Synthesis and in silico studies of triazene-substituted sulfamerazine derivatives as acetylcholinesterase and carbonic anhydrases inhibitors.

A novel series of sulfonamides, 4-(3-phenyltriaz-1-en-1-yl)-N-(4-methyl-2-pyrimidinyl)benzenesulfonamides (1-9), was designed and synthesized by the diazo reaction between sulfamerazine and substituted aromatic amines for the first time. Their chemical structures were characterized by 1 H nuclear magnetic resonance (NMR), 13 C NMR, and high-resolution mass spectra. The newly synthesized compounds were evaluated in terms of acetylcholineasterase (AChE) and human carbonic anhydrases (hCA) I and II isoenzymes inhibitory activities. According to the AChE inhibition results, the Ki values of the compounds 1-9 were in the range of 19.9 ± 1.5 to 96.5 ± 20.7 nM against AChE. Tacrine was used as the reference drug and its Ki value was 49.2 ± 2.7 nM against AChE. The Ki values of the compounds 1-9 were in the range of 10.2 ± 2.6 to 101.4 ± 27.8 nM against hCA I, whereas they were 18.3 ± 4.4 to 48.1 ± 4.5 nM against hCA II. Acetazolamide was used as a reference drug and its Ki values were 72.2 ± 5.4 and 52.2 ± 5.7 nM against hCA I and hCA II, respectively. The most active compounds, 1 (nonsubstituted) against AChE, 5 (4-ethoxy-substituted) against hCA I, and 8 (4-bromo-substituted) against hCA II, were chosen and docked at the binding sites of these enzymes to explain the inhibitory activities of the series. The newly synthesized compounds presented satisfactory pharmacokinetic properties via the estimation of ADME properties.

An amide-based sulfenamide prodrug of gamma secretase inhibitor BMS-708163 delivers parent drug from an oral conventional solid dosage form in male beagle dog.

The objective of this Letter is to report the first (to our knowledge) in vivo proof of concept for a sulfenamide prodrug to orally deliver a poorly soluble drug containing a weakly-acidic NH-acid from a conventional solid dosage formulation. This proof of concept was established using BMS-708163 (1), a gamma secretase inhibitor containing a weakly acidic primary amide NH-acid as the chemical handle for attaching a series of thiol-based promoieties via a sulfenamide linkage. Aqueous stabilities and solubilities are reported for a series of six sulfenamide prodrugs (2-7) of 1. The sulfenamide prodrug containing the cysteine methyl ester promoiety (5) was chosen for a orally-dosed PK study in male beagle dog comparing a solubilized formulation of 1 against a solid dosage form of 5 in a cross-over fashion at an equivalent molar dose of 3 mg/kg. Prodrug 5 delivered essentially a superimposable PK profile of 1 compared to the solubilized formulation of 1, without any detectable exposure of 5 in systemic circulation.

Sulfenamide derivatives can improve transporter-mediated cellular uptake of metformin and induce cytotoxicity in human breast adenocarcinoma cell lines.

Metformin, the most frequently administered oral anti-diabetic drug, is a substrate for organic cation transporters (OCTs). This determines not only its pharmacokinetic properties but also its biochemical effects in humans, including its recently-discovered antiproliferative properties. The aim of the study was to verify the hypothesis whether chemical modification of its biguanide backbone may increase the cellular uptake and antiproliferative efficacy of metformin. The study examines five sulfenamide derivatives of metformin with differing lengths of alkyl chains. It determines their cellular uptake and the role of OCTs in their transport in human breast adenocarcinoma cells (epithelial-like MCF-7, and MDA-MB-231). It also evaluates whether increased cellular uptake of metformin derivatives is associated with their cytotoxic properties. Sulfenamide derivatives were characterized by a greater ability to bind to OCTs than metformin. Compound 2 with n-octyl alkyl chain was found to possess the greatest affinity towards OCTs, as measured by determination of [14C]choline uptake inhibition (IC50 = 236.1 ±â€¯1.28 µmol/L, and 217.4 ±â€¯1.33 µmol/L, for MCF-7 and MDA-MB-231 respectively). Sulfenamides were also found to exhibit better cellular uptake in comparison with the parent drug, metformin. For instance, the uptake of cyclohexyl derivative 1 was 1.28 ±â€¯0.19 nmol/min/mg of proteins and thus was 12-fold higher than the metformin in MCF-7 cells. Furthermore, higher uptake was associated with the greatest antiproliferative properties expressed as the lowest IC50 value i.e. inhibiting the growth of 50% of the cells (IC50 = 0.72 ±â€¯1.31 µmol/L). Collectively, chemical modification of metformin into sulfenamides with different alkyl substituents obtains better substrates for OCTs, and subsequently higher cellular uptake in MCF-7 and MDA-MB-231 cells. Additionally, the length of alkyl chain introduced to the sulfenamides was found to influence selectivity and transport efficiency via OCT1 compared to other possible transporters, as well as potential intracellular activity and cytotoxicity.

Novel sulfenamides and sulfonamides based on pyridazinone and pyridazine scaffolds as CB1 receptor ligand antagonists.

A series of sulfenamide and sulfonamide derivatives was synthesized and evaluated for the affinity at CB1 and CB2 receptors. The N-bornyl-S-(5,6-di-p-tolylpyridazin-3-yl)-sulfenamide, compound 11, displayed good affinity and high selectivity for CB1 receptors (Ki values of 44.6 nM for CB1 receptors and >40 µM for CB2 receptors, respectively). The N-isopinocampheyl-sulfenamide 12 and its sulfonamide analogue 22 showed similar selectivity for CB1 receptors with Ki values of 75.5 and 73.2 nM, respectively. These novel compounds behave as antagonists/inverse agonists at CB1 receptor in the [35S]-GTPγS binding assays, and none showed adequate predictive blood-brain barrier permeation, exhibiting low estimated LD50. However, testing compound 12 in a supraspinal analgesic test (hot-plate) revealed that it was as effective as the classic CB1 receptor antagonist rimonabant, in reversing the analgesic effect of a cannabinoid agonist.

Sulfa drugs as inhibitors of carbonic anhydrase: new targets for the old drugs.

Sulfa drugs are well-known antibacterial agents containing N-substituted sulfonamide group on para position of aniline ring (NH2RSO2NHR'). In this study 2,4-dichloro-1,3,5-triazine derivatives of sulfa drugs, sulfamerazine (1b), sulfaquinoxaline (2b), sulfadiazine (3b), sulfadimidine (4b), and sulfachloropyrazine (5b) (1a-5a) were synthesized and characterized. Their carbonic anhydrase inhibition activity was evaluated against bovine cytosolic carbonic anhydrase isozyme II (bCA II). For the sake of comparison the CA inhibition activity of the parent sulfa drugs (1b-5b) was also evaluated. A significant increase in CA inhibition activity of sulfa drugs was observed upon substitution with 2,4-dichloro-1,3,5-triazine moiety. Molecular docking studies were carried out to highlight binding site interactions. ADME properties were calculated to evaluate drug likeness of the compounds.

Convenient microwave-assisted synthesis of lipophilic sulfenamide prodrugs of metformin.

A convenient microwave-assisted synthesis of lipophilic sulfenamide prodrugs of antidiabetic agent, metformin, is reported in this study. These acyclic prodrugs were synthesized directly from selected disulfides with basic metformin and silver nitrate by a one-pot reaction under microwave irradiation. The prepared prodrugs had significantly increased lipophilicity, which resulted in excellent permeability of the octylthio prodrug of metformin across a Caco-2 cell monolayer. According to our preliminary in vivo studies, the octylthio prodrug was also absorbed mostly intact after oral administration in rats. In conclusion, this study shows that these types of more lipophilic sulfenamide prodrugs can be promising candidates to improve permeability and passive absorption of highly water-soluble metformin.

Synthesis and evaluation of novel sulfenamides as novel anti Methicillin-resistant Staphylococcus aureus agents.

A total of 29 novel sulfenamide compounds were synthesized, spectroscopically characterized and evaluated in vitro for antimicrobial activity against various infectious pathogens. Compounds 1b and 2c exhibited potent inhibition against clinical Methicillin-resistant Staphylococcus aureus (MRSA) strains with minimum inhibitory concentration (MIC) values of 1.56 µg/mL.

[Coordinative compounds of zinc with N-substituted thiocarbamoyl-N'-pentamethylensulfenamides--activity modifiers of enzymes of proteolytic and glycolytic action].

The influence of a number of coordinative compounds of zinc with N-substituted thiocarbamoil-N'-pentamethylensulfenamides on activity of elastase, alpha-L-rhamnosidase and alpha-galactosidases evidence for a possibility of their usage as stimulators or inhibitors of enzymes tested have been studied. It was shown that all the compounds in concentration of 0.1 and 0.01% inhibited by 90-100% Bacillus thuringiensis 27-88Els+ elastase activity. [Zn(L2)Br2], [Zn(L1)(NCS)2] and [Zn(L3)(NCS)2] at 20 h exposition activated Cryptococcus albidus 1001 alpha-L-rhamnosidase activity. The rest of compounds influenced it on the control level or inhibited it by 7-23%. The obtained results testify that essential role is not played by separate fragments (L-ligand and anions), but by molecules of zinc complexes as a whole. All the studied complexes, exept for [Zn(L3)(NCS)2], induced alpha-L-rhamnosidase activity of Eupenicillium erubescens 248 (7 to 60%). All zinc compounds (concentration 0.01%, exposition time - 60 min) influenced at the control level Aspergillus niger and Cladosporium cladosporioides alpha-galactosidases activity, however inhibited (up to 20%) activity of Penicillium canescens alpha-galactosidase. The increasing of exposition time of the compounds tested with enzymes up to 20 h testify to selective action of separate compounds on enzymes tested. The data obtained prove, that the character of interaction of zinc complexes is changed depending on the enzyme tested and its strain-producer.

MDCK cell permeability characteristics of a sulfenamide prodrug: strategic implications in considering sulfenamide prodrugs for oral delivery of NH-acids.

The objective of this Letter is both to report the permeability results of a linezolid-based sulfenamide prodrug in an MDCK cell model (enterocyte surrogate system) and to discuss the strategic implications of these results for considering sulfenamide prodrugs to enhance the oral delivery of weakly acidic NH-acids (e.g., amides, ureas, etc.). The two main findings from this study are that the sulfenamide prodrug does not appear to survive intracellular transport due to conversion to linezolid and that there appears to be an apically-oriented surface conversion pathway that can additionally serve to convert the sulfenamide prodrug to linezolid upon approach of the apical membrane. It is hoped that these findings, along with the discussion of the strategic implications, will facilitate a greater awareness of the potential strengths and weaknesses inherent in the sulfenamide prodrug approach for enhancing the oral delivery of weakly acidic NH-acid drugs.

Preparation, characterization and in vivo conversion of new water-soluble sulfenamide prodrugs of carbamazepine.

Improved synthetic methods are reported for the preparation of sulfenamide derivatives of carbamazepine (CBZ) for evaluation as prodrugs. These sulfenamide prodrugs were designed to rapidly release CBZ in vivo by cleavage of the sulfenamide bond by chemical reaction with glutathione and other sulfhydryl compounds. Physicochemical characterization and in vivo conversion of a new prodrug of CBZ was evaluated to further establish the proof of concept of the sulfenamide prodrug approach.

Comparison of benzene, nitrobenzene, and dinitrobenzene 2-arylsulfenylpyrroles.

The effectiveness of the 2,4-dinitrobenzenesulfenyl and 4-nitrobenzenesulfenyl groups as masking and directing groups at the 2-position of pyrrole has been investigated and compared to that of 2-phenylthiopyrrole. The presence of the nitro group(s) enhances stability of the corresponding pyrrole toward acid and does not significantly decrease the ability of the pyrrolic unit to undergo electrophilic aromatic substitution reactions in the form of formylation, nitration, and condensation with aldehydes. The synthetic utility of 2-(2,4-dinitrobenzenesulfenyl)pyrrole was demonstrated through the synthesis of meso-substituted dipyrromethanes. The sulfoxides 2-(2,4-dinitrobenzenesulfinyl)pyrrole and 2-(4-nitrobenzenesulfinyl)pyrrole underwent neither formylation nor nitration, and the increasing presence of nitro groups within the moiety at the 2-position resulted in decreased stability under acidic conditions.

Synthesis and evaluation of galactofuranosyl N,N-dialkyl sulfenamides and sulfonamides as antimycobacterial agents.

The recent emergence of clinically oppressive superbugs, some with resistance to nearly all frontline drug therapies, has challenged our ability to combat such infectious organisms as Mycobacterium tuberculosis, the causative agent of tuberculosis (TB). Our medicinal chemistry program targeting this pathogen has identified several potent galactofuranose-based in vitro inhibitors of mycobacterial growth. The most potent compound, the Galf N,N-didecyl sulfenamide 8d, displayed anti-mycobacterial activity (MIC) of 1 microg/mL in a cell based assay against a representative strain of Mycobacterium smegmatis.

New glycomimetics: anomeric sulfonates, sulfenamides, and sulfonamides.

The synthesis of a variety of new 1-thio-D-glucopyranose derivatives oxidized at the sulfur atom is described, including seven 1-C-sulfonic acids, three sulfonate esters, three sulfinate esters, an S,S'-diglycosyl thiolsulfonate and thiolsulfinate, four S-glycosyl sulfenamides, an S-glycosyl sulfinamide, and two S-glycosyl sulfonamides. These compounds possess unusual anomeric functionality that might be resistant or even inhibitory to normal enzymatic carbohydrate processing, and therefore, they may be of future use in studies of enzyme inhibition, structure, mechanism, and function.

Rate constants for anilidyl radical cyclization reactions.

[reaction: see text] N-Aryl-5,5-diphenyl-4-pentenamidyl radicals (3) were produced by 266 nm laser-flash photolysis of the corresponding N-(phenylthio) derivatives, and the rate constants for the cyclizations of these radicals were measured directly. The 5-exo cyclization reactions were fast (k(c) > 2 x 10(5) s(-1)), and radicals 3 generally behaved as electrophilic reactants with a Hammett correlation of rho = 1.9 for five of the six radicals studied. However, the p-methoxyphenyl-substituted radical 3f cyclized much faster than expected from the Hammett analysis. Variable temperature studies of parent radical 3a (aryl = phenyl) gave an Arrhenius function with log k = 9.2 - 4.4/2.3RT (kcal/mol). The rate constant for the reaction of p-ethylphenyl-substituted anilidyl radical 3b with Bu(3)SnH at 65 degrees C was k(T) = 4 x 10(5) M(-1) s(-1).

Novel approaches to the syntheses of N-substituted S-glycosyl-sulfenamides.

Bis(tetra-O-acetyl-beta-D-glucopyranosyl)disulfide reacts, under silver ion activation, with primary and secondary aliphatic as well as aromatic amines to furnish the title compounds in moderate to good yields. The same derivatives could also be obtained from (tetra-O-acetyl)-beta-D-glucopyranosyl methanethiolsulfonate 1 by nucleophilic substitution with amines. It was shown that the polarization of the S-S-bond in 1 is enhanced by Ag+ so as to allow reaction with sterically hindered amines as well.

Amination and [2,3]-sigmatropic rearrangement of propargylic sulfides using a ketomalonate-derived oxaziridine: synthesis of N-allenylsulfenimides.

Amination of propargylic sulfides with a ketomalonate-derived oxaziridine under metal free conditions gives N-Boc-N-allenylsulfenimides via [2,3]-sigmatropic rearrangement.

Antifungal activity of silver and zinc complexes of sulfadrug derivatives incorporating arylsulfonylureido moieties.

Two well known antimicrobial sulfonamides, sulfadiazine and sulfamerazine were reacted with arylsulfonyl isocyanates, affording several new arylsulfonylureido derivatives. These compounds were subsequently used as ligands (in the form of conjugate bases, as sulfonamide anions) for the preparation of metal complexes containing silver and zinc. The newly synthesized complexes, unlike the free ligands, proved to act as effective antifungal agents against several Aspergillus and Candida spp., some of them showing activities comparable to ketoconazole, with minimum inhibitory concentrations in the range of 1.5-5 microg/ml. The mechanism of antifungal action of these complexes seems to be different from that of the azole antifungals acting as lanosterol-14-alpha-demethylase inhibitors. Levels of sterols assayed in the fungi cultures treated with these new antifungals were equal in the absence or in the presence of the tested compounds. This is in strong contrast with similar experiments in which ketoconazole has been used as antifungal, when drastically reduced ergosterol amounts could be detected. Thus, it is probable that the inhibition of phosphomannose isomerase, a key enzyme in the biosynthesis of yeast cell walls, imparts antifungal activity to the new metal complexes reported here.