Comparing the crystal structures and spectroscopic properties of a p-hydroxy styrylquinolinium dye with those of its p-dimethylamino analogue.

Two previously synthesized styrylquinolinium dyes, namely (E)-1-butyl-4-(4-(dimethylamino)styryl)quinolinium iodide (D36) and (E)-1-butyl-4-(4-hydroxystyryl)quinolinium iodide (D34), were compared in terms of their properties by single-crystal X-ray diffraction (XRD), Hirshfeld surface analysis, Fourier transform Raman (FT-Raman), Fourier transform infrared (FT-IR), fluorescence, and ultraviolet-visible (UV-Vis) spectroscopy, and 1H- and 13C-NMR methods. Both dyes D36 and D34 crystallized in the triclinic and monoclinic systems in the centrosymmetric space groups P-1 and P21/n, respectively. The unit cell of D36 contains two molecules of the dye, participating in weak intermolecular interactions, whereas that of D34 contains four formula units. The phenolic hydroxy group of D34 participates in the formation of a hydrogen bond with the iodide anion. The 4-styrylquinolinium moieties of the cationic dye molecules are nearly planar. The dihedral angle between the mean planes through the ten-membered quinolinium system and the benzene ring is 7.5° in D36 and 5.9(1)° in D34. The structural parameters planarity and bond length alternation (BLA) are discussed, which are important for the evaluation of the first hyperpolarizability ß at the molecular level, even in a centrosymmetric crystal. The UV-visible spectra of the dyes in 14 solvents of different polarities were investigated. The reversible solvatochromic behavior of the dyes is demonstrated experimentally and compared with known "binuclear dyes" by evaluating the Rezende model. Dye D36 does not fluoresce, and D34 has a very low emission in the solvents tested.

Nα-Aroyl-N-Aryl-Phenylalanine Amides: A Promising Class of Antimycobacterial Agents Targeting the RNA Polymerase.

Tuberculosis (TB), caused by Mycobacterium tuberculosis, remains the leading cause of death from a bacterium in the world. The global prevalence of clinically relevant infections with opportunistically pathogenic non-tuberculous mycobacteria (NTM) has also been on the rise. Pharmacological treatment of both TB and NTM infections usually requires prolonged regimens of drug combinations, and is often challenging because of developed or inherent resistance to common antibiotic drugs. Medicinal chemistry efforts are thus needed to improve treatment options and therapeutic outcomes. Nα-aroyl-N-aryl-phenylalanine amides (AAPs) have been identified as potent antimycobacterial agents that target the RNA polymerase with a low probability of cross resistance to rifamycins, the clinically most important class of antibiotics known to inhibit the bacterial RNA polymerase. In this review, we describe recent developments in the field of AAPs, including synthesis, structural characterization, in vitro microbiological profiling, structure-activity relationships, physicochemical properties, pharmacokinetics and early cytotoxicity assessment.

Synthesis and in†vitro Metabolic Stability of Sterically Shielded Antimycobacterial Phenylalanine Amides.

Nα-aroyl-N-aryl-phenylalanine amides (AAPs) are RNA polymerase inhibitors with activity against Mycobacterium tuberculosis and non-tuberculous mycobacteria. We observed that AAPs rapidly degrade in microsomal suspensions, suggesting that avoiding hepatic metabolism is critical for their effectiveness in vivo. As both amide bonds are potential metabolic weak points of the molecule, we synthesized 16 novel AAP analogs in which the amide bonds are shielded by methyl or fluoro substituents in close proximity. Some derivatives show improved microsomal stability, while being plasma-stable and non-cytotoxic. In parallel with the metabolic stability studies, the antimycobacterial activity of the AAPs against Mycobacterium tuberculosis, Mycobacterium abscessus, Mycobacterium avium and Mycobacterium intracellulare was determined. The stability data are discussed in relation to the antimycobacterial activity of the panel of compounds and reveal that the concept of steric shielding of the anilide groups by a fluoro substituent has the potential to improve the stability and bioavailability of AAPs.

Pyridin-4-ylmethanaminium perchlorate mono-hydrate.

Pyridin-4-ylmethanaminium perchlorate monohydrate (synonym: 4-picolyl-ammonium perchlorate monohydrate), C6H9N2 +·ClO4 -·H2O, crystallizes in the monoclinic system (space group P21/n) with the asymmetric unit comprising two formula units (Z' = 2). All mol-ecular entities are located on general positions. The two crystallographically distinct 4-picolyl-ammonium cations exhibit different conformations. The two unique perchlorate anions are non-disordered, showing an r.m.s. deviation of 0.011 Šfrom mol-ecular T d symmetry. The supra-molecular structure in the solid state features an intricate tri-periodic network of N-H⋯O, O-H⋯N and O-H⋯O hydrogen bonds.

Synthesis, structures, reactivity and medicinal chemistry of antitubercular benzothiazinones.

Tuberculosis is the leading bacterial killer worldwide. 8-Nitro-4H-benzo[e][1,3]thiazin-4-ones are a potent class of antitubercular agents with a new mechanism of action. BTZ043 and PBTZ169 (macozinone) have progressed to clinical studies. Herein, we give a comprehensive account of this important class of potential new drugs to treat tuberculosis. We present an overview of recent developments in the field of antitubercular benzothiazinones (BTZs) and summarize our own contributions. The review covers synthesis, structures and reactivity, mechanism of action, in vitro activity and structure activity relationships (SARs), physicochemical and pharmacokinetic properties as well as a brief summary of in vivo models and clinical studies. We address bioavailability issues and the challenge of the potentially toxic nitroaromatic moiety, including reactivity towards nucleophiles in vivo and highlight possible directions of further research into BTZs through chemical modification.

Synthesis and Characterization of Phenylalanine Amides Active against Mycobacterium abscessus and Other Mycobacteria.

Nα-2-thiophenoyl-d-phenylalanine-2-morpholinoanilide [MMV688845, Pathogen Box; Medicines for Malaria Venture; IUPAC: (2R)-N-(1-((2-morpholinophenyl)amino)-1-oxo-3-phenylpropan-2-yl)thiophene-2-carboxamide)] is a hit compound, which shows activity against Mycobacterium abscessus (MIC90 6.25-12.5 µM) and other mycobacteria. This work describes derivatization of MMV688845 by introducing a thiomorpholine moiety and the preparation of the corresponding sulfones and sulfoxides. The molecular structures of three analogs are confirmed by X-ray crystallography. Conservation of the essential R configuration during synthesis is proven by chiral HPLC for an exemplary compound. All analogs were characterized in a MIC assay against M. abscessus, Mycobacterium intracellulare, Mycobacterium smegmatis, and Mycobacterium tuberculosis. The sulfone derivatives exhibit lower MIC90 values (M. abscessus: 0.78 µM), and the sulfoxides show higher aqueous solubility than the hit compound. The most potent derivatives possess bactericidal activity (99% inactivation of M. abscessus at 12.5 µM), while they are not cytotoxic against mammalian cell lines.

Methyl 1-[(6-meth-oxy-5-methyl-pyrimidin-4-yl)meth-yl]-1H-benzo[d]imidazole-7-carboxyl-ate: a combined X-ray and DFT study.

The title compound, C16H16N4O3, was obtained as a side product during the synthesis of the previously reported anti-tubercular agent N-(2-fluoro-eth-yl)-1-[(6-meth-oxy-5-methyl-pyrimidin-4-yl)meth-yl]-1H-benzo[d]imidazole-4-carboxamide and structurally characterized by X-ray crystallography and computational methods. In the crystal (space group P21/n, Z = 4), the title compound adopts a twisted conformation with a dihedral angle between the benzimidazole and pyrimidine mean planes of 84.11 (3)°. The carboxyl-ate group and the 5-methyl group on the pyrimidine ring exhibit partial disorder. The DFT-optimized mol-ecular structure resembles the structure of the minor component in the crystal.

Crystal structure and anti-mycobacterial evaluation of 2-(cyclo-hexyl-meth-yl)-7-nitro-5-(tri-fluoro-meth-yl)benzo[d]iso-thia-zol-3(2H)-one.

The title compound, C15H15F3N2O3S, crystallizes in the monoclinic system, space group I2/a, with Z = 8. As expected, the nine-membered heterobicyclic system is virtually planar and the cyclo-hexyl group adopts a chair conformation. There is structural evidence for intra-molecular N-S⋯O chalcogen bonding between the benziso-thia-zolinone S atom and one O atom of the nitro group, approximately aligned along the extension of the covalent N-S bond [N-S⋯O = 162.7 (1)°]. In the crystal, the mol-ecules form centrosymmetric dimers through C-H⋯O weak hydrogen bonding between a C-H group of the electron-deficient benzene ring and the benzo-thia-zolinone carbonyl O atom with an R 2 2(10) motif. In contrast to the previously described N-acyl 7-nitro-5-(tri-fluoro-meth-yl)benzo[d]iso-thia-zol-3(2H)-ones, the title N-cyclo-hexyl-methyl analogue does not inhibit growth of Mycobacterium aurum and Mycobacterium smegmatis in vitro.

BTZ-Derived Benzisothiazolinones with In Vitro Activity against Mycobacterium tuberculosis.

8-Nitro-1,3-benzothiazin-4-ones (BTZs) are known as potent antitubercular agents. BTZ043 as one of the most advanced compounds has reached clinical trials. The putative oxidation products of BTZ043, namely, the corresponding BTZ sulfoxide and sulfone, were reported in this journal (Tiwari et al. ACS Med. Chem Lett. 2015, 6, 128-133). The molecular structures were later revised to the constitutionally isomeric benzisothiazolone and its 1-oxide, respectively. Here, we report two BTZ043-derived benzisothiazolinones (BITs) with in vitro activity against mycobacteria. The constitutionally isomeric O-acyl benzisothiazol-3-ols, in contrast, show little or no antimycobacterial activity in vitro. The structures of the four compounds were investigated by X-ray crystallography and NMR spectroscopy. Molecular covalent docking of the new compounds to Mycobacerium tuberculosis decaprenylphosphoryl-ß-d-ribose 2'-epimerase (DprE1) suggests that the active BITs exert antimycobacterial activity through inhibition of DprE1 like BTZs.

New Insight into Dearomatization and Decarbonylation of Antitubercular 4H-Benzo[e][1,3]thiazinones: Stable 5H- and 7H-Benzo[e][1,3]thiazines.

8-Nitro-4H-benzo[e][1,3]thiazinones (BTZs) are potent in vitro antimycobacterial agents. New chemical transformations, viz. dearomatization and decarbonylation, of two BTZs and their influence on the compounds' antimycobacterial properties are described. Reactions of 8-nitro-2-(piperidin-1-yl)-6-(trifluoromethyl)-4H-benzo[e][1,3]thiazin-4-one and the clinical drug candidate BTZ043 with the Grignard reagent CH3 MgBr afford the corresponding dearomatized stable 4,5-dimethyl-5H- and 4,7-dimethyl-7H-benzo[e][1,3]thiazines. These methine compounds are structurally characterized by X-ray crystallography for the first time. Reduction of the BTZ carbonyl group, leading to the corresponding markedly non-planar 4H-benzo[e][1,3]thiazine systems, is achieved using the reducing agent (CH3 )2 S ⋅ BH3 . Double methylation with dearomatization and decarbonylation renders the two BTZs studied inactive against Mycobacterium tuberculosis and Mycobacterium smegmatis, as proven by in vitro growth inhibition assays.

Efficient Synthesis of Benzothiazinone Analogues with Activity against Intracellular Mycobacterium tuberculosis.

8-Nitrobenzothiazinones (BTZs) are a promising class of antimycobacterial agents currently under investigation in clinical trials. Starting from thiourea derivatives, a new synthetic pathway to BTZs was established. It allows the formation of the thiazinone ring system in one synthetic step and is applicable for preparation of a wide variety of BTZ analogues. The synthetic procedure furthermore facilitates the replacement of the sulphur atom in the thiazinone ring system by oxygen or nitrogen to afford the analogous benzoxazinone and quinazolinone systems. 36 BTZ analogues were prepared and tested in luminescence-based assays for in vitro activity against Mycobacterium tuberculosis (Mtb) using the microdilution broth method and a high-throughput macrophage infection assay.

Racemization-free synthesis of Nα-2-thiophenoyl-phenylalanine-2-morpholinoanilide enantiomers and their antimycobacterial activity.

Nα-2-thiophenoyl-D-phenylalanine-2-morpholinoanilide (MMV688845, IUPAC: N-(1-((2-morpholinophenyl)amino)-1-oxo-3-phenylpropan-2-yl)thiophene-2-carboxamide) from the Pathogen Box® library (Medicines for Malaria Ventures, MMV) is a promising lead compound for antimycobacterial drug development. Two straightforward synthetic routes to the title compound starting from phenylalanine or its Boc-protected derivative are reported. Employing Boc-phenylalanine as starting material and the T3P® and PyBOP® amide coupling reagents enables racemization-free synthesis, avoiding the need for subsequent separation of the enantiomers. The crystal structure of the racemic counterpart gives insight into the molecular structure and hydrogen bonding interactions in the solid state. The R-enantiomer of the title compound (derived from D-phenylalanine) exhibits activity against non-pathogenic and pathogenic mycobacterial strains, whereas the S-enantiomer is inactive. Neither of the enantiomers and the racemate of the title compound shows cytotoxicity against various mammalian cells.

Synthesis, structural characterization and antimycobacterial evaluation of several halogenated non-nitro benzothiazinones.

8-Nitro-1,3-benzothiazin-4-ones (BTZs), with BTZ043 and PBTZ169 as the most advanced compounds, represent a new class of potent antitubercular agents, which irreversibly inhibit decaprenylphosphoryl-ß-d-ribose-2'-epimerase (DprE1), an enzyme crucial for cell wall synthesis in the pathogen Mycobacterium tuberculosis. Synthesis, structural characterization and in vitro testing against Mycobacterium aurum DSM 43999 and M. tuberculosis H37Rv of halogenated 2-(4-ethoxycarbonylpiperazin-1-yl)-1,3-benzothiazin-4-ones lacking a nitro group are reported. X-ray crystallography reveals that the structure of the BTZ scaffold can significantly deviate from planarity. In contrast to recent reports, the results of the present study indicate that further investigation of halogenated non-nitro BTZs for antitubercular activity is less than a promising approach.

2-Chloro-3-nitro-5-(tri-fluoro-meth-yl)benzoic acid and -benzamide: structural characterization of two precursors for anti-tubercular benzo-thia-zinones.

8-Nitro-1,3-benzo-thia-zin-4-ones are a promising class of new anti-tubercular agents, two candidates of which, namely BTZ043 and PBTZ169 (INN: macozinone), have reached clinical trials. The crystal and mol-ecular structures of two synthetic precursors, 2-chloro-3-nitro-5-(tri-fluoro-meth-yl)benzoic acid, C8H3ClF3NO4 (1), and 2-chloro-3-nitro-5-(tri-fluoro-meth-yl)benzamide, C8H4ClF3N2O3 (2), are reported. In 1 and 2, the respective carb-oxy, carboxamide and the nitro groups are significantly twisted out of the plane of the benzene ring. In 1, the nitro group is oriented almost perpendicular to the benzene ring plane. In the crystal, 1 and 2 form O-H⋯O and N-H⋯O hydrogen-bonded dimers, respectively, which in 2 extend into primary amide tapes along the [101] direction. The tri-fluoro-methyl group in 2 exhibits rotational disorder with an occupancy ratio of 0.876 (3):0.124 (3).

Crystallographic evidence for unintended benzisothiazolinone 1-oxide formation from benzothiazinones through oxidation.

1,3-Benzothiazin-4-ones (BTZs) are a promising new class of drugs with activity against Mycobacterium tuberculosis, which have already reached clinical trials. A product obtained in low yield upon treatment of 8-nitro-2-(piperidin-1-yl)-6-(trifluoromethyl)-4H-benzothiazin-4-one with 3-chloroperbenzoic acid, in analogy to a literature report describing the formation of sulfoxide and sulfone derived from BTZ043 [Tiwari et al. (2015). ACS Med. Chem. Lett. 6, 128-133], is a ring-contracted benzisothiazolinone (BIT) 1-oxide, namely, 7-nitro-2-(piperidine-1-carbonyl)-5-(trifluoromethyl)benzo[d]isothiazol-3(2H)-one 1-oxide, C14H12F3N3O5S, as revealed by X-ray crystallography. Single-crystal X-ray analysis of the oxidation product originally assigned as BTZ043 sulfone provides clear evidence that the structure of the purported BTZ043 sulfone is likewise the corresponding BIT 1-oxide, namely, 2-[(S)-2-methyl-1,4-dioxa-8-azaspiro[4.5]decane-8-carbonyl]-7-nitro-5-(trifluoromethyl)benzo[d]isothiazol-3(2H)-one 1-oxide, C17H16F3N3O7S. A possible mechanism for the ring contraction affording the BIT 1-oxides instead of the anticipated constitutionally isomeric BTZ sulfones and antimycobacterial activities thereof are discussed.

[2-Chloro-3-nitro-5-(tri-fluoro-meth-yl)phen-yl](piperidin-1-yl)methanone: structural characterization of a side product in benzo-thia-zinone synthesis.

1,3-Benzo-thia-zin-4-ones (BTZs) are a promising new class of anti-tuberculosis drug candidates, some of which have reached clinical trials. The title compound, the benzamide derivative [2-chloro-3-nitro-5-(tri-fluoro-meth-yl)phen-yl](piper-id-in-1-yl)methanone, C13H12ClF3N2O3, occurs as a side product as a result of competitive reaction pathways in the nucleophilic attack during the synthesis of the BTZ 8-nitro-2-(piperidin-1-yl)-6-(tri-fluoro-meth-yl)-1,3-benzo-thia-zin-4-one, following the original synthetic route, whereby the corresponding benzoyl iso-thio-cyanate is reacted with piperidine as secondary amine. In the title compound, the nitro group and the nearly planar amide group are significantly twisted out of the plane of the benzene ring. The piperidine ring adopts a chair conformation. The tri-fluoro-methyl group exhibits slight rotational disorder with a refined ratio of occupancies of 0.972 (2):0.028 (2). There is structural evidence for inter-molecular weak C-H⋯O hydrogen bonds.

A solid solution of ethyl and d 3-methyl 2-[(4-meth-yl-pyridin-2-yl)amino]-4-(pyridin-2-yl)thia-zole-5-carboxyl-ate.

The synthesis of ethyl 2-[(4-methyl-pyridin-2-yl)amino)-4-(pyridin-2-yl)thia-zole- 5-carboxyl-ate via the Hantzsch reaction and partial in situ transesterification during recrystallization from methanol-d 4 to the d 3-methyl ester, resulting in the title solid solution, ethyl 2-[(4-methyl-pyridin-2-yl)amino)-4-(pyridin-2-yl)thia-zole-5-carboxyl-ate-d 3-methyl 2-[(4-methyl-pyridin-2-yl)amino)-4-(pyridin-2-yl)thia-zole-5-carboxyl-ate (0.88/0.12), 0.88C17H16N4O2S·0.12C16D3H11N4O2S, is reported. The refined ratio of ethyl to d 3-methyl ester in the crystal is 0.880 (6):0.120 (6). The pyridine ring is significantly twisted out of the plane of the approximately planar picoline thia-zole ester moiety. N-H⋯N hydrogen bonds between the secondary amino group and the pyridine nitro-gen atom of an adjacent symmetry-related mol-ecule link the mol-ecules into polymeric hydrogen-bonded zigzag tapes extending by glide symmetry in the [001] direction. There is structural evidence for intra-molecular N⋯S chalcogen bonding and inter-molecular weak C-H⋯O hydrogen bonds between adjacent zigzag tapes.

Re-refinement of sodium ammonium sulfate dihydrate at 170†K.

The title compound, sodium ammonium sulfate dihydrate (SASD), NaNH4SO4·2H2O, a synthetic analogue of the mineral lecontite, is a well known ferroelectric. The crystal structure of the paraelectric phase has been re-refined at 170 K on the basis of single-crystal X-ray data, improving the previous study [Arzt & Glazer (1994 ▸). Acta Cryst. B50, 425-431] in terms of accuracy regarding hydrogen-atom positions and thus details of the hydrogen bonding. O-H⋯O and N-H⋯O hydrogen bonds between the principal building units [Na(OH2)4O2 octa-hedra, SO4 tetra-hedra and ammonium cations] constitute a three-dimensional network structure.

Crystal structure of catena-poly[[di-iodidomer-cury(II)]-µ-2,2'-di-thio-bis-(pyridine N-oxide)-κ2O:O'].

The title compound, [HgI2(C10H8N2O2S2)] n , a one-dimensional coordination polymer with HgI2 units and 2,2'-di-thio-bis-(pyridine N-oxide) spacer ligands in an alternating fashion, forms helical chains running along the b axis in the crystal. Within a single coordination polymer strand, the axially chiral 2,2'-di-thio-bis-(pyridine N-oxide) ligands are homochiral, but the enanti-omeric conformation is present in adjacent strands. Within a coordination polymer strand, the iodido ligands point towards the centroids of the aromatic rings of the pyridine N-oxide moieties in the coordination sphere of HgII. Moreover, intra-strand C-H⋯O and C-H⋯I inter-actions, and inter-strand short S⋯I and S⋯O contacts are observed.

Adiponitrile at 100†K.

Adiponitrile, C6H8N2, is a key intermediate in the synthesis of the polyamide Nylon 66 and is produced industrially on a large scale. We have determined the crystal and molecular structure of adiponitrile by single-crystal X-ray analysis at 100 K, a suitable crystal (m.p. 275 K) having been grown from the melt at low temperature. The compound crystallizes in the monoclinic space group P21/c with Z = 2. In the crystal structure, the molecule adopts an exact Ci-symmetric gauche-anti-gauche conformation of the C-C-C-C skeleton about an inversion centre. The molecules are densely packed, with short intermolecular contacts between the α-H and nitrile N atoms.