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.

Synthesis and isolation of a triplet bismuthinidene with a quenched magnetic response.

Large spin-orbit coupling (SOC) is an intrinsic property of the heavy elements that directly affects the electronic structures of the compounds. In this work, we report the synthesis and characterization of a monocoordinate bismuthinidene that features a rigid and bulky ligand. All magnetic measurements [superconducting quantum interference device (SQUID), nuclear magnetic resonance (NMR)] point to a diamagnetic compound. However, multiconfigurational quantum chemical calculations predict the ground state of the compound to be dominated (76%) by a spin triplet. The apparent diamagnetism is explained by an extremely large SOC-induced positive zero-field splitting of more than 4500 wavenumbers that leaves the MS = 0 magnetic sublevel thermally isolated in the electronic ground state.

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.

Strain-Release Pentafluorosulfanylation and Tetrafluoro(aryl)sulfanylation of [1.1.1]Propellane: Reactivity and Structural Insight.

We leveraged the recent increase in synthetic accessibility of SF5 Cl and Ar-SF4 Cl compounds to combine chemistry of the SF5 and SF4 Ar groups with strain-release functionalization. By effectively adding SF5 and SF4 Ar radicals across [1.1.1]propellane, we accessed structurally unique bicyclopentanes, bearing two distinct elements of bioisosterism. Upon evaluating these "hybrid isostere" motifs in the solid state, we measured exceptionally short transannular distances; in one case, the distance rivals the shortest nonbonding C⋅⋅⋅C contact reported to date. This prompted SC-XRD and DFT analyses that support the notion that a donor-acceptor interaction involving the "wing" C-C bonds is playing an important role in stabilization. Thus, these heretofore unknown structures expand the palette for highly coveted three-dimensional fluorinated building blocks and provide insight to a more general effect observed in bicyclopentanes.

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.

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.

A New Ligand Design Based on London Dispersion Empowers Chiral Bismuth-Rhodium Paddlewheel Catalysts.

Heterobimetallic bismuth-rhodium paddlewheel complexes with phenylglycine ligands carrying TIPS-groups at the meta-positions of the aromatic ring exhibit outstanding levels of selectivity in reactions of donor/acceptor and donor/donor carbenes; at the same time, the reaction rates are much faster and the substrate scope is considerably wider than those of previous generations of chiral [BiRh] catalysts. As shown by a combined experimental, crystallographic, and computational study, the new catalysts draw their excellent application profile largely from the stabilization of the chiral ligand sphere by London dispersion (LD) interactions of the peripheral silyl substituents.

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).

Hydrogenative Metathesis of Enynes via Piano-Stool Ruthenium Carbene Complexes Formed by Alkyne gem-Hydrogenation.

The only recently discovered gem-hydrogenation of internal alkynes is a fundamentally new transformation, in which both H atoms of dihydrogen are transferred to the same C atom of a triple bond while the other position transforms into a discrete metal carbene complex. [Cp*RuCl]4 is presently the catalyst of choice: the resulting piano-stool ruthenium carbenes can engage a tethered alkene into either cyclopropanation or metathesis, and a prototypical example of such a reactive intermediate with an olefin ligated to the ruthenium center has been isolated and characterized by X-ray diffraction. It is the substitution pattern of the olefin that determines whether metathesis or cyclopropanation takes place: a systematic survey using alkenes of largely different character in combination with a computational study of the mechanism at the local coupled cluster level of theory allowed the preparative results to be sorted and an intuitive model with predictive power to be proposed. This model links the course of the reaction to the polarization of the double bond as well as to the stability of the secondary carbene complex formed, if metathesis were to take place. The first application of "hydrogenative metathesis" to the total synthesis of sinularones E and F concurred with this interpretation and allowed the proposed structure of these marine natural products to be confirmed. During this synthesis, it was found that gem-hydrogenation also provides opportunities for C-H functionalization. Moreover, silylated alkynes are shown to participate well in hydrogenative metathesis, which opens a new entry into valuable allylsilane building blocks. Crystallographic evidence suggests that the polarized [Ru-Cl] bond of the catalyst interacts with the neighboring R3Si group. Since attractive interligand Cl/R3Si contacts had already previously been invoked to explain the outcome of various ruthenium-catalyzed reactions, including trans-hydrosilylation, the experimental confirmation provided herein has implications beyond the present case.

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.

Chiral Heterobimetallic Bismuth-Rhodium Paddlewheel Catalysts: A Conceptually New Approach to Asymmetric Cyclopropanation.

Cyclopropanation reactions of styrene derivatives with donor-acceptor carbenes formed in situ are significantly more enantioselective when catalyzed by the heterobimetallic bismuth-rhodium complex 5 a endowed with N-phthalimido tert-leucine paddlewheel ligands rather than by its homobimetallic dirhodium analogue 1 a. This virtue is likely the result of two synergizing factors: the conical shape of 5 a translates into a narrower calyx-like chiral binding site about the catalytically active Rh center; the Bi atom, although fully solvent exposed, does not decompose aryl diazoacetates and is hence incapable of promoting a racemic background reaction. Moreover, ligand variation proved that successful catalyst design mandates that the anisotropy of the conical heterobimetallic core be matched by proper directionality of the ligand sphere.

A Highly Reduced Ni-Li-Olefin Complex for Catalytic Kumada-Corriu Cross-Couplings.

The catalytic activity of a highly reduced Ni catalyst in the context of a Kumada-Corriu cross-coupling has been studied. This nickel complex is characterized by its high electron density, stabilized by simple olefin ligands in combination with two Li ions. Landmark reactivity has been found with this precatalyst which operates at cryogenic temperatures, thus allowing the presence of sensitive functionalities. Structural elucidation of oxidative addition intermediates and their reactivity suggest highly reduced species being operative in the C-C bond forming event.

Complete charge separation provoked by full cation encapsulation in the radical mono- and di-anions of 5,6:11,12-di-o-phenylene-tetracene.

Herein, we report the synthesis and molecular structure of the mono- and dianionic aromatic molecules [(B15C5-κ5O)2K+](LDOPT˙-) (1) and [(B15C5-κ5O)2K+]2(LDOPT2-)THFsolv (2) derived from the parent aromatic polyhydrocarbon 5,6:11,12-di-o-phenylenetetracene (DOPT, LDOPT) by a controlled stepwise one and two electron chemical reduction. The effect of single and double electron charge transfer to a polycondensed aromatic hydrocarbon (PAH) without any disturbing influence of an associated metal cation has been demonstrated. This was achieved by fully sandwiching the cationic K+ counterions between two benzo-15-crown-5-ether (B15C5) ligands resulting in a fully encapsulating (κ10O) geometry which ensures a complete separation of the K+ counterions and the bare anionic PAH species [LDOPT˙-] and [LDOPT2-]. The structural changes accompanied by the stepwise reduction from LDOPT to [LDOPT˙-] to [LDOPT2-] are discussed and compared to earlier predictions based on density functional theory (DFT) as well as the results of previous studies of alkaline metal cationic PAH anion interactions of DOPT in which only a partial metal cation encapsulation has been achieved so far.