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As a result of a high-throughput compound screening campaign using Mycobacterium tuberculosis -infected macrophages, a new drug candidate for the treatment of tuberculosis has been identified. GSK2556286 inhibits growth within human macrophages (50% inhibitory concentration [IC 50 ] = 0.07 μM), is active against extracellular bacteria in cholesterol-containing culture medium, and exhibits no cross-resistance with known antitubercular drugs.

In the course of optimizing a novel indazole sulfonamide series that inhibits β-ketoacyl-ACP synthase (KasA) of Mycobacterium tuberculosis, a mutagenic aniline metabolite was identified. Further lead optimization efforts were therefore dedicated to eliminating this critical liability by removing the embedded aniline moiety or modifying its steric or electronic environment. While the narrow SAR space against the target ultimately rendered this goal unsuccessful, key structural knowledge around the binding site of this underexplored target for TB was generated to inform future discovery efforts.

Phenotypic screening of inhibitors of the essential Mycobacterium tuberculosis FAS-II dehydratase HadAB led to the identification of GSK3011724A, a compound previously reported to inhibit the condensation step of FAS-II. Whole-cell-based and cell-free assays confirmed the lack of activity of GSK3011724A against the dehydratase despite evidence of cross-resistance between GSK3011724A and HadAB inhibitors. The nature of the resistance mechanisms is suggestive of alterations in the FAS-II interactome reducing access of GSK3011724A to KasA.

Background Whole‐cell phenotypic screening is the driving force behind modern anti‐tubercular drug discovery efforts. Focus has shifted from screening for bactericidal scaffolds to screens incorporating target deconvolution. Target‐based screening aims to direct drug discovery toward known effective targets and avoid investing resources into unproductive lines of enquiry. The protein synthesis pipeline, including RNA polymerase and the ribosome, is a clinically proven target in Mycobacterium tuberculosis. Screening for new hits of this effective target pathway is an invaluable tool in the drug discovery arsenal. Methods Using M. tuberculosis H37Rv augmented with anhydrotetracycline‐inducible expression of mCherry, a phenotypic screen was developed for the identification of protein synthesis inhibitors in a medium throughput screening format. Results The assay was validated using known inhibitors of protein synthesis to show a dose‐dependent reduction in mCherry fluorescence. This was expanded to a proprietary screen of hypothetical protein synthesis hits and modified to include quantitative viability measurement of cells using resazurin. Conclusion Following the success of the proprietary screen, a larger scale screen of the GlaxoSmithKline anti‐tubercular library containing 2799 compounds was conducted. Combined single shot and dose‐response screening yielded 18 hits, 0.64% of all screened compounds.

Society urgently needs new, effective medicines for the treatment of tuberculosis. To kick-start the required hit-to-lead campaigns, the libraries of pharmaceutical companies have recently been evaluated for starting points. The GlaxoSmithKline (GSK) library yielded many high-quality hits, and the associated data were placed in the public domain to stimulate engagement by the wider community. One such series, the spiro compounds, are described here. The compounds were explored by a combination of traditional in-house research and open source methods. The series benefits from a particularly simple structure and a short associated synthetic chemistry route. Many members of the series displayed striking potency and low toxicity, and highly promising in vivo activity in a mouse model was confirmed with one of the analogues. Ultimately the series was discontinued due to concerns over safety, but the associated data remain public domain, empowering others to resume the series if the perceived deficiencies can be overcome.

Enantiomerically pure THPPs are useful pharmacological agents in relevant therapeutic areas such as tuberculosis, osteoporosis and hepatitis C. Typically resolved by preparative chiral HPLC, in this work the catalytic approach – via hydrolase-catalyzed kinetic resolution – has been demonstrated for the first time. After biocatalytic successful proof-of-concept, future opportunities for protein engineering and process set-up appear.

The feasibility of using chiral Lewis acids as catalysts to promotethe inverse-electron-demand Diels-Alder reactions of 1-azadieneswith vinyl ethers has been demonstrated. Two catalyst systems wereidentified for this reaction, both relying on the presence of acoordinating 2-pyridylsulfonyl or 8-quinolylsulfonyl group at theimine nitrogen of the 1-azadiene. The combination of a 8-quinolylsulfonylmoiety and nickel(II)/DBFOX-Ph proved to be highly efficient,allowing the synthesis of substituted piperidine derivatives ingood yields, excellent ENDO selectivity,and enantio-selectivities typically in the range of 77to 92% ee.

The different behavior of N-tosyl imines and N-(2-pyridyl)sulfonyl imines in Cu (II)-catalyzed AFCR is described. DFT theoretical calculations on the mode of coordination of the copper atom to both types of substrates allow understanding this different reactivity.

Nano conjugated thienylethenyl and thienylethynyl compounds with controlled structure and dimensions have been efficiently prepared, by heterocoupling reaction between 1,4-(thienylethynyl)phenylacetylene (or thienylethenyl)phenylacetylene and 2- or 2,5-dihalothiophene. Conjugated 1,4-di(2-thienylethynylphenyl)- (or 2-thienylethenylphenyl)-1,3-butadiyne were obtained by the homocoupling of the terminal acetylenes in excellent yield. The end-capped (N,N-dimethylaminophenyl)- and [3,5-di(trimethylsilylethynyl)-1-ethynyl]-2,5-di(phenylethynyl)nthiophene were obtained by the heterocoupling between the corresponding terminal acetylene and 2,5-di(iodo)thiophene, catalyzed by the bis(triphenylphosphine)palladium and cuprous iodide system in excellent yield.

[reaction: see text] The enantioselective catalytic 1,4-addition to alpha,beta-unsaturated ketimines is an unprecedented process. Herein, we document the copper-catalyzed addition of dialkylzinc reagents to (2-pyridylsulfonyl)imines of chalcones. This process occurs rapidly in the presence of a chiral phosphoramidite ligand to afford exclusively the 1,4-addition product. In the case of addition of dimethylzinc, enantioselectivities in the range 70-80% ee are obtained. The presence of the metal-coordinating 2-pyridylsulfonyl group proved to be essential for this reaction to proceed.

End-capped (N,N-dimethylaminophenyl) and 2′-thienylethynyl 2,5-thiophene oligomer structures were synthesized by heterocoupling between the terminal acetylenes such as: p-(N,N-dimethylaminophenyl)ethyne (3) [or 1-(p-(N,N-dimethylaminophenyl)-2-p-(ethynylphenyl)ethyne, 4]; p-(β-ethenyl-2′-thienyl)phenylethyne (E-9) [or p-(β-ethynyl-2′-thienyl)phenylethyne, 11], and 2,5-diiodothiophene, catalyzed by the Cl2Pd(PPh3)2/CuI system, in good to excellent yields. The 2,5-di[(3′,5′-di(trimethylsilylethynyl)phenyl]x-1-ethynyl]thiophene oligomers were prepared by heterocoupling between 3′,5′-di[(trimethylsilylethynyl)phenyl]x-1-ethyne (n = 0–2) terminal acetylenes and 2,5-diiodothiophene, in excellent yields. The terminal acetylenes were efficiently prepared by a specific protection-deprotection methodology. All the ethynylphenyl compounds obtained show fluorescence radiation emission, with a bathochromic shift of the wavelength that increases with the chain conjugation.

Because an array of interesting target molecules include ketones that bear an α-aryl substituent, the development of methods for the synthesis of this structural motif has been an active area of investigation.[1] For example, extensive effort has recently been devoted to the discovery of palladium catalysts for the cross-coupling of ketones with aryl halides in the presence of a Bronsted base (path A in eq 1; via an enolate).[2] Furthermore, in the case of α, α-disubstituted ketones, catalytic asymmetric α-arylations have been described wherein quaternary stereocenters are generated with excellent enantioselectivity.[3,4] Unfortunately, these methods cannot be applied to the asymmetric synthesis of more commonly encountered tertiary stereocenters, due to the propensity of α-arylketones such as 1 to enolize under the reaction conditions.[5,6] (1) Alternatively, an umpolung arylation process, whereby a ketone that bears an α leaving group reacts with an arylmetal reagent, could provide the target α-arylketone (path B in eq 1). Until recently, there were no examples of palladium- or nickel-catalyzed cross-couplings between secondary α-halocarbonyl compounds and arylmetals (metal = B, Si, Sn, or Zn). In 2007, we reported that a nickel catalyst can achieve Hiyama arylation reactions with a wide array of electrophiles, including secondary α-halocarbonyl compounds (and Lei later described a nickel-based method for Suzuki couplings).[7] In the case of α-haloesters, we were able to subsequently develop a catalytic asymmetric α-arylation process that furnishes tertiary stereocenters (eq 2; TBAT = [F2SiPh3]−[NBu4).[8] However, we could not apply this method to corresponding Hiyama arylations of α-haloketones, presumably due to the Bronsted-basic reaction conditions.[9,10] (2) Unlike cross-coupling processes such as the Hiyama and Suzuki reactions, which often employ Lewis/Bronsted-basic activators, the Negishi reaction typically proceeds without an additive,[11,12] thereby making it an attractive starting point for the development of a method for the catalytic asymmetric α-arylation of ketones to generate (potentially labile) tertiary stereocenters. In this report, we establish that a nickel/pybox catalyst can indeed achieve enantioselective cross-couplings of racemic α-bromoketones with arylzinc reagents under very mild conditions in good ee and yield (eq3).[13,14] (3) The data in Table 1 illustrate the role that various reaction parameters play in determining the efficiency of this stereoconvergent Negishi α-arylation of ketones. Thus, no cross-coupling occurs if NiCl2·glyme is omitted (Table 1, entry 2), whereas carbon-carbon bond formation does proceed in the absence of ligand 2[15] (Table 1, entry 3). Pybox ligands other than 2 furnish lower ee and yield (Table 1, entries 4 and 5), as do solvents other than a glyme/THF mixture (Table 1, entries 6–8). At room temperature, the catalyst system is somewhat less effective than at −30 °C (Table 1, entry 9). Table 1 Catalytic asymmetric arylations of racemic α-bromoketones: Effect of reaction parameters With our optimized method, we can achieve Negishi cross-couplings of racemic 2-bromopropiophenone with an array of arylzinc reagents in excellent ee and good yield (Table 2)[16] although the efficiency of the process is sensitive to the steric demand of the nucleophile (Table 2, entry 2). The organozinc can include a range of functional groups, such as OR, halogen, NR2, and SR. Diarylzinc reagents (Ar2Zn) and arylzinc iodides (ArZnl) generally furnish similar enantioselectivities and yields (e.g., Table 2, entry 1)[17] The α-arylated ketone is stable to racemization under these conditions. Table 2 Catalytic asymmetric arylations of racemic α-bromoketones: Variation of the nucleophile We have examined the scope of this method for the catalytic asymmetric α-arylation of ketones not only with respect to the nucleophile (Table 2), but also the electrophile (Table 3). Very good ee’s and useful yields are observed with a variety of α-alkyl substituents, including those that are functionalized (Table 3, entries 2 and 3) and β-branched (Table 3, entry 4); however, if R is large, little of the cross-coupling product is formed (Table 3, entry 5). If the aryl group of the ketone is bulky, the reaction proceeds with moderate enantioselectivity (Table 3, entries 6 and 7). On the other hand, good ee’s are observed regardless of whether the group is electron-rich (Table 3, entry 8) or electron-poor (Table 3, entry 9). A thiophene is compatible with this nickel-based coupling process (Table 3, entry 10).[18] Table 3 Catalytic asymmetric arylations of racemic α-bromoketones: Variation of the electrophile In conclusion, we have developed the first catalytic asymmetric method for cross-coupling arylmetal reagents with α-haloketones, specifically, the NiCl2·glyme/2-catalyzed reaction of arylzincs with racemic secondary α-bromoketones. This stereoconvergent carbon–carbon bond-forming process occurs under unusually mild conditions (−30 °C and no activators), thereby allowing the generation of potentially labile tertiary stereocenters. Ongoing efforts are directed at further expanding the scope of cross-coupling reactions of alkyl electrophiles.

Mycobacterium tuberculosis is a major human pathogen and the causative agent for the pulmonary disease, tuberculosis (TB). Current treatment programs to combat TB are under threat due to the emergence of multi-drug and extensively-drug resistant TB. As part of our efforts towards the discovery of new anti-tubercular leads, a number of potent tetrahydropyrazolo[1,5-a]pyrimidine-3-ca​rboxamide(THPP) and N-benzyl-6′,7′-dihydrospiro[piperidine-4,​4′-thieno[3,2-c]pyran](Spiro) analogues were recently identified against Mycobacterium tuberculosis and Mycobacterium bovis BCG through a high-throughput whole-cell screening campaign. Herein, we describe the attractive in vitro and in vivo anti-tubercular profiles of both lead series. The generation of M. tuberculosis spontaneous mutants and subsequent whole genome sequencing of several resistant mutants identified single mutations in the essential mmpL3 gene. This ‘genetic phenotype’ was further confirmed by a ‘chemical phenotype’, whereby M. bovis BCG treated with both the THPP and Spiro series resulted in the accumulation of trehalose monomycolate. In vivo efficacy evaluation of two optimized THPP and Spiro leads showed how the compounds were able to reduce >2 logs bacterial cfu counts in the lungs of infected mice.

Drug therapy is the mainstay of antimalarial therapy, yet current drugs are threatened by the development of resistance. In an effort to identify new potential anti-malarials we have undertaken a lead optimization program around our previously identified triazolopyrimidine-based series of Plasmodium falciparum dihydroorotate dehydrogenase (PfDHODH) inhibitors. The X-ray structure of PfDHODH was used to inform the medicinal chemistry program allowing the identification of a potent and selective inhibitor (DSM265) that acts through DHODH inhibition to kill both sensitive and drug resistant strains of the parasite. This compound has similar potency to chloroquine in the humanized SCID mouse P. falciparum model, can be synthesized by a simple route, and rodent pharmacokinetic studies demonstrated it has excellent oral bioavailability, a long half-life and low clearance. These studies have identified the first candidate in the triazolopyrimidine series to meet previously established progression criteria for efficacy and ADME properties, justifying further development of this compound towards clinical candidate status.

Because an array of interesting target molecules include ketones that bear an α-aryl substituent, the development of methods for the synthesis of this structural motif has been an active area of investigation.[1] For example, extensive effort has recently been devoted to the discovery of palladium catalysts for the cross-coupling of ketones with aryl halides in the presence of a Bronsted base (path A in eq 1; via an enolate).[2] Furthermore, in the case of α, α-disubstituted ketones, catalytic asymmetric α-arylations have been described wherein quaternary stereocenters are generated with excellent enantioselectivity.[3,4] Unfortunately, these methods cannot be applied to the asymmetric synthesis of more commonly encountered tertiary stereocenters, due to the propensity of α-arylketones such as 1 to enolize under the reaction conditions.[5,6] (1) Alternatively, an umpolung arylation process, whereby a ketone that bears an α leaving group reacts with an arylmetal reagent, could provide the target α-arylketone (path B in eq 1). Until recently, there were no examples of palladium- or nickel-catalyzed cross-couplings between secondary α-halocarbonyl compounds and arylmetals (metal = B, Si, Sn, or Zn). In 2007, we reported that a nickel catalyst can achieve Hiyama arylation reactions with a wide array of electrophiles, including secondary α-halocarbonyl compounds (and Lei later described a nickel-based method for Suzuki couplings).[7] In the case of α-haloesters, we were able to subsequently develop a catalytic asymmetric α-arylation process that furnishes tertiary stereocenters (eq 2; TBAT = [F2SiPh3]−[NBu4).[8] However, we could not apply this method to corresponding Hiyama arylations of α-haloketones, presumably due to the Bronsted-basic reaction conditions.[9,10] (2) Unlike cross-coupling processes such as the Hiyama and Suzuki reactions, which often employ Lewis/Bronsted-basic activators, the Negishi reaction typically proceeds without an additive,[11,12] thereby making it an attractive starting point for the development of a method for the catalytic asymmetric α-arylation of ketones to generate (potentially labile) tertiary stereocenters. In this report, we establish that a nickel/pybox catalyst can indeed achieve enantioselective cross-couplings of racemic α-bromoketones with arylzinc reagents under very mild conditions in good ee and yield (eq3).[13,14] (3) The data in Table 1 illustrate the role that various reaction parameters play in determining the efficiency of this stereoconvergent Negishi α-arylation of ketones. Thus, no cross-coupling occurs if NiCl2·glyme is omitted (Table 1, entry 2), whereas carbon-carbon bond formation does proceed in the absence of ligand 2[15] (Table 1, entry 3). Pybox ligands other than 2 furnish lower ee and yield (Table 1, entries 4 and 5), as do solvents other than a glyme/THF mixture (Table 1, entries 6–8). At room temperature, the catalyst system is somewhat less effective than at −30 °C (Table 1, entry 9). Table 1 Catalytic asymmetric arylations of racemic α-bromoketones: Effect of reaction parameters With our optimized method, we can achieve Negishi cross-couplings of racemic 2-bromopropiophenone with an array of arylzinc reagents in excellent ee and good yield (Table 2)[16] although the efficiency of the process is sensitive to the steric demand of the nucleophile (Table 2, entry 2). The organozinc can include a range of functional groups, such as OR, halogen, NR2, and SR. Diarylzinc reagents (Ar2Zn) and arylzinc iodides (ArZnl) generally furnish similar enantioselectivities and yields (e.g., Table 2, entry 1)[17] The α-arylated ketone is stable to racemization under these conditions. Table 2 Catalytic asymmetric arylations of racemic α-bromoketones: Variation of the nucleophile We have examined the scope of this method for the catalytic asymmetric α-arylation of ketones not only with respect to the nucleophile (Table 2), but also the electrophile (Table 3). Very good ee’s and useful yields are observed with a variety of α-alkyl substituents, including those that are functionalized (Table 3, entries 2 and 3) and β-branched (Table 3, entry 4); however, if R is large, little of the cross-coupling product is formed (Table 3, entry 5). If the aryl group of the ketone is bulky, the reaction proceeds with moderate enantioselectivity (Table 3, entries 6 and 7). On the other hand, good ee’s are observed regardless of whether the group is electron-rich (Table 3, entry 8) or electron-poor (Table 3, entry 9). A thiophene is compatible with this nickel-based coupling process (Table 3, entry 10).[18] Table 3 Catalytic asymmetric arylations of racemic α-bromoketones: Variation of the electrophile In conclusion, we have developed the first catalytic asymmetric method for cross-coupling arylmetal reagents with α-haloketones, specifically, the NiCl2·glyme/2-catalyzed reaction of arylzincs with racemic secondary α-bromoketones. This stereoconvergent carbon–carbon bond-forming process occurs under unusually mild conditions (−30 °C and no activators), thereby allowing the generation of potentially labile tertiary stereocenters. Ongoing efforts are directed at further expanding the scope of cross-coupling reactions of alkyl electrophiles.

A convenient and efficient synthesis of 3,5-di(trimethylsilylethynyl)phenylacetylene and p-[3,5-di(trimethylsilylethynyl)-1-phenylethynyl]phenylacetylene and the naphthylethynyl homologues terminal acetylenes of 5-(N,N-dimethylamino)naphthylethyne have been carried out. These terminal acetylene compounds serve to prepare nanometer-sized conjugated 1,3,5-tri(ethynylphenyl)benzene and 1,3,5-tri(ethynylnaphthyl)benzene oligomers, by means of heterocoupling with 1,3,5-triiodobenzene, catalysed by palladium, in excellent yields. Both the ethynylphenyl or ethynylnaphthyl homologues chains show fluorescence emission radiation, with important quantum yield.

Nanometer-sized conjugated 1,4- and 1,3,5-ethynylphenyl oligomers were synthesized starting from 3,5-di(trimethylsilylethynyl)phenylacetylene and p-[3,5-di(trimethylsilylethynyl)-1-ethynylphenyl]phenyl acetylene by cross-coupling reaction with a convenient haloaryl derivative, catalyzed by palladium(II)/copper(I), in excellent yield. The terminal acetylenes were efficiently prepared by a specific protection-deprotection methodology. All ethynylphenyl homologues obtained show fluorescence emission, with the bathochromic shift of approximately 20 nm by each ethynylphenyl unit increasing the conjugate chain. Parallel conjugated ethynylphenyl chains were prepared through the insertion of a 1,5-naphthalene subunit, and the compounds exhibit fluorescence radiation emission.