Endocyclic Sulfur Research Articles

Evaluation and discovery of novel benzothiazole derivatives as promising hits against Leishmania infantum.

An early exploration of the benzothiazole class against two kinetoplastid parasites, Leishmania infantum and Trypanosoma cruzi, has been performed after the identification of a benzothiazole derivative as a suitable antileishmanial initial hit. The first series of derivatives focused on the acyl fragment of its class, evaluating diverse linear and cyclic, alkyl and aromatic substituents, and identified two other potent compounds, the phenyl and cyclohexyl derivatives. Subsequently, new compounds were designed to assess the impact of the presence of diverse substituents on the benzothiazole ring or the replacement of the endocyclic sulfur by other heteroatoms. All compounds showed relatively low cytotoxicity, resulting in decent selectivity indexes for the most active compounds. Ultimately, the invitro ADME properties of these compounds were assessed, revealing a satisfying water solubility, gastrointestinal permeability, despite their low metabolic stability and high lipophilicity. Consequently, compounds 5 and 6 were identified as promising hits for further hit-to-lead exploration within this benzothiazole class against L. infantum, thus providing promising starting points for the development of antileishmanial candidates.

Asymmetric systematic synthesis, structures, and (chir)optical properties of a series of dihetero[8]helicenes.

A series of dihetero[8]helicenes have been systematically synthesized in enantiomerically enriched forms by utilizing the characteristic transformations of the organosulfur functionality. The synthetic route begins with assembling a ternaphthyl common synthetic intermediate from 2-naphthol and bissulfinylnaphthalene through an extended Pummerer reaction followed by facile multi-gram-scale resolution. The subsequent cyclization reactions into dioxa- and dithia[8]helicenes take place with excellent axial-to-helical chirality conversion. Dithia[8]helicene is further transformed into the nitrogen and the carbon analogs by replacing the two endocyclic sulfur atoms via SNAr-based skeletal reconstruction. The efficient systematic synthesis has enabled comprehensive evaluation of physical properties, which has clarified the effect of the endocyclic atoms on their structures and (chir)optical properties as well as the unexpected conformational stability of the common helical framework.

Topology of Ladder Supramolecular Assemblies in Azahetorocyclic Phosphonates: A Structural and Computational Approach

Topologies of ladder packing arrangements in crystal structures of five azaheterocyclic phosphonates were characterized by four geometrical descriptors introduced in the paper. The structural analysis was augmented by detailed calculations on interactions stabilizing the molecular assemblies. Intermolecular energies were evaluated using PIXEL and DFT(M062x-GD3) methods. Additionally, fingerprint plots derived from the Hirshfeld surfaces were generated for each structure to characterize the crystal packing arrangement in detail. All structures are stabilized by the relatively weak hydrogen bonds and nonbonding interactions involving aromatic rings, i.e., π···π, C–H···π, and (lp)···π effects. Distribution of the molecular electrostatic potential demonstrates that positively charged, endocyclic sulfur atoms are prone to chalcogen–chalcogen (S···O) bonding. Analysis of the supramolecular motifs shows the lack of a common synthon responsible for the ladder packing arrangements. However, the striking geometry similarity of all molecules indicates that ladder packing is based on a shape oriented molecular recognition and mostly driven by the van der Waals forces. The intermolecular electrostatic effects are crucial for stabilizing and fixing geometry of the already formed molecular clusters.

Naphthyl Thio- and Carba-xylopyranosides for Exploration of the Active Site of β-1,4-Galactosyltransferase 7 (β4GalT7).

Xyloside analogues with substitution of the endocyclic oxygen atom by sulfur or carbon were investigated as substrates for β-1,4-galactosyltransferase 7 (β4GalT7), a key enzyme in the biosynthesis of glycosaminoglycan chains. The analogues with an endocyclic sulfur atom proved to be excellent substrates for β4GalT7, and were galactosylated approximately fifteen times more efficiently than the corresponding xyloside. The 5a-carba-β-xylopyranoside in the d-configuration proved to be a good substrate for β4GalT7, whereas the enantiomer in the l-configuration showed no activity. Further investigations by X-ray crystallography, NMR spectroscopy, and molecular modeling provided a rationale for the pronounced activity of the sulfur analogues. Favorable π-π interactions between the 2-naphthyl moiety and a tyrosine side chain of the enzyme were observed for the thio analogues, which open up for the design of efficient GAG primers and inhibitors.

Discovering protein-ligand chalcogen bonding in the protein data bank using endocyclic sulfur-containing heterocycles as ligand search subsets.

The chalcogen bond, the noncovalent, electrostatic attraction between covalently bonded atoms in group 16 and Lewis bases, is present in protein-ligand interactions based on X-ray structures deposited in the Protein Data Bank (PDB). Discovering protein-ligand chalcogen bonding in the PDB employed a strategy that focused on searching the database for protein complexes of five-membered, heterocyclic ligands containing endocyclic sulfur with endo electron-withdrawing groups (isothiazoles; thiazoles; 1,2,3-, 1,2.4-, 1,2,5-, 1,3,4-thiadiazoles) and thiophenes with exo electron-withdrawing groups, e.g., 2-chloro, 2-bromo, 2-amino, 2-alkylthio. Out of 930 ligands investigated, 33 or 3.5% have protein-ligand S---O interactions of which 31 are chalcogen bonds and two appear to be S---HO hydrogen bonds. The bond angles for some of the chalcogen bonds found in the PDB are less than 90°, and an electrostatic model is proposed to explain this phenomenon.

Catalysis with Chalcogen Bonds.

Herein, we introduce catalysts that operate with chalcogen bonds. Compared to conventional hydrogen bonds, chalcogen bonds are similar in strength but more directional and hydrophobic, thus ideal for precision catalysis in apolar solvents. For the transfer hydrogenation of quinolines and imines, rate enhancements well beyond a factor of 1000 are obtained with chalcogen bonds. Better activities with deeper σ holes and wider bite angles, chloride inhibition and correlation with computed anion binding energies are consistent with operational chalcogen bonds. Comparable to classics, such as 2,2'-bipyrroles or 2,2'-bipyridines, dithieno[3,2-b;2',3'-d]thiophenes (DTTs), particularly their diimides, but also wide-angle cyclopentadithiazole-4-ones are identified as privileged motifs to stabilize transition states in the focal point of the σ holes on their two co-facial endocyclic sulfur atoms.

Anion Transport with Chalcogen Bonds

In this report, we introduce synthetic anion transporters that operate with chalcogen bonds. Electron-deficient dithieno[3,2-b;2',3'-d]thiophenes (DTTs) are identified as ideal to bind anions in the focal point of the σ holes on the cofacial endocyclic sulfur atoms. Anion binding in solution and anion transport across lipid bilayers are found to increase with the depth of the σ holes of the DTT anionophores. These results introduce DTTs and related architectures as a privileged motif to engineer chalcogen bonds into functional systems, complementary in scope to classics such as 2,2'-bipyrroles or 2,2'-bipyridines that operate with hydrogen bonds and lone pairs, respectively.

Systematic Evaluation of the Metabolism and Toxicity of Thiazolidinone and Imidazolidinone Heterocycles.

The thiazolidine and imidazolidine heterocyclic scaffolds, i.e., the rhodanines, 2,4-thiazolidinediones, 2-thiohydantoins, and hydantoins have been the subject of debate on their suitability as starting points in drug discovery. This attention arose from the wide variety of biological activities exhibited by these scaffolds and their frequent occurrence as hits in screening campaigns. Studies have been conducted to evaluate their value in drug discovery in terms of their biological activity, chemical reactivity, aggregation-based promiscuity, and electronic properties. However, the metabolic profiles and toxicities have not been systematically assessed. In this study, a series of five-membered multiheterocyclic (FMMH) compounds were selected for a systematic evaluation of their metabolic profiles and toxicities on TAMH cells, a metabolically competent rodent liver cell line and HepG2 cells, a model of human hepatocytes. Our studies showed that generally the rhodanines are the most toxic, followed by the thiazolidinediones, thiohydantoins, and hydantoins. However, not all compounds within the family of heterocycles were toxic. In terms of metabolic stability, 5-substituted rhodanines and 5-benzylidene thiohydantoins were found to have short half-lives in the presence of human liver microsomes (t1/2 < 30 min) suggesting that the presence of the endocyclic sulfur and thiocarbonyl group or a combination of C5 benzylidene substituent and thiocarbonyl group in these heterocycles could be recognition motifs for P450 metabolism. However, the stability of these compounds could be improved by installing hydrophilic functional groups. Therefore, the toxicities and metabolic profiles of FMMH derivatives will ultimately depend on the overall chemical entity, and a blanket statement on the effect of the FMMH scaffold on toxicity or metabolic stability cannot and should not be made.

Synthesis of 1,2,3-triazoles from xylosyl and 5-thioxylosyl azides: evaluation of the xylose scaffold for the design of potential glycogen phosphorylase inhibitors

Various acetylenic derivatives and acetylated β-d-xylopyranosyl azide or the 5-thio-β-d-xylopyranosyl analogue were coupled by Cu(I)-catalyzed azide alkyne 1,3-dipolar cycloaddition (CuAAC) to afford a series of 1-xylosyl-4-substituted 1,2,3-triazoles. Controlled oxidation of the endocyclic sulfur atom of the 5-thioxylose moiety led to the corresponding sulfoxides and sulfones. Deacetylation afforded 19 hydroxylated xylose and 5-thioxylose derivatives, found to be only sparingly water-soluble. Compared to glucose-based analogues, they appeared to be much weaker inhibitors of glycogen phosphorylase, as the absence of a hydroxymethyl group weakens their binding at the enzyme active site. However, such new xylose derivatives might be useful glycomimetics.

Platinum(II) Complexes Bearing a Thiolate/Thioether Ligand – Hemilability vs. Dealkylation

AbstractSubstitution of the chloro ligands of cis‐[Pt(PEt3)2Cl2] by 4‐methylthio‐2‐thioxo‐1,3‐dithiole‐5‐thiolate (L) leads to the thiolato complexes trans‐[Pt(PEt3)2ClL] (2) and trans‐[Pt(PEt3)2L2] (1), which have been characterised by X‐ray crystallography. In the solid state, the square planar arrangement is capped by an endocyclic sulfur atom of L, which gives rise to distorted square‐pyramidal and pseudooctahedral geometries for 2 and 1, respectively. Complex 1 coexists in solution with [Pt(PEt3)(η1‐L)(η2‐L)] (3), which results from the reversible dissociation of one phosphane ligand. The combination of η1‐(thiolato) and η2‐(thiolato/thioether) L in 3 has been established by variable‐temperature 1H NMR spectroscopy and crystal structure determination. The η2‐coordination mode of L is also observed in cis‐[Pt(PEt3)2L]+ (4), which results from the abstraction of the chloro ligand of 2 by excess TlPF6. An S‐demethylation reaction occurs when 1 is heated in acetonitrile to yield the structurally‐characterised dithiolene complex [Pt(PEt3)2(dmit)] (5) (dmit2– = 2‐thioxo‐1,3‐dithiole‐4,5‐dithiolate) and MeL. Treatment of cis‐[Pt(PPh3)2Cl2] with 2 equiv. of L leads to a mixture of [Pt(PPh3)2(dmit)] (6) and [Pt(PPh3)(η1‐L)(η2‐L)] (7). Complex 7 predominates in solution over its parent compound,[Pt(PPh3)2L2]. The identification of CH3Cl by 1H NMR spectroscopy proves that [Pt(PPh3)2ClL] is involved as an intermediate in the demethylation process. The reaction of L with platinum precursors that are blocked in a cis arrangement by chelation of 1,1‐bis(diphenylphosphanyl)methane (dppm) and 1,1‐bis(diphenylphosphanyl)ethane (dppe) leads to the formation of the thiolato complexes cis‐[Pt(η2‐dppm)L2] (8) and cis‐[Pt(η2‐dppe)L2] (9). The solid‐state structure of 8 reveals the occurrence of an additional weak interaction between a thiomethyl group and the platinum centre (Pt–S 3.073 Å).

Multinuclear NMR studies and ab initio structure calculations of hindered phencyclone diels‐alder adducts from symmetrical cyclic dienophiles: Cyclohexene, vinylene carbonate, vinylene trithiocarbonate and two N‐aryl maleimides

AbstractA series of hindered Diels‐Alder adducts have been prepared from phencyclone, 1, with various unusual symmetrical cyclic dienophiles, including cyclohexene, 2a; vinylene carbonate, 2b; vinylene trithiocarbonate, 2c; and the N‐aryl maleimides: N‐(4‐dimethylamino‐3,5‐dinitrophenyl)maleimide (“Tuppy's maleimide”), 2d; and N‐[3,5‐bis(trifluoromethyl)phenyl]maleimide, 2e. The highly hindered adducts, 3a‐e, respectively, were extensively characterized by one‐ and two‐dimensional NMR methods, observing proton, carbon‐13 and fluorine‐19. High resolution COSY45 spectra permitted rigorous proton NMR assignments. The 2D heteronuclear C‐H chemical shift correlation spectra (HETCOR, XHCORR) were obtained for adducts 3a‐d, allowing specific assignments for protonated carbons. Corrections to earlier proton NMR assignments for the vinylene carbonate adduct are given; results of the gated decoupling 13C NMR experiment for this adduct supported endo adduct stereochemistry. Relative proton chemical shifts for bridgehead phenyls of adduct 3c appeared anomalous relative to other adducts, suggesting possible special anisotropic interactions (with endocyclic sulfur or other anisotropic groups in the product) due to the unusual calculated orientation of the phenyls. The unsubstituted bridgehead phenyls in all adducts were shown to exhibit slow exchange limit (SEL) 1H and 13C spectra on the NMR timescales at ambient temperatures (7 tesla) showing slow rotations about the C(sp3)‐C(aryl sp2) bonds. The rapid rotation of the N‐aryl rings of the maleimide adducts was indicated by fast exchange limit spectra, suggesting that ortho substitution of the N‐aryl ring may be necessary to slow this rotation to the SEL regime. Ab initio geometry optimizations at the Hartree‐Fock level were carried out for each adduct, with the 6‐31G* basis sets. Appreciable geometry differences were seen in calculated structures, and significant NMR chemical shift differences were experimentally observed, depending on the nature of the groups attached to the (Z)‐HC=CH moiety of the dienophiles.

4‐ and 4,5‐Substituted N‐Methoxythiazole‐2(3H)‐thiones – Preparation,UV/Vis Spectra, and Assignment of Electronic Transitions in Comparison to N‐Methoxypyridine‐2(1H)‐thione Using Time‐Dependent Density Functional Theory Calculations

AbstractExperimentally observed absorptions in UV/Vis spectra of N‐methoxy‐4‐methylthiazole‐2(3H)‐thione, N‐methoxy‐5‐(p‐methoxyphenyl)‐4‐methylthiazole‐2(3H)‐thione, N‐methoxypyridine‐2(1H)‐thione, and selected N‐hydroxy derivatives thereof have been assigned to π→π*‐type transitions as dominating character, using the results from ab initio calculations [time‐dependent density functional theory (TD)RI‐BLYP/TZVPP]. Theory further predicts that electronic excitations in N‐methoxythiazole‐2(3H)‐thiones on one side and N‐meth‐oxypyridine‐2(1H)‐thione on the other side differ significantly with respect to character and statistical weight of contributing transitions. These effects originate predominantly from contributions of the endocyclic sulfur atom onto orbital energies and shapes in thiazole‐2(3H)‐thiones, and may be intensified by substituents such as a p‐methoxyphenyl group located in position 5. Since the majority of the calculated spectral differences between thiazole‐ and pyridinethiones refers to excitations of low intensity, the findings from the present study correlate with two important experimental facts: (i) Apart from minor shifts in the exact spectral location of UV/Vis absorptions, electronic spectra of N‐hydroxy‐ or N‐methoxy‐substituted pyridine‐2(1H)‐thiones and thiazole‐2(3H)‐thiones are surprisingly similar in shape. (ii) N‐alkoxypyridine‐2(1H)‐thiones and N‐alkoxythiazole‐2(3H)‐thiones liberate upon UV/Vis excitation oxygen‐centered radicals with a comparable efficiency. (© Wiley‐VCH Verlag GmbH &amp; Co. KGaA, 69451 Weinheim, Germany, 2005)

Dithiocarbamates, Thiocarbamic Esters, Dithiocarboimidates, Guanidines, Thioureas, Isothioureas, and Tetraazathiapentalene Derived from 2‐Aminobenzothiazole

AbstractReactions between CS2 and the exocyclic amino groups of 2‐aminobenzothiazoles gave series of molecules bearing thiourea, isothiourea, dithiocarbamate, dithiocarboimine, dimethyldithiocarbamate, methyldithiocarbamate, S‐CH3 and O‐alkyl thiocarbamic ester, and guanidine groups. Preferred tautomers and conformers were determined. Most compounds present coordinative bonds between the endocyclic sulfur atom, which behaves as a Lewis acid, and oxygen, nitrogen, and sulfur acting as bases. A new dibenzothiazolyltetraazathiapentalene containing a T‐shaped hypervalent sulfur atom and displaying “single bond‐no bond resonance” is discussed. X‐ray structures of eleven compounds are reported. (© Wiley‐VCH Verlag GmbH &amp; Co. KGaA, 69451 Weinheim, Germany, 2004)

ChemInform Abstract: Synthesis and Diuretic Activity of N‐Substituted Condensed Derivatives of 3‐Methylxanthine with Endocyclic Sulfur Atom.

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

Synthesis and diuretic activity of N-substituted condensed derivatives of 3-methylxanthine with endocyclic sulfur atom

Synthesis and diuretic activity of N-substituted condensed derivatives of 3-methylxanthine with endocyclic sulfur atom

Inapplicability of the Antiperiplanar Lone Pair Hypothesis to C-P Bond Breaking and Formation in Some S-C-P(+) Systems.

Both C(2)-P bond breaking and formation in the S-C-P(+) system do not occur according to the antiperiplanar lone pair hypothesis. Experiments using 2-phosphonio derivatives of 5-tert-butyl-1,3-dithiane and cis-4,6-dimethyl-1,3-dithiane are against the participation of higher-energy boat conformers as reactive intermediates. The results obtained support a possibility of conformational adjustment in the course of the reaction. Stereoelectronic control of the C(2)-P bond breaking and formation results from interplay of several factors. The role of the n(S)-sigma(C(2))(-)(P) and sigma(C(4,6))(-)(S)-sigma(C(2))(-)(P) hyperconjugation, as well as of the repulsive interactions between lone electron pairs pi(S) of endocyclic sulfur atoms and pi-electrons of the phenyl ring(s) connected with phosphorus, is discussed.

Effect of Sulfur Substitution on the Floral Odor of Tetrahydropyranyl and Tetrahydrofuranyl Ethers

Sulfur-containing analogues of tetrahydropyranyl and tetrahydrofuranyl derivatives of selected alcohols and phenols have been prepared and their odor properties evaluated. The compounds include derivatives in which either one or both of the oxygen atoms had been replaced with sulfur. Derivatives with two sulfur atoms do not exhibit pleasant odors; those with an endocyclic oxygen and an exocyclic sulfur generally exhibit green notes. The floral character is found only in a few derivatives with an endocyclic sulfur and an exocyclic oxygen

Factors affecting the rates of thermal decomposition of azidothiophenes

The thermolysis rate of 4-methoxy-1 -azidobenzene reveals that the methoxy group increases the rate much less than the endocyclic sulfur does in 3-azidothiophene. With 3-azidothiophene, the neighbouring groups 2-acetyl and 2-nitro enhanced the rate in decalin solution only 5- and 17-fold, respectively, whereas in azidobenzene the corresponding enhancements are 413 and 1060. It is argued that the preferred electron distribution in the transition state for decomposition of 3-azidothiophene is not consistent with that required for effective neighbouring group participation. 2-Cyano and 2-methoxycarbonyl substituents, which are not known as effective neighbouring groups in thermal decompositions of azides, have very little effect on the rate for 3-azidothiophene.

New P,N-Cyclic Ligands

Abstract The anions of P,N-cyclic metaphosphimic acids (MPmn-, n = =3, 4…) interact with cations as conformationally labile multidentate ligands. They belong to the cyclophosphazane class and can be obtained from chloroderivatives (NPCl2)n associated with a related class of P,N-compounds (cyclophosphazenes. Besides halogens, a great variety of organic radicals can act as substituents in the cyclophospnazenes. An additional introduction of donating atoms or groups in these radicals results in new multidentate ligands. Like the MPmn- they demonstrate a cation binding ability. Thus P,N-cyclic ligands can contain endocyclic functional groups POO- which are inherent to common MPmn- or various exo-cyclic groups, e.g. -COO−, -PR2O−, -PROO−, -NR2etc., linked to the cycle via side chains. Furthermore, miscellaneous phosphazane-phosphazene structures as well as those with an additional heteroatom can be designed. We have obtained the first examples of P,N-cyclic chelantes of some structural types. These are bicycles based on MPmn- cross-linked by organic bridges. Such ligands can take a sandwich configuration. Neutral and acido-ligands of cyclo-pendante type involving groups -COO−, -PPh2O and >O as well as a ligand with endocyclic sulfur have been obtained too. Selective or universal chelantes, extragents, coloured ligands and other reagents can be synthesized depending on a ligand structure design, the nature of organic fragments linked to the cycle and the type of functional groups.

New P,N-Cyclic Ligands

Abstract The anions of P,N-cyclic metaphosphimic acids (MPmn-, n = =3, 4…) interact with cations as conformationally labile multidentate ligands. They belong to the cyclophosphazane class and can be obtained from chloroderivatives (NPCl2)n associated with a related class of P,N-compounds (cyclophosphazenes. Besides halogens, a great variety of organic radicals can act as substituents in the cyclophospnazenes. An additional introduction of donating atoms or groups in these radicals results in new multidentate ligands. Like the MPmn- they demonstrate a cation binding ability. Thus P,N-cyclic ligands can contain endocyclic functional groups POO- which are inherent to common MPmn- or various exo-cyclic groups, e.g. -COO−, -PR2O−, -PROO−, -NR2etc., linked to the cycle via side chains. Furthermore, miscellaneous phosphazane-phosphazene structures as well as those with an additional heteroatom can be designed. We have obtained the first examples of P,N-cyclic chelantes of some structural types. These are bicycles based on MPmn- cross-linked by organic bridges. Such ligands can take a sandwich configuration. Neutral and acido-ligands of cyclo-pendante type involving groups -COO−, -PPh2O and >O as well as a ligand with endocyclic sulfur have been obtained too. Selective or universal chelantes, extragents, coloured ligands and other reagents can be synthesized depending on a ligand structure design, the nature of organic fragments linked to the cycle and the type of functional groups.