Structure activity relationship studies on rhodanines and derived enethiol inhibitors of metallo-ß-lactamases.

Metallo-ß-lactamases (MBLs) enable bacterial resistance to almost all classes of ß-lactam antibiotics. We report studies on enethiol containing MBL inhibitors, which were prepared by rhodanine hydrolysis. The enethiols inhibit MBLs from different subclasses. Crystallographic analyses reveal that the enethiol sulphur displaces the di-Zn(II) ion bridging 'hydrolytic' water. In some, but not all, cases biophysical analyses provide evidence that rhodanine/enethiol inhibition involves formation of a ternary MBL enethiol rhodanine complex. The results demonstrate how low molecular weight active site Zn(II) chelating compounds can inhibit a range of clinically relevant MBLs and provide additional evidence for the potential of rhodanines to be hydrolysed to potent inhibitors of MBL protein fold and, maybe, other metallo-enzymes, perhaps contributing to the complex biological effects of rhodanines. The results imply that any medicinal chemistry studies employing rhodanines (and related scaffolds) as inhibitors should as a matter of course include testing of their hydrolysis products.

3H-1,2-benzoxathiepine 2,2-dioxides: a new class of isoform-selective carbonic anhydrase inhibitors.

A new chemotype with carbonic anhydrase (CA, EC 4.2.1.1) inhibitory action has been discovered, the homo-sulfocoumarins (3H-1,2-benzoxathiepine 2,2-dioxides) which have been designed considering the (sulfo)coumarins as lead molecules. An original synthetic strategy of a panel of such derivatives led to compounds with a unique inhibitory profile and very high selectivity for the inhibition of the tumour associated (CA IX/XII) over the cytosolic (CA I/II) isoforms. Although the CA inhibition mechanism with these new compounds is unknown for the moment, we hypothesize that it may be similar to that of the sulfocoumarins, i.e. hydrolysis to the corresponding sulfonic acids which thereafter anchor to the zinc-coordinated water molecule within the enzyme active site.

Synthesis and Applications of Silyl 2-Methylprop-2-ene-1-sulfinates in Preparative Silylation and GC-Derivatization Reactions of Polyols and Carbohydrates.

Trimethylsilyl, triethylsilyl, tert-butyldimethylsilyl, and triisopropylsilyl 2-methylprop-2-ene-1-sulfinates were prepared through (CuOTf)2⋅C6H6-catalyzed sila-ene reactions of the corresponding methallylsilanes with SO2 at 50 °C. Sterically hindered, epimerizable, and base-sensitive alcohols gave the corresponding silyl ethers in high yields and purities at room temperature and under neutral conditions. As the byproducts of the silylation reaction (SO2 +isobutylene) are volatile, the workup was simplified to solvent evaporation. The developed method can be employed for the chemo- and regioselective semiprotection of polyols and glycosides and for the silylation of unstable aldols. The high reactivity of the developed reagents is shown by the synthesis of sterically hindered per-O-tert-butyldimethylsilyl-α-D-glucopyranose, the X-ray crystallographic analysis of which is the first for a per-O-silylated hexopyranose. The per-O-silylation of polyols, hydroxy carboxylic acids, and carbohydrates with trimethylsilyl 2-methylprop-2-ene-1-sulfinate was coupled with the GC analysis of nonvolatile polyhydroxy compounds both qualitatively and quantitatively.

Crystal structure of 3-amino-5,5-dimethyl-2-[(E)-2-nitro-ethen-yl]cyclo-hex-2-en-1-one.

The asymmetric unit of the title compound, C10H14N2O3, contains two independent mol-ecules with similar conformations. In the both mol-ecules, the cyclo-hexene rings adopt the same envelope conformation with the flap C atoms lying 0.658 (3) and 0.668 (3) Šfrom the mean planes formed by the remaining atoms. In the crystal, adjacent mol-ecules are connected via N-H⋯O hydrogen bonds and weak C-H⋯O inter-actions, forming supra-molecular layers parallel to (-101).

Betulin 3,28-di-O-tosyl-ate.

The title compound, C44H62O6S2 {systematic name: (1R,3aS,5aR,5bR,7aR,9S,11aR,11bR,13aR,13bR)-5a,5b,8,8,11a-penta-methyl-1-(prop-1-en-2-yl)-3a-[(tos-yloxy)meth-yl]icosa-hydro-1H-cyclo-penta-[a]chrysen-9-yl 4-methyl-benzene-sulfonate}, was obtained by tosyl-ation of naturally occurring betulin. All the cyclo-hexane rings adopt chair conformations and the cyclo-pentane ring adopts a twisted envelope conformation, with the C atom bearing the tosyl-methyl substituent forming the flap. In the crystal, mol-ecules form a three-dimensional network through multiple weak C-H⋯O hydrogen bonds.

2,6-Di-chloro-9-(2',3',5'-tri-O-acetyl-ß-d-ribo-furanos-yl)-9H-purine.

The title synthetic analog of purine nucleosides, C16H16Cl2N4O7, has its acetyl-ated ß-furan-ose ring in a 3'ß-envelope conformation, with the corresponding C atom deviating by 0.602 (5) Šfrom the rest of the ring. The planar part of the furan-ose ring forms a dihedral angle of 65.0 (1)° with the mean plane of the purine bicycle. In the crystal, mol-ecules form a three-dimensional network through multiple C-H⋯O and C-H⋯N hydrogen bonds and C-H⋯π interactions.

Multicomponent pharmaceutical cocrystals: furosemide and pentoxifylline.

The combination of the active pharmaceutical ingredients furosemide [4-chloro-2-(furan-2-ylmethylamino)-5-sulfamoylbenzoic acid] and pentoxifylline [3,7-dimethyl-1-(5-oxohexyl)-3,7-dihydro-1H-purine-2,6-dione] produces a 1:1 cocrystal, C(12)H(11)ClN(2)O(5)S·C(13)H(18)N(4)O(3), (I), a 1:1 cocrystal hydrate, C(12)H(11)ClN(2)O(5)S·C(13)H(18)N(4)O(3)·H(2)O, (II), and a 1:1 cocrystal acetone solvate, C(12)H(11)ClN(2)O(5)S·C(13)H(18)N(4)O(3)·C(2)H(6)O, (III). These structures exhibit the presence of a rarely encountered synthon with the graph set R(2)(2)(7). All potential hydrogen-bond donors of furosemide participate in hydrogen-bond formation in (I)-(III). However, only two hydrogen-bond acceptors of furosemide are active in (I) and (II), and only one is active in (III). Four hydrogen-bond acceptors of pentoxifylline are active in (II), three in (I) and two in (III). These observations are in good agreement with the calculated packing indexes of 69.5, 69.6 and 68.8% for (II), (I) and (III), respectively.

Monoclinic polymorph of 3,7-dimethyl-1-(5-oxohex-yl)-3,7-dihydro-1H-purine-2,6-dione.

The structure of the title compound, pentoxifylline, C(13)H(18)N(4)O(3), has been previously characterized as a triclinic polymorph [Pavelcík et al. (1989 ▶). Acta Cryst. C45, 836-837]. We have discovered the monoclinic form. There are no strong hydrogen bonds in the crystal structure, rather, moderate C-H⋯O hydrogen bonds are present, which serve to stabilize the three-dimensional architecture.

Crystal structure of 3-de-oxy-3-nitro-methyl-1,2;5,6-di-O-iso-propyl-idene-α-d-allo-furan-ose.

The title compound, C13H21NO7 {systematic name: (3aR,5S,6R,6aR)-5-[(R)-2,2-dimethyl-1,3-dioxolan-4-yl]-2,2-dimethyl-6-(nitro-meth-yl)tetra-hydro-furo[2,3-d][1,3]dioxole}, consists of a substituted 2,2-di-methyl-tetra-hydro-furo[2,3-d][1,3]dioxolane skeleton. The furan-ose ring A adopts a (o)T 4 conformation. The fused dioxolane ring B and the substituent dioxolane ring C also have twisted conformations. There are no strong hydrogen bonds in the crystal structure: only weak C-H⋯O contacts are present, which link the mol-ecules to form a three-dimensional structure.

Crystal structure of 3-(4-hy-droxy-phen-yl)-2-[(E)-2-phenyl-ethen-yl]quinazolin-4(3H)-one.

The title compound, C22H16N2O2 {systematic name: 3-(4-hy-droxy-phen-yl)-2-[(E)-2-phenyl-ethen-yl]quinazolin-4(3H)-one}, consists of a substituted 2-[(E)-2-aryl-ethen-yl]-3-aryl-quinazolin-4(3H)-one skeleton. The substituents at the ethyl-ene fragment are located in trans positions. The phenyl ring is inclined to the quinazolone ring by 26.44 (19)°, while the 4-hy-droxy-phenyl ring is inclined to the quinazolone ring by 81.25 (8)°. The phenyl ring and the 4-hy-droxy-phenyl ring are inclined to one another by 78.28 (2)°. In the crystal, mol-ecules are connected via O-H⋯O hydrogen bonds, forming a helix along the a-axis direction. The helices are linked by C-H⋯π inter-actions, forming slabs parallel to (001).

Structural characterization of cevimeline and its trans-impurity by single crystal XRD.

Cevimeline is muscarinic receptor agonist which increases secretion of exocrine glands. Cevimeline base is a liquid (m.p. 20-25 °C) at ambient conditions, therefore its pharmaceutical formulation as a solid hydrochloride hemihydrate has been developed. The synthesis of cevimeline yields its cis- and trans-isomers and only the cis-isomer is recognized as the API and used in the finished formulation. In this study structural and physicochemical investigations of hydrochloride hemihydrates of cis- and trans-cevimelines have been performed. Single crystal X-ray analyses of both cis- and trans-isomers of cevimeline are reported here for the first time. It was found that the cis-isomer, the API, has less dense crystal packing, lower melting point and higher solubility in comparison to the trans-isomer.

Crystal structures of two (±)-exo-N-isobornyl-acetamides.

The title compounds consist of a bornane skeleton with attached acetamide, C12H21NO (±)-(1) {systematic name: (±)-N-[(1RS,2RS,4RS)-1,7,7-tri-methylbi-cyclo-[2.2.1]heptan-2-yl]acetamide}, and chloro-acetamide, C12H20ClNO (±)-(2) {systematic name: (±)-2-chloro-N-[(1RS,2RS,4RS)-1,7,7-tri-methylbi-cyclo-[2.2.1]heptan-2-yl]-acetamide}, functionalities to the 2-exo-position. The crystal structure of the first monoclinic polymorph of (±)-(1) has been reported previously [Ung et al. (2014 ▸). Monatsh. Chem. 145, 983-992]. Compound (±)-(1) crystallizes in the space group P21/n with two independent mol-ecules in the asymmetric unit, in contrast to the above-mentioned polymorph which crystallized in the space group C2/c with one mol-ecule in the asymmetric unit. In the title compounds, the bicyclic bornane moieties have normal geometries. In the crystals of both compounds, mol-ecules are linked by N-H⋯O hydrogen bonds, reinforced by C-H⋯O contacts, forming trans-amide chains propagating along the a-axis direction. In the case of compound (±)-(1), neighbouring chains are linked by further C-H⋯O contacts, forming double-chain ribbons along [100].

Crystal structure of 3-C-(N-benzyl-oxy-carbon-yl)amino-methyl-3-de-oxy-1,2:5,6-di-O-iso-propyl-idene-α-d-allo-furan-ose.

The title compound, C21H29NO7 (1) [systematic name: benzyl ({(3aR,5S,6R,6aR)-5-[(R)-2,2-dimethyl-1,3-dioxolan-4-yl]-2,2-di-methyl-tetrahydro-furo[2,3-d][1,3]dioxol-6-yl}meth-yl)carbamate], consists of a substituted 2,2-di-methyl-tetra-hydro-furo[2,3-d][1,3]dioxolane skeleton. The furan-ose ring adopts an envelope conformation close to C 3-exo, where the C atom substituted by the benzyl carbamate group is the flap. The fused dioxolane ring also adopts an envelope conformation, as does the terminal dioxolane ring, with in each case an O atom as the flap. In the crystal, mol-ecules are linked by N-H⋯O and C-H⋯O hydrogen bonds, forming chains propagating along the b-axis direction.

Crystal structure of 3-O-benzyl-4(R)-C-(1-benzyl-1H-1,2,3-triazol-4-yl)-1,2-O-iso-propyl-idene-α-d-erythro-furan-ose.

The title compound, C23H25N3O4, {systematic name: 1-benzyl-4-[(3aR,5R,6R,6aR)-6-benz-yloxy-2,2-di-methyl-tetra-hydro-furo[2,3-d][1,3]dioxol-5-yl]-1H-1,2,3-triazole}, consists of a substituted 2,2-di-methyl-tetra-hydro-furo[2,3-d][1,3]dioxole. The furan-ose ring adopts an envelope conformation close to C 3-exo, where the C atom substituted by the benz-yloxy group is the flap. The fused dioxolane ring also adopts an envelope conformation, with the methyl-ene C atom as the flap. In the crystal, mol-ecules are linked by weak C-H⋯O hydrogen bonds, forming zigzag chains along [010].

Crystal structure of 5-[4-(di-ethyl-amino)-benzyl-idene]-2,2-dimethyl-1,3-dioxane-4,6-dione.

The title compound, C17H21NO4, consists of substituted Meldrum's acid with a [4-(di-ethyl-amino)-phen-yl]methyl-idene fragment attached to the fifth position. The heterocycle assumes a distorted boat conformation. The planar part of heterocycle is almost coplanar with the benzene ring due to the presence of a long conjugated system in the mol-ecule. This leads to the formation of C-H⋯O-type intra-molecular contacts. As a result of the absence of hydrogen-bond donors in the structure, the crystal packing is controlled by van der Waals forces and weak C-H⋯O inter-actions, which associate the mol-ecules into inversion dimers.