Synthesis of Novel Isoxazoline and Pyrazoline N-Substituted Saccharin Derivatives Under Microwave Irradiation

Novel isoxazoline and pyrazoline derivatives of N-substituted saccharin were synthesized in good yields by 1,3-dipolar cycloaddition of N-crotonoyl- or N-cinnamoylsaccharin as dipolarophile to arylnitrile oxides or nitrile imines using p-HAP300 as catalyst under solventfree microwave conditions. In this process, the yields were significantly improved compared to classical conditions without alteration of the selectivity. The regioselectivity as well as the nonthermal specific microwave effect are discussed.

ChemInform Abstract: Synthesis of Diazirine‐Based Photoreactive Saccharin Derivatives for the Photoaffinity Labeling of Gustatory Receptors.

AbstractAn improved short synthesis of diazirinyl saccharin derivatives (VIII) and (X) is presented.

Highly Stereoselective Synthesis of Saccharin-Substituted β-Lactams via in Situ Generation of a Heterosubstituted Ketene and a Zwitterionic Intermediate as Potential Antibacterial Agents.

Highly stereoselective synthesis of saccharin derivatives containing functionalized 2-azetidinone moiety was achieved starting from saccharin as an available precursor. The approach to these valuable heterocyclic scaffolds involves a formal [2π + 2π] cycloaddition between Schiff bases and the saccharinylketene as a novel ketene which was generated in situ and an electrocyclic reaction of a zwitterionic intermediate. The identification of the ketene was confirmed by reaction with the stable free radical TEMPO (TO•). Also, the antimicrobial activities of some new substituted saccharin against nine standard bacteria, four bacteria which were isolated from clinical samples and one yeast, were evaluated.

Copper-catalyzed arenes amination with saccharins

A novel copper-catalyzed direct C-N formation reaction of simple arenes with cheap and pharmacological saccharin derivatives under relatively mild conditions was developed with arenes as limiting reagents. This work provided a new method for oxidative coupling of aromatic C(sp2)-H bonds and N-H bonds.

Synthesis of Diazirine‐Based Photoreactive Saccharin Derivatives for the Photoaffinity Labeling of Gustatory Receptors

AbstractSaccharin is one of the most common artificial sweeteners that has a bitter taste at high concentrations. Currently, there are no detailed functional analyses of these gustatory receptors. Therefore, we designed and synthesized photoreactive saccharin derivatives that contain a (trifluoromethyl)diazirinyl moiety at the 5‐ or 6‐position for use as functional analysis tools for photoaffinity labeling.

Synthesis and biological evaluation of novel saccharin derivatives containing 1,2,3-triazole moiety

A series of novel saccharin derivatives containing 1,2,3-triazole moiety was synthesized in satisfactory yields. The structures of all the compounds were elucidated and confirmed by Fourier transform infrared(FTIR) spectroscopy, 1H and 13C nuclear magnetic resonance(1H NMR, 13C NMR) spectroscopy, and high resolution mass spectrometry(HRMS). The bioassays indicated that most of the title compounds displayed some extent herbicidal activities at 100 μg/mL.

X-ray crystallography-promoted drug design of carbonic anhydrase inhibitors.

1-N-Alkylated-6-sulfamoyl saccharin derivatives were prepared and assayed as carbonic anhydrase inhibitors (CAIs). During X-ray crystallographic experiments an unexpected hydrolysis of the isothiazole ring was evidenced which allowed us to prepare highly potent enzyme inhibitors with selectivity for some isoforms with medical applications.

Saccharin derivatives as inhibitors of interferon-mediated inflammation.

A series of novel, saccharin-based antagonists have been identified for the interferon signaling pathway. Through in vitro high-throughput screening with the Colorado Center for Drug Discovery (C2D2) Pilot Library, we identified hit compound 1, which was the basis for extensive structure–activity relationship studies. Our efforts produced a lead anti-inflammatory compound, tert-butyl N-(furan-2-ylmethyl)-N-{4-[(1,1,3-trioxo-2,3-dihydro-1λ6,2-benzothiazol-2-yl)methyl]benzoyl}carbamate CU-CPD103 (103), as a potent inhibitor using an established nitric oxide (NO) signaling assay. With further studies of its inhibitory mechanisms, we demonstrated that 103 carries out this inhibition through the JAK/STAT1 pathway, providing a drug-like small molecule inflammation suppressant for possible therapeutic uses.

Design, synthesis and evaluation of N-substituted saccharin derivatives as selective inhibitors of tumor-associated carbonic anhydrase XII

A series of N-alkylated saccharin derivatives were synthesized and tested for the inhibition of four different isoforms of human carbonic anhydrase (CA, EC 4. 2.1.1): the transmembrane tumor-associated CA IX and XII, and the cytosolic CA I and II. Most of the reported derivatives inhibited CA XII in the nanomolar/low micromolar range, hCA IX with KIs ranging between 11 and 390nM, whereas they were inactive against both CA I (KIs >50μM) and II (KIs ranging between 39.1nM and 50μM). Since CA I and II are off-targets of antitumor carbonic anhydrase inhibitors (CAIs), the obtained results represent an encouraging achievement for the development of new anticancer candidates without the common side effects of non-selective CAIs. Moreover, the lack of an explicit zinc binding function on these inhibitors opens the way towards the exploration of novel mechanisms of inhibition that could explain the high selectivity of these compounds for the inhibition of the transmembrane, tumor-associated isoforms over the cytosolic ones.

ChemInform Abstract: Methods of Sultam Synthesis

AbstractReview: 97 refs.

Methods of Sultam Synthesis

Many compounds bearing a sulfonamide fragment have been used in medicinal practice for a long time, e.g., as antibacterial or hypoglycaemic agents [1, 2]. However, the interest in sulfonamides as potential medications has not decreased until now [3]. Recently, there has been a sharp increase in the number of publications concerning the synthesis and use of sultams as the cyclic analogs of sulfonamides. This is related, on one hand, to the absence of general methods for their synthesis and, on the other hand, to their potential biological activity, since several types of sultams are already well established in clinical practice as anticonvulsant [4], 1-adrenoblocking [5], and diuretic [6] agents. Oxicams can also serve as examples of a large class of nonsteroidal anti-inflammatory medications, which are widely used in clinical practice in many countries (e.g., ampiroxicam), as anxiolytic agents based on alkylated saccharin derivatives (ipsaspirone), and as sulthiame – a drug used in the treatment of epilepsy. Several sultams are used as pesticides in agriculture [7]. Finally, they are widely employed in asymmetric synthesis. Hence camphorsultams [9] have been quite recently introduced as one of the most popular chiral auxiliaries [8] in synthetic practice.

In vitro inhibition effect and structure–activity relationships of some saccharin derivatives on erythrocyte carbonic anhydrase I and II

In this study, in vitro inhibitory effects of some saccharin derivatives on purified carbonic anhydrase I and II were investigated using CO2 as a substrate. The results showed that all compounds inhibited the hCA I and hCA II enzyme activities. Among the compounds, 6-(p-tolylthiourenyl) saccharin (6m) was found to be the most active one for hCA I activity (IC50 = 13.67 μM) and 6-(m-methoxyphenylurenyl) saccharin (6b) was found to be the most active one for hCA II activity (IC50 = 6.54 μM). Structure–activity relationships (SARs) study showed that, generally, thiourea derivatives (6l--v) inhibited more hCA I and hCA II than urea derivatives (6a–k). All compounds (excluding 6c and 6r) have higher inhibitory activity on hCA II than on hCA I.

A new family of covalent inhibitors block nucleotide binding to the active site of pyruvate kinase.

PYK (pyruvate kinase) plays a central role in the metabolism of many organisms and cell types, but the elucidation of the details of its function in a systems biology context has been hampered by the lack of specific high-affinity small-molecule inhibitors. High-throughput screening has been used to identify a family of saccharin derivatives which inhibit LmPYK (Leishmania mexicana PYK) activity in a time- (and dose-) dependent manner, a characteristic of irreversible inhibition. The crystal structure of DBS {4-[(1,1-dioxo-1,2-benzothiazol-3-yl)sulfanyl]benzoic acid} complexed with LmPYK shows that the saccharin moiety reacts with an active-site lysine residue (Lys335), forming a covalent bond and sterically hindering the binding of ADP/ATP. Mutation of the lysine residue to an arginine residue eliminated the effect of the inhibitor molecule, providing confirmation of the proposed inhibitor mechanism. This lysine residue is conserved in the active sites of the four human PYK isoenzymes, which were also found to be irreversibly inhibited by DBS. X-ray structures of PYK isoforms show structural differences at the DBS-binding pocket, and this covalent inhibitor of PYK provides a chemical scaffold for the design of new families of potentially isoform-specific irreversible inhibitors.

New saccharin derivatives as tyrosinase inhibitors

A newly series of 6-(phenylurenyl/thiourenyl) saccharin (6a–y) derivatives were synthesized and their inhibitory effects on the diphenolase activity of banana tyrosinase were evaluated. A 70-fold purification of the enzyme with 6.85% yield was achieved by using a Sepharose 4B-l-tyrosine-p-amino benzoic acid affinity column. The result showed that all the synthesized compounds inhibited the tyrosinase enzyme activity. Among the compounds synthesized, 6-(3-iodophenylthiourenyl) saccharin (6s) was found to be most active one (Ki=3.95μM) and the inhibition kinetics analyzed by Lineweaver–Burk double reciprocal plots revealed that compound 6s was a competitive inhibitor. Structure–activity relationships study showed that generally, most of the 6-(phenylthiourenyl) saccharin derivatives (6m–y) exhibited higher inhibitory activity than 6-(phenylurenyl) saccharin derivatives (6a–l). An electron-withdrawing group at 3-position of phenylurenyl-ring increased in activity and the halogen series at 3-position of phenylthiourenyl-ring showed a qualitative relationship for higher inhibitory activity with increasing size and polarizability. We also calculated HOMO–LUMO energy levels and dipole moments of some selected the synthesized compounds (6a, 6h, 6m and 6s) using Gaussian software.