Investigating the efficacy of green solvents and solvent-free conditions in hydrogen-bonding mediated organocatalyzed model reactions.

In this study, we have delved into various reactions conducted using green solvents or under solvent-free conditions, employing hydrogen bonding organocatalysis to advance more sustainable practices in chemical synthesis. The outcomes suggest that cyclopentyl methyl ether could potentially replace non-polar organic solvents such as hexane and toluene with comparable enantioselectivity and yields. The non-polar nature of liquefied or supercritical CO2 restricts its application to reactions that require non-polar solvents. Furthermore, pursuing solvent-free conditions, even without liquid substrates, might result in similar conversion rates with reduced catalyst loading. These findings highlight the potential of exploring solvent-free conditions when enantioselectivity is not of concern. Based on the results, solvent-free conditions and bio-based solvents can serve as viable alternatives to conventional organic solvents without compromising performance. This is expected to influence the way chemists approach reaction optimisation within method development in the field, fostering a broader adoption of environmentally friendly approaches.

Synthesis and biological evaluation of novel ß-lactam-metallo ß-lactamase inhibitors.

ß-lactamases are enzymes that deactivate ß-lactam antibiotics through a hydrolysis mechanism. There are two known types of ß-lactamases: serine ß-lactamases (SBLs) and metallo ß-lactamases (MBLs). The two existing strategies to overcome ß-lactamase-mediated resistance are (a) to develop novel ß-lactam antibiotics that are not susceptible to hydrolysis by these enzymes; or (b) to develop ß-lactamase inhibitors that deactivate the enzyme and thereby restore the efficacy of the co-administered antibiotics. Many commercially available SBL inhibitors are used in combination therapy with antibiotics to treat antimicrobial resistant infections; however, there are only a handful of MBL inhibitors undergoing clinical trials. In this study, we present 11 novel potential MBL inhibitors (via multi-step chemical synthesis), that have shown to completely restore the efficacy of meropenem (≤2 mg L-1) against New Delhi metallo-ß-lactamase (NDM) producing Klebsiella pneumoniae in vitro. These compounds contain a cyclic amino acid zinc chelator conjugated to various commercially available ß-lactam antibiotic scaffolds with the aim to improve the overall drug transport, lipophilicity, and pharmacokinetic/pharmacodynamic properties as compared to the chelator alone. Biological evaluation of compounds 24b and 24c has further highlighted the downstream application of these MBLs, since they are non-toxic at the selected doses. Time-kill assays indicate that compounds 24b and 24c exhibit sterilizing activity towards NDM producing Klebsiella pneumoniae in vitro using minimal concentrations of meropenem. Furthermore, 24b and 24c proved to be promising inhibitors of VIM-2 (Ki = 0.85 and 1.87, respectively). This study has revealed a novel series of ß-lactam MBLIs that are potent, efficacious, and safe leads with the potential to develop into therapeutic MBLIs.

Neutralizing Carbapenem Resistance by Co-Administering Meropenem with Novel ß-Lactam-Metallo-ß-Lactamase Inhibitors.

Virulent Enterobacterale strains expressing serine and metallo-ß-lactamases (MBL) genes have emerged responsible for conferring resistance to hard-to-treat infectious diseases. One strategy that exists is to develop ß-lactamase inhibitors to counter this resistance. Currently, serine ß-lactamase inhibitors (SBLIs) are in therapeutic use. However, an urgent global need for clinical metallo-ß-lactamase inhibitors (MBLIs) has become dire. To address this problem, this study evaluated BP2, a novel beta-lactam-derived ß-lactamase inhibitor, co-administered with meropenem. According to the antimicrobial susceptibility results, BP2 potentiates the synergistic activity of meropenem to a minimum inhibitory concentration (MIC) of ≤1 mg/L. In addition, BP2 is bactericidal over 24 h and safe to administer at the selected concentrations. Enzyme inhibition kinetics showed that BP2 had an apparent inhibitory constant (Kiapp) of 35.3 µM and 30.9 µM against New Delhi Metallo-ß-lactamase (NDM-1) and Verona Integron-encoded Metallo-ß-lactamase (VIM-2), respectively. BP2 did not interact with glyoxylase II enzyme up to 500 µM, indicating specific (MBL) binding. In a murine infection model, BP2 co-administered with meropenem was efficacious, observed by the >3 log10 reduction in K. pneumoniae NDM cfu/thigh. Given the promising pre-clinical results, BP2 is a suitable candidate for further research and development as an (MBLI).

In Vitro and In Vivo Development of a ß-Lactam-Metallo-ß-Lactamase Inhibitor: Targeting Carbapenem-Resistant Enterobacterales.

ß-lactams are the most prescribed class of antibiotics due to their potent, broad-spectrum antimicrobial activities. However, alarming rates of antimicrobial resistance now threaten the clinical relevance of these drugs, especially for the carbapenem-resistant Enterobacterales expressing metallo-ß-lactamases (MBLs). Antimicrobial agents that specifically target these enzymes to restore the efficacy of last resort ß-lactam drugs, that is, carbapenems, are therefore desperately needed. Herein, we present a cyclic zinc chelator covalently attached to a ß-lactam scaffold (cephalosporin), that is, BP1. Observations from in vitro assays (with seven MBL expressing bacteria from different geographies) have indicated that BP1 restored the efficacy of meropenem to ≤ 0.5 mg/L, with sterilizing activity occurring from 8 h postinoculation. Furthermore, BP1 was nontoxic against human hepatocarcinoma cells (IC50 > 1000 mg/L) and exhibited a potency of (Kiapp) 24.8 and 97.4 µM against Verona integron-encoded MBL (VIM-2) and New Delhi metallo ß-lactamase (NDM-1), respectively. There was no inhibition observed from BP1 with the human zinc-containing enzyme glyoxylase II up to 500 µM. Preliminary molecular docking of BP1 with NDM-1 and VIM-2 sheds light on BP1's mode of action. In Klebsiella pneumoniae NDM infected mice, BP1 coadministered with meropenem was efficacious in reducing the bacterial load by >3 log10 units' postinfection. The findings herein propose a favorable therapeutic combination strategy that restores the activity of the carbapenem antibiotic class and complements the few MBL inhibitors under development, with the ultimate goal of curbing antimicrobial resistance.

Potential of brain mast cells for therapeutic application in the immune response to bacterial and viral infections.

A wide range of microorganisms can infect the central nervous system (CNS). The immune response of the CNS provides limited protection against microbes penetrating the blood-brain barrier. This results in a neurological deficit and sometimes leads to high morbidity and mortality rates despite advanced therapies. For the last two decades, different studies have expanded our understanding of the molecular basis of human neuroinfectious diseases, especially concerning the contributions of mast cell interactions with other central nervous system compartments. Brain mast cells are multifunctional cells derived from the bone marrow and reside in the brain. Their proximity to blood vessels, their role as "first responders" their unique receptors systems and their ability to rapidly release pathogen responsive mediators enable them to exert a crucial defensive role in the host-defense system. This review describes key biological and physiological functions of mast cells, concerning their ability to recognize pathogens via various receptor systems, followed by a coordinated and selective mediator release upon specific interactions with pathogenic stimulating factors. The goal of this review is to direct attention to the possibilities for therapeutic applications of mast cells against bacterial and viral related infections. We also focus on opportunities for future research activating mast cells via adjuvants.

Correction to "Improved Synthesis and Isolation of Bedaquiline".

[This corrects the article DOI: 10.1021/acsomega.9b04037.].

Characterization of More Selective Central Nervous System Nrf2-Activating Novel Vinyl Sulfoximine Compounds Compared to Dimethyl Fumarate.

The Nrf2 transcription factor is a key regulator of redox reactions and considered the main target for the multiple sclerosis (MS) drug dimethyl fumarate (DMF). However, exploration of additional Nrf2-activating compounds is motivated, since DMF displays significant off-target effects and has a relatively poor penetrance to the central nervous system (CNS). We de novo synthesized eight vinyl sulfone and sulfoximine compounds (CH-1-CH-8) and evaluated their capacity to activate the transcription factors Nrf2, NFκB, and HIF1 in comparison with DMF using the pTRAF platform. The novel sulfoximine CH-3 was the most promising candidate and selected for further comparison in vivo and later an experimental model for traumatic brain injury (TBI). CH-3 and DMF displayed comparable capacity to activate Nrf2 and downstream transcripts in vitro, but with less off-target effects on HIF1 from CH-3. This was verified in cultured microglia and oligodendrocytes (OLs) and subsequently in vivo in rats. Following TBI, DMF lowered the number of leukocytes in blood and also decreased axonal degeneration. CH-3 preserved or increased the number of pre-myelinating OL. While both CH-3 and DMF activated Nrf2, CH-3 showed less off-target effects and displayed more selective OL associated effects. Further studies with Nrf2-acting compounds are promising candidates to explore potential myelin protective or regenerative effects in demyelinating disorders.

A 2018-2019 patent review of metallo beta-lactamase inhibitors.

INTRODUCTION: Antibiotic resistance caused by beta-lactamase expressing bacteria poses a concern given its global dissemination and proliferation. The emergence of the metallo beta-lactamases is an indefinite health threat toward which current antibiotics have limited clinical efficacy. One solution is to develop metallo beta-lactamase inhibitors (MBLIs) capable of restoring the activity of beta-lactam drugs. AREAS COVERED: This review focuses on potential metallo beta-lactamase inhibitors that have been patented during the period of 2018-2019. The aim is to provide insight into the diverse class of compounds which exhibit a synergistic inhibitory effect on carbapenem-resistant bacteria, when co-administered with a beta-lactam antibiotic. EXPERT OPINION: The treatment strategy, of creating a broad-spectrum beta-lactamase inhibitor, is beneficial to the health sector as well as rural communities. Unfortunately, most of the inhibitors lack published data from both in vitro and in vivo evaluation, thus preventing an expert opinion on the likelihood to progress as candidates for clinical trials. From this report, the bismuth complexes, pyridinyl-nicotinamide derived sugars, boronic acid, and thiazole sulfonamide derivatives, portray promising properties for further advancement. Since there is currently no FDA approved MBLI, there remains an urgent need for the development of these combination treatment strategies.

Comprehensive chemical proteomics for target deconvolution of the redox active drug auranofin.

Chemical proteomics encompasses novel drug target deconvolution methods in which compound modification is not required. Herein we use Thermal Proteome Profiling, Functional Identification of Target by Expression Proteomics and multiplexed redox proteomics for deconvolution of auranofin targets to aid elucidation of its mechanisms of action. Auranofin (Ridaura®) was approved for treatment of rheumatoid arthritis in 1985. Because several clinical trials are currently ongoing to repurpose auranofin for cancer therapy, comprehensive characterization of its targets and effects in cancer cells is important. Together, our chemical proteomics tools confirmed thioredoxin reductase 1 (TXNRD1, EC:1.8.1.9) as a main auranofin target, with perturbation of oxidoreductase pathways as the top mechanism of drug action. Additional indirect targets included NFKB2 and CHORDC1. Our comprehensive data can be used as a proteomic signature resource for further analyses of the effects of auranofin. Here we also assessed the orthogonality and complementarity of different chemical proteomics methods that can furnish invaluable mechanistic information and thus the approach can facilitate drug discovery efforts in general.

Improved Synthesis and Isolation of Bedaquiline.

Bedaquiline (BDQ) is the most critical pharmaceutical in the world for treating multidrug-resistant Mycobacterium tuberculosis. Despite it being highly effective, BDQ asymmetric synthesis remains a challenge. Herein, the influence of chiral bases, namely, bis(1-phenylethyl)amine, bisoxazoline, and sparteine on the diastereoselective lithiation reaction to obtain BDQ was investigated. The highest diastereoselective ratio (dr) emerged as 90:10 from the (+)-bis[(R)-1-phenylethyl] lithium amide. This is a significant improvement from the 50:50 dr achieved from the commercial synthesis. Thereafter, the desired (90:10 RS, SR) diastereomeric mixture was easily isolated via a gravity column and subjected to chiral supercritical fluid chromatography (SFC) to access the desired enantiomer (1R, 2S)-BDQ. The advantages of this procedure are enhanced diastereoselection as well as a greener, faster way to achieve excellent enantioseparation (up to 1.0 g scale).

N-Trifluoromethylthiolated Sulfonimidamides and Sulfoximines: Anti-microbial, Anti-mycobacterial, and Cytotoxic Activity.

Herein we demonstrate the expanded utility of a recently described N-trifluoromethylthiolation protocol to sulfonimidamide containing substances. The novel N-trifluoromethylthio sulfonimidamide derivatives thus obtained were evaluated for antibacterial activity against Mycobacterium tuberculosis (M. tb.) and Mycobacterium abscessus and Gram + Ve (Streptococcus aureus, Bacillus subtilis), and Gram - Ve (Escherichia coli, Pseudomonas aeruginosa) bacteria. Two compounds, 13 and 15 showed high antimycobacterial activity with MIC value of 4-8 µg/mL; i.e. comparable to WHO recommended first line antibiotic for TB infection ethambutol. The same compounds were also found to be cytotoxic in HepG2 cells (compound 13 IC50 = 15 µg/mL; compound 15 IC50 = 65 µg/mL). A structure activity relationship, using matched pair analysis, gave the unexpected conclusion that the trifluoromethylthio moiety was responsible for the cellular and bacterial toxicity. Given the increasing use of the trifluoromethylthio group in contemporary medicinal chemistry, this observation calls for considerations before implementation of the functionality in drug design.

The downfall of TBA-354 - a possible explanation for its neurotoxicity via mass spectrometric imaging.

1. TBA-354 was a promising antitubercular compound with activity against both replicating and static Mycobacterium tuberculosis (M.tb), making it the focal point of many clinical trials conducted by the TB Alliance. However, findings from these trials have shown that TBA-354 results in mild signs of reversible neurotoxicity; this left the TB Alliance with no other choice but to stop the research. 2. In this study, mass spectrometric methods were used to evaluate the pharmacokinetics and spatial distribution of TBA-354 in the brain using a validated liquid chromatography tandem-mass spectrometry (LCMS/MS) and mass spectrometric imaging (MSI), respectively. Healthy female Sprague-Dawley rats received intraperitoneal (i.p.) doses of TBA-354 (20 mg/kg bw). 3. The concentrationtime profiles showed a gradual absorption and tissue penetration of TBA-354 reaching the Cmax at 6 h post dose, followed by a rapid elimination. MSI analysis showed a time-dependent drug distribution, with highest drug concentration mainly in the neocortical regions of the brain. 4. The distribution of TBA-354 provides a possible explanation for the motor dysfunction observed in clinical trials. These results prove the importance of MSI as a potential tool in preclinical evaluations of suspected neurotoxic compounds.

Clofazimine protects against Mycobacterium tuberculosis dissemination in the central nervous system following aerosol challenge in a murine model.

Tuberculosis (TB) has been the scourge of the human race for many decades, claiming countless number of lives. This is further complicated by the ability of Mycobacterium tuberculosis to infect extrapulmonary sites, specifically the brain. These extrapulmonary forms of TB are difficult to treat owing to problems associated with drug delivery across the blood-brain barrier. Linezolid (LIN) and clofazimine (CFZ) are two of the more promising anti-TB drugs in recent times. In this study, BALB/c mice were aerosol-infected with M. tuberculosis H37Rv and were treated for 4 weeks with LIN [100 mg/kg body weight (BW)] or CFZ (100 mg/kg BW). Concurrently, it was investigated whether an aerosol TB infection would lead to dissemination of TB bacilli into the brain. Post-treatment brain and lung CFUs were determined together with serum, lung and brain drug concentrations. CFZ displayed a strong bactericidal effect in the lung, whilst LIN had a bacteriostatic effect. Mycobacterium tuberculosis appeared at 2 weeks post-infection in the untreated group (2.38 ± 0.43 log10 CFU) and more surprisingly at 3 weeks post-infection in the LIN-treated group (1.14 ± 0.99 log10 CFU). TB bacilli could not be detected in the brains of the CFZ-treated group. To the best of our knowledge, this is the first study showing the appearance of M. tuberculosis in the brain following a murine aerosol TB infection. This study may advocate the use of CFZ as prophylactic treatment to prevent the development of extrapulmonary TB of the central nervous system using a two-pronged approach.

Synthesis of novel 1,2,4-thiadiazinane 1,1-dioxides via three component SuFEx type reaction.

Herein, we report the preparation of 1,2,4-thiadiazinane 1,1-dioxides from reaction of ß-aminoethane sulfonamides with dichloromethane, dibromomethane and formaldehyde as methylene donors. The ß-aminoethane sulfonamides were obtained through sequential Michael addition of amines to α,ß-unsaturated ethenesulfonyl fluorides followed by further DBU mediated sulfur(vi) fluoride exchange (SuFEx) reaction with amines at the S-F bond.

Institutional profile: the national Swedish academic drug discovery & development platform at SciLifeLab.

The Science for Life Laboratory Drug Discovery and Development Platform (SciLifeLab DDD) was established in Stockholm and Uppsala, Sweden, in 2014. It is one of ten platforms of the Swedish national SciLifeLab which support projects run by Swedish academic researchers with large-scale technologies for molecular biosciences with a focus on health and environment. SciLifeLab was created by the coordinated effort of four universities in Stockholm and Uppsala: Stockholm University, Karolinska Institutet, KTH Royal Institute of Technology and Uppsala University, and has recently expanded to other Swedish university locations. The primary goal of the SciLifeLab DDD is to support selected academic discovery and development research projects with tools and resources to discover novel lead therapeutics, either molecules or human antibodies. Intellectual property developed with the help of SciLifeLab DDD is wholly owned by the academic research group. The bulk of SciLifeLab DDD's research and service activities are funded from the Swedish state, with only consumables paid by the academic research group through individual grants.

On the bridge over the translational valley of death: interview with Per I Arvidsson.

Per I Arvidsson speaks to Francesca Lake, Managing Editor: Per received his PhD in organic chemistry from Gothenburg University (Sweden) in 1999, where he continued as a lecturer for a short time. Following 2 years at the ETH Zurich (Switzerland) as a postdoctoral fellow, he went on to establish an independent research group at the Department of Biochemistry and Organic Chemistry at Uppsala University (Sweden). In 2006, he joined AstraZeneca R&D Södertälje (Sweden). After 1-year in-house training for future leaders in drug discovery and development, he became team leader in Medicinal Chemistry in 2007. In 2008, he was appointed Candidate Drug Delivery team leader with responsibility for preclinical drug discoveries in several CNS and pain projects. In 2010, he became Project Director at the innovative medicine unit for CNS & Pain research in Södertälje with responsibility from lead optimization to end of Phase II for projects in the neurodegeneration area. After joining AstraZeneca, he continued to pursue academic research as Adjunct Professor in bioorganic chemistry at the Department of Biochemistry and Organic Chemistry, Uppsala University (2007-2010), and the Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry, Uppsala University (2010-2013). In 2010, he was appointed honorary professor in Pharmacy and Pharmacology at the University of KwaZulu Natal (South Africa). In 2013, he was recruited to the Karolinska Institute in Stockholm as Director of Drug Discovery & Development, to build up the National Swedish infrastructure for Drug Discovery & Development at the Science for Life Laboratory (SciLifeLab). Since 2013, he has been a part-time research professor at the College of Health Science at the University of KwaZulu Natal. He is named inventor on over 15 patent applications, and coauthor to over 100 publications, two of which have won 'most cited papers' awards.

Lansoprazole-sulfide, pharmacokinetics of this promising anti-tuberculous agent.

Lansoprazole (LPZ) is a commercially available proton-pump inhibitor whose primary metabolite, lansoprazole sulfide (LPZS) was recently reported to have in vitro and in vivo activity against Mycobacterium tuberculosis. It was also reported that a 300 mg kg-1 oral administration of LPZS was necessary to reach therapeutic levels in the lung, with the equivalent human dose being unrealistic. A validated liquid chromatography-tandem mass spectrometric method (LC-MS/MS) for the simultaneous quantification LPZ and LPZS in rat plasma and lung homogenates was developed. We administered 15 mg kg-1 oral doses of LPZ to a healthy rat model to determine the pharmacokinetics of its active metabolite, LPZS, in plasma and lung tissue. We found that the LPZS was present in amounts that were below the limit of quantification. This prompted us to administer the same dose of LPZS to the experimental animals intraperitoneally (i.p.). Using this approach, we found high concentrations of LPZS in plasma and lung, 7841.1 and 9761.2 ng mL-1 , respectively, which were significantly greater than the minimum inhibitory concentration (MIC) for Mycobacterium tuberculosis. While oral and i.p. administration of LPZ resulted in significant concentrations in the lung, it did not undergo sufficient cellular conversion to its anti-TB metabolite. However, when LPZS itself was administered i.p., significant amounts penetrated the tissue. These results have implications for future in vivo studies exploring the potential of LPZS as an anti-TB compound.

Synthetic approaches to radiochemical probes for imaging of bacterial infections.

This present review provides an account on the available synthetic strategies employed to radiolabel commercial and potential bacteria-selective probes for tomographic imaging. These molecular probes encompass leukocytes, antibodies, small molecules, peptides, antibiotics, macrolides, vitamins, oligomers and siderophores. Although this technique has shown to be a valuable tool for non-invasive infection imaging, more development is required to create easy-to-radiolabel kit solutions/procedures for the preparation of the probes.

A Synthesis of "Dual Warhead" ß-Aryl Ethenesulfonyl Fluorides and One-Pot Reaction to ß-Sultams.

Herein, we report an operationally simple, ligand- and additive-free oxidative boron-Heck coupling that is compatible with the ethenesulfonyl fluoride functional group. The protocol proceeds at room temperature with chemoselectivity and E-isomer selectivity and offers facile access to a wide range of ß-aryl/heteroaryl ethenesulfonyl fluorides from commercial boronic acids. Furthermore, we demonstrate a "one-pot click" reaction to directly transform the products to aryl-substituted ß-sultams.

Sulfonimidamides in Medicinal and Agricultural Chemistry.

The synthesis and evaluation of structural analogues and isosteres are of central importance in medicinal and agricultural chemistry. The sulfonamide functional group represents one of the most important amide isosteres in contemporary drug design, and about 500 such compounds have overcome both the pharmacological and regulatory hurdles that precede studies in humans. The mono aza analogues of sulfonamides, that is, sulfonimidamides, are rapidly gaining popularity as a novel functional group among synthetic chemists involved in the design of biologically active compounds for both pharmaceutical and agrochemical applications. Herein, we review these recent developments to showcase the promise of this functional group.