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Mycobacterium tuberculosis cell wall is intricate and impermeable to many agents. A D, D-carboxypeptidase (DacB1) is one of the enzymes involved in the biosynthesis of cell wall peptidoglycan and catalyzes the terminal D-alanine cleavage from pentapeptide precursors. Catalytic activity and mechanism by which DacB1 functions is poorly understood. Herein, we investigated the acylation mechanism of DacB1 by β-lactams using a 6-membered ring transition state model that involves a catalytic water molecule in the reaction pathway. The full transition states (TS) optimization plus frequency were achieved using the ONIOM (B3LYP/6-31 + G(d): AMBER) method. Subsequently, the activation free energies were computed via single-point calculations on fully optimized structures using B3LYP/6-311++(d,p): AMBER and M06-2X/6-311++(d,p): AMBER with an electronic embedding scheme. The 6-membered ring transition state is an effective model to examine the inactivation of DacB1 via acylation by β-lactams antibiotics (imipenem, meropenem, and faropenem) in the presence of the catalytic water. The ΔG# values obtained suggest that the nucleophilic attack on the carbonyl carbon is the rate-limiting step with 13.62, 19.60 and 30.29 kcal mol−1 for Imi–DacB1, Mero–DacB1 and Faro–DacB1, respectively. The electrostatic potential (ESP) and natural bond orbital (NBO) analysis provided significant electronic details of the electron-rich region and charge delocalization, respectively, based on the concerted 6-membered ring transition state. The stabilization energies of charge transfer within the catalytic reaction pathway concurred with the obtained activation free energies. The outcomes of this study provide important molecular insight into the inactivation of D, D-carboxypeptidase by β-lactams. Communicated by Ramaswamy H. Sarma

Overdose is the main cause of mortality among heroin users. Many of these overdose-induced deaths can be prevented through the timely administration of naloxone (NLX), a nonselective mu (μ)-, kappa (κ)-, and delta (δ)-opioid receptor antagonist. NLX competitively inhibits opioid-overdose-induced respiratory depression without eliciting any narcotic effect itself. The aim of this study was to investigate the antagonistic action of NLX by comparing its distribution to that of 6-monacetylmorphine (6-MAM), heroin's major metabolite, in a rodent model using mass spectrometric imaging (MSI) in combination with liquid chromatography-tandem mass spectrometry (LC-MS/MS). Male Sprague-Dawley rats (n = 5) received heroin (10 mg kg-1) intraperitoneally, NLX (10 mg kg-1) intranasally, and NLX injected intranasally 5 min after heroin administration. The animals were sacrificed 15 min after dose and brain tissues were harvested. The MSI image analysis showed a region-specific distribution of 6-MAM in the brain regions including the corpus callosum, hippocampal formation, cerebral cortex, corticospinal tracts, caudate putamen, thalamus, globus pallidus, hypothalamus, and basal forebrain regions of the brain. The antagonist had a similar biodistribution throughout the brain in both groups of animals that received NLX or NLX after heroin administration. The MSI analysis demonstrated that the intensity of 6-MAM in these brain regions was reduced following NLX treatment. The decrease in 6-MAM intensity was caused by its displacement by the antagonist and its binding to these receptors in these specific brain regions, consequently enhancing the opioid elimination. These findings will contribute to the evaluation of other narcotic antagonists that might be considered for use in the treatment of drug overdose via MSI.

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).

An efficient catalyst-free radical cross-coupling reaction between aromatic aldehydes and sulfoximines was developed. The reaction took place in the presence of N-bromosuccinimide as the radical initiator under microwave irradiation to afford the corresponding acylated sulfoximines in moderate to excellent yields (27 examples). This protocol proved to be rapid, easy to handle, and applicable to a broad scope of substrates.

In this study, a significantly improved method for the synthesis of modular meso-BODIPY (boron dipyrromethene) derivatives possessing a free carboxylic acid group (which was subsequently coupled to peptides), is disclosed. This method provides a vastly efficient synthetic route with a > threefold higher overall yield than other reports. The resultant meso-BODIPY acid allowed for further easy incorporation into peptides. The meso-BODIPY peptides showed absorption maxima from 495–498 nm and emission maxima from 504–506 nm, molar absorptivity coefficients from 33 383–80 434 M−1 cm−1 and fluorescent quantum yields from 0.508–0.849. The meso-BODIPY-c(RGDyK) peptide was evaluated for plasma stability and (proved to be durable even up to 4 h) was then assessed for its fluorescence imaging applicability in vivo and ex vivo. The optical imaging in vivo was limited due to autofluorescence, however, the ex vivo tissue analysis displayed BODIPY-c(RGDyK) internalization and cancer detection thereby making it a novel tumor-integrin associated fluorescent probe while displaying the lack of interference the dye has on the properties of this ligand to bind the receptor.

HIV in the central nervous system (CNS) contributes to the development of HIV-associated neurological disorders (HAND), even with chronic antiretroviral therapy. In order for antiretroviral therapy to be effective in protecting the CNS, these drugs should have the ability to localize in brain areas known to be affected by HIV. Consequently, this study aimed to investigate the localization patterns of three first-line antiretroviral drugs, namely, efavirenz, tenofovir, and emtricitabine, in the rat brain. Liquid chromatography–tandem mass spectrometry (LC–MS/MS) and matrix-assisted laser desorption ionization mass spectrometry imaging (MALDI-MSI) were utilized to assess the pharmacokinetics and brain spatial distribution of the three drugs. Each drug was administered (50 mg/kg) to healthy female Sprague–Dawley rats via intraperitoneal administration. LC–MS/MS results showed that all three drugs could be delivered into the brain, although they varied in blood–brain barrier permeability. MALDI-MSI showed a high degree of efavirenz localization across the entire brain, while tenofovir localized mainly in the cortex. Emtricitabine distributed heterogeneously mainly in the thalamus, corpus callosum, and hypothalamus. This study showed that efavirenz, tenofovir, and emtricitabine might be a potential drug combination antiretroviral therapy for CNS protection against HAND.

Rationale The complexity of central nervous system (CNS) drug delivery is the main obstacle with the blood-brain barrier (BBB) known to restrict access of most pharmaceutical drugs into the brain. Mass spectrometry imaging (MSI) offers possibilities for studying drug deposition into the CNS. Methods The deposition and spatial distribution of the two antiretroviral drugs elvitegravir and tenofovir in the brain were investigated in healthy female Sprague-Dawley rats following a single intraperitoneal administration (50 mg/kg). This was achieved by the utilization of quantitative liquid chromatography/tandem mass spectrometry (LC/MS/MS) and matrix-assisted laser desorption/ionization (MALDI) MSI. Results LC/MS/MS showed that elvitegravir has better BBB penetration, reaching maximum concentration in the brain (Cmax brain) of 976.5 ng/g. In contrast, tenofovir displayed relatively lower BBB penetration, reaching Cmax brain of 54.5 ng/g. MALDI-MSI showed the heterogeneous distribution of both drugs in various brain regions including the cerebral cortex. Conclusions LC/MS/MS and MALDI-MSI provided valuable information about the relative concentration and the spatial distribution of the two common antiretroviral drugs. This study has also shown the capability of MALDI-MSI for direct visualization of pharmaceutical drugs in situ.

β-lactam antibiotics, which are used to treat infectious diseases, are currently the most widely used class of antibiotics. This study focused on the chemical reactivity of five- and six-membered ring systems attached to the β-lactam ring. The ring strain energy (RSE), force constant (FC) of amide (C-N), acylation transition states and second-order perturbation stabilization energies of 13 basic structural units of β-lactam derivatives were computed using the M06-2X and G3/B3LYP multistep method. In the ring strain calculations, an isodesmic reaction scheme was used to obtain the total energies. RSE is relatively greater in the five-(1a-2c) compared to the six-membered ring systems except for 4b, which gives a RSE that is comparable to five-membered ring lactams. These variations were also observed in the calculated inter-atomic amide bond distances (C-N), which is why the six-membered ring lactams C-N bond are more rigid than those with five-membered ring lactams. The calculated ΔG# values from the acylation reaction of the lactams (involving the S-H group of the cysteine active residue from L,D transpeptidase 2) revealed a faster rate of C-N cleavage in the five-membered ring lactams especially in the 1-2 derivatives (17.58 kcal mol-1 ). This observation is also reflected in the calculated amide bond force constant (1.26 mDyn/A) indicating a weaker bond strength, suggesting that electronic factors (electron delocalization) play more of a role on reactivity of the β-lactam ring, than ring strain.

HIV-1 is an infectious virus that causes acquired immunodeficiency syndrome (AIDS) and it is one of the major causes of deaths worldwide. The production of HIV-1 protease (PR) on a large scale has been a problem for scientists due to its cytotoxicity, low yield, insolubility, and low activity. HIV-1 C-SA protease has been cloned, expressed, and purified previously, however, with low recovery (0.25 mg/L). Herein we report an optimal expression and solubilisation procedure to recover active HIV-1 C-SA protease enzyme from inclusion bodies. The HIV protease was expressed in seven different vectors (pET11b, pET15b, pET28a pET32a, pET39b, pET41b and pGEX 6P-1). The highest expression was achieved when the vector pET32a (Trx tag) was employed. A total of 19.5 mg of fusion protein was refolded of which 5.5 mg of active protease was obtained after cleavage. The free protease had a high specific activity of 2.81 µmoles/min/mg. Interestingly the Trx-fusion protein also showed activity closer (1.24 µmoles/min/mg) to that of the free protease suggesting that the pET32a vector (Trx tag) expressed in BL21(DE3) pLysS provides a more efficient way to obtain HIV-1 protease.

Computer-aided drug design (CADD) is one of the pivotal approaches to contemporary pre-clinical drug discovery, and various computational techniques and software programs are typically used in combination, in a bid to achieve the desired outcome. Several approved drugs have been developed with the aid of CADD. On SciFinder®, we evaluated more than 600 publications through systematic searching and refining, using the terms, virtual screening; software methods; computational studies and publication year, in order to obtain data concerning particular aspects of CADD. The primary focus of this review was on the databases screened, virtual screening and/or molecular docking software program used. Furthermore, we evaluated the studies that subsequently performed molecular dynamics (MD) simulations and we reviewed the software programs applied, the application of density functional theory (DFT) calculations and experimental assays. To represent the latest trends, the most recent data obtained was between 2015 and 2020, consequently the most frequently employed techniques and software programs were recorded. Among these, the ZINC database was the most widely preferred with an average use of 31.2%. Structure-based virtual screening (SBVS) was the most prominently used type of virtual screening and it accounted for an average of 57.6%, with AutoDock being the preferred virtual screening/molecular docking program with 41.8% usage. Following the screening process, 38.5% of the studies performed MD simulations to complement the virtual screening and GROMACS with 39.3% usage, was the popular MD software program. Among the computational techniques, DFT was the least applied whereby it only accounts for 0.02% average use. An average of 36.5% of the studies included reports on experimental evaluations following virtual screening. Ultimately, since the inception and application of CADD in pre-clinical drug discovery, more than 70 approved drugs have been discovered, and this number is steadily increasing over time.

Advances in Nuclear Magnetic Resonance (NMR) spectroscopy is a cornerstone in structure elucidation of polycyclic 'cage' scaffolds. Due to the compactness of these compounds, much overlap, as well as unique through-space and bond NMR interactions are frequently observed. This review serves as a guide for the NMR elucidation of future derivatives by providing some of the typical and relevant aspects of the characteristic trends, substituent patterns and chemical shift behaviour for the identification of the polycyclic structures, namely adamantane, pentacycloundecane and trishomocubane derivatives. Keywords: adamantane, NMR elucidation, pentacycloundecane, polycyclic compounds, trishomocubane

Peptide drugs are essential components of the pharmaceutical industry with a multiplicity of therapeutic properties, such as being anti-hypertensive, anti-microbial, anti-diabetic, and having anti-cancer potential. These molecules are similar in physiological structure and function to the body's endogenous signalling molecules and are therefore ideal candidates for the development of the next-generation of drugs. However, the purification of these peptides can be problematic due to poor solubility and stability, which often results in low peptide yields. Peptides are traditionally purified via RP-HPLC methods, which are tedious and employ harsh solvents that generate harmful waste to the environment. There is a growing need for more cost-effective and sustainable purification methods of these biologics. SFC can provide a greener peptide purification approach with more environmentally friendly mobile phases such as CO2 and methanol, which can easily be recycled with minimal environmental impact. Currently, there is limited knowledge regarding the SFC purification of peptides. Herein, this study investigated SFC methods to purify a tetrapeptide (LYLV), octapeptide (DRVYIHPF), and nonapeptide (LYLVCGERG) on commercially available columns at an analytical scale. The 2-ethyl pyridine column proved to be optimal based on its reproducibility, peak shapes, efficient separations, and retention factors with peptide recoveries ranging from 80 to 102%. The run times were reduced to 13 min, as opposed to the traditional RP-HPLC methods of 50 min, thus making this SFC method an efficient, greener, and more cost-effective approach for the purification of these peptides.

There is a paucity of knowledge surrounding the SFC purification of human insulin. The current conventional method of insulin purification involves traditional RP-HPLC that utilises copious amounts of toxic solvents. In this study, we envisaged the development of an environmentally friendly SFC method for biosynthesized human insulin purification. Various commercially available SFC columns derived with silica, 2′ethyl pyridine, diol-HILIC, and the PFP functionalities were evaluated to determine the optimal stationary phase for purification. The PFP column gave the best results with respect to efficiencies of this important biologic that yielded average recoveries of 84%. LC-MS was used to initially detect and quantify the SFC purified standard sample of insulin (purchased) as well as the biosynthesized version. Protein sequencing was employed to verify the amino acid sequencing of the insulins; as such, the standard had a 90% probability to human insulin from the database, whereas the biosynthesized version had a 96% probability. The biological activities of both versions of the SFC purified proteins were assessed in vitro using a MTT assay. The results indicated that the biological activities of both samples were retained subsequent to SFC purification. This study successfully proposes a greener and more efficient method for the purification of insulin derivatives.

HIV-1 protease (HIV-1 PR) is an essential enzyme for the replication process of its virus, and therefore considered an important target for the development of drugs against the acquired immunodeficiency syndrome (AIDS). Our previous study shows that the catalytic mechanism of subtype B/C-SA HIV-1 PR follows a one-step concerted acyclic hydrolysis reaction process using a two-layered ONIOM B3LYP/6-31++G(d,p) method. This present work is aimed at exploring the proposed mechanism of the proteolysis catalyzed by HIV-1 PR and to ensure our proposed mechanism is not an artefact of a single theoretical technique. Hence, we present umbrella sampling method that is suitable for calculating potential mean force (PMF) for non-covalent ligand/substrate-enzyme association/dissociation interactions which provide thermodynamic details for molecular recognition. The free activation energy results were computed in terms of PMF analysis within the hybrid QM(DFTB)/MM approach. The theoretical findings suggest that the proposed mechanism corresponds in principle with experimental data. Given our observations, we suggest that the QM/MM MD method can be used as a reliable computational technique to rationalize lead compounds against specific targets such as the HIV-1 protease.

Insulin has captured researchers’ attention worldwide. There is a rapid global rise in the number of diabetic patients, which increases the demand for insulin. Current methods of insulin production are expensive and time-consuming. A PCR-based strategy was employed for the cloning and verification of human insulin. The human insulin protein was then overexpressed in E. coli on a laboratory scale. Thereafter, optimisation of human insulin expression was conducted. The yield of human insulin produced was approximately 520.92 (mg/L), located in the intracellular fraction. Human insulin was detected using the MALDI-TOF-MS and LC–MS methods. The crude biosynthesised protein sequence was verified using protein sequencing, which had a 100% similarity to the human insulin sequence. The biological activity of human insulin was tested in vitro using a MTT assay, which revealed that the crude biosynthesised human insulin displayed a similar degree of efficacy to the standard human insulin. This study eliminated the use of affinity tags since an untagged pET21b expression vector was employed. Tedious protein renaturation, inclusion body recovery steps, and the expensive enzymatic cleavage of the C-peptide of insulin were eliminated, thereby making this method of biosynthesising human insulin a novel and more efficient method.

Aim: To enhance the drug delivery to the brain with an oil-in-water nanoemulsion of pretomanid via intranasal (IN) administration. Materials & methods: The study involved 70 male Sprague–Dawley rats (160–180 g) that received either 20 mg/kg body weight (b.w.) a nanoemulsion or a 20 mg/kg b.w. of pretomanid in solution via the IN route. The drug was quantified by liquid chromatography–tandem mass spectrometry to investigate whole tissue–drug concentrations, and mass spectrometric imaging to visualize drug localization in the brain. Results: Nanoemulsion delivery concentrations of pretomanid in the brain reached peak concentrations (Cmax) of 12,062.3 ng/g that is significantly higher than the required therapeutic level. The mass spectrometric imaging analysis clearly showed a time dependent and uniform distribution in the brain. Conclusion: The results of this study show that IN delivery of oil-in-water nanoemulsion may be very promising for targeting anatomical tuberculosis reservoirs, such as the brain.

Herein we report a peculiar organocatalyzed domino-reaction on the carbapenem core structure. As previously reported, 30 mol% of proline yields diazabicyclo[4.2.1]nonane analogues, while we currently report the formation of novel 1,4-diazepin-5-ones from the same starting material in the presence of 100 mol% proline. The inherent chirality of the starting material led to the stereochemical preference of the products with excellent diastereoselectivity (>99 : 1). The diazepinone products were confirmed using X-ray diffraction and 2D-NMR structure elucidation. A plausible mechanism of the re-arrangement, involving an unactivated retro-Dieckmann condensation, is also presented.

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

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 log 10 CFU) and more surprisingly at 3 weeks post-infection in the LIN-treated group (1.14 ± 0.99 log 10 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.

C34H39NOSi, triclinic, P1̅ (no. 2), a = 10.0901(2) Å, b = 11.5016(2) Å, c = 14.4098(3) Å, α = 69.207(1)°, β = 86.555(2)°, γ = 65.579(3)°, V = 1416.10(6) Å3, Z = 2, R gt(F) = 0.0463, wR ref(F 2) = 0.1200, T = 100(2) K.

C23.5H23FN2O2S, Mr = 416.50, monoclinic, C2/c (no. 15), a = 27.2594(19) Å, b = 5.7351(4) Å, c = 26.1139(18) Å, β = 102.009(2)°, V = 3993.2(5) Å3, Z = 8, R gt(F) = 0.0358, wR ref(F 2) = 0.0958 T = 100(2) K.

Buprenorphine is an opioid drug used in the management of pain and the treatment opioid addiction. Like other opioids, it is believed that it achieves these effects by altering functional neurotransmitter pathways and the expression of important transcription factors; cyclic AMP response element-binding protein (CREB) and brain-derived neurotrophic factor (BDNF) in the brain. However, there is a lack of scientific evidence to support these theories. This study investigated the pharmacodynamic effects of BUP administration by assessing neurotransmitter and molecular changes in the healthy rodent brain. Sprague-Dawley rats (150–200 g) were intranasally administered buprenorphine (0.3 mg/mL) and sacrificed at different time points: 0.25, 0.5, 1, 2, 4, 6, 8 and 24 h post drug administration. LC-MS was used to quantify BUP and neurotransmitters (GABA, GLUT, DA, NE and 5-HT) in the brain, while CREB and BDNF gene expression was determined using qPCR. Results showed that BUP reached a Cmax of 1.21 ± 0.0523 ng/mL after 2 h, with all neurotransmitters showing an increase in their concentration over time, with GABA, GLUT and NE reaching their maximum concentration after 8 h. DA and 5-HT reached their maximum concentrations at 1 h and 24 h, respectively post drug administration. Treatment with BUP resulted in significant upregulation in BDNF expression throughout the treatment period while CREB showed patterns of significant upregulation at 2 and 8 h, and downregulation at 1 and 6 h. This study contributes to the understanding of the pharmacodynamic effects of BUP in opioid addiction by proving that the drug significantly influences NT pathways that are implicated in opioid addiction.

Bacterial infections are a major concern in the human health sector due to poor diagnosis and development of multidrug-resistant strains. PET/CT provides a means for the non-invasive detection and localization of the infectious foci; however, the radiotracers available are either cumbersome to prepare or their exact contribution toward the imaging is not yet established. Human antimicrobial peptides are of interest for development as PET radiotracers as they are an integral component of the immune system, non-immunogenic toward the recipient, and show selectivity toward pathogens such as bacteria. Herein we report on the potential of LL37, a human cathelicidin antimicrobial peptide, as a radiotracer for bacterial imaging. Bifunctional chelator 1,4,7-triazacyclononane,1-glutaric acid-4,7-acetic acid was utilized to functionalize the antimicrobial peptide, which in turn was capable of chelating gallium. The synthesized nat Ga-CDP1 showed bacterial selectivity and low affinity toward hepatic cells, which are favorable characteristics for further preclinical application.

Synthesis and evaluation of structural analogues and isosteres represent a cornerstone methodology among the practitioners of medicinal- and agrochemistry. The sulfonamide functional group represents one of the most important amide isosteres in contemporary drug design, with some 500 compounds that has overcome both the pharmacological and regulatory hurdles that precede studies in humans. We note that mono aza-analogues of sulfonamides, i.e. sulfonimidamides, are rapidly gaining popularity as a novel functional group among molecular architects involved in the design of biologically active compounds for both pharmaceutical- and agrochemical applications. Herein, we review these recent developments with the ambition to showcase the promise of this functional group to the wider chemical community.

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.

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 β-aryl/heteroaryl ethenesulfonyl fluorides from commercial boronic acids. Furthermore, we demonstrate a "one-pot click" reaction to directly transform the products to aryl-substituted β-sultams.

Three analogues of 3-oxopyrrolidines; (S)-1-tert-butyl 2-ethyl-2-((S)-2-nitro-1-p-tolylethyl)-3-oxopyrrolidine-1,2-dicarboxylate, 1, (S)-1-tert-butyl 2-ethyl 2-((S)-1-(4-methoxyphenyl)-2-nitroethyl)-3-oxopyrrolidine-1,2-dicarboxylate 2, and Ethyl 1-((S)-2-(((benzyloxy)carbonyl)amino)-3-phenylpropanoyl)-2-(2-nitro-1-phenylethyl)-3-oxopyrrolidine-2-carboxylate 3, were synthesized and crystallized in suitable solvents. Crystal structure analysis was carried out by single crystal X-ray diffraction to provide a detailed investigation of the packing and supramolecular arrangement of these analogues. The weak interactions such as C H⋯O/C H⋯π present in the crystal structure of all these analogues (1–3) played a vital role in controlling the conformation of the molecules and construction of dissimilar supramolecular assemblies. This study provides some insight; that even though these oxopyrrolidine analogues, lack a hydrogen bond donor and acceptor system, that upon bulky substitutions, this scaffold can still form fascinating supramolecular assemblies through various weak interactions. The surface interaction was carried out by means of Hirshfeld surface analysis, which depicted the significant intermolecular interactions of a molecule with its neighbor within the structures.

[Image: see text] 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 IC(50) = 15 μg/mL; compound 15 IC(50) = 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.

Herein, we report the effect of nine FDA approved protease inhibitor drugs against a new HIV-1 subtype C mutant protease, E35D↑G↑S. The mutant has five mutations, E35D, two insertions, position 36 (G and S), and D60E. Kinetics, inhibition constants, vitality, Gibbs free binding energies are reported. The variant showed a decreased affinity for substrate and low catalytic efficiency compared to the wild type. There was a significant decrease in the binding of seven FDA approved protease inhibitors against the mutant (p

As the HIV epidemic continues to contribute to global morbidity and mortality, the prevalence of HIV-associated neurological disorders (HAND) also continues to be a major concern in infected individuals, despite the widespread use of combination antiretroviral therapy. Therefore, current antiretroviral drugs should be able to reach therapeutic levels in the brain for the treatment of HAND. The brain distribution of the next-generation non-nucleoside reverse transcriptase inhibitor, rilpivirine (RPV) was investigated in healthy female Sprague–Dawley (SD) rats. The presented study involves the use of liquid chromatography-tandem mass spectrometry (LC–MS/MS) to estimate the concentrations of RPV in plasma and brain homogenate samples. The use of matrix-assisted laser desorption/ionization mass spectrometry imaging (MALDI-MSI) provided regional spatial distribution of RPV in brain tissue sections. The localization of RPV was found to be relatively high in the hypothalamus, thalamus and corpus callosum, brain regions known to be associated with neurodegeneration during HAND (including the cerebral cortex). This study has shown that RPV has an excellent blood–brain barrier penetrability. Thus, in combination with other antiretroviral drugs, better central nervous system (CNS) protection against HAND can possibly be achieved.

The β-ketoester structural motif continues to intrigue chemists with its electrophilic and nucleophilic sites. Proven to be a valuable tool within organic synthesis, natural product, and medicinal chemistry, reports on chiral β-ketoester molecular skeletons display a steady increase. With the reignition of organocatalysis in the past decade, asymmetric methods available for the synthesis of this structural unit has significantly expanded, making it one of the most exploited substrates for organocatalytic transformations. This review provides comprehensive information on the plethora of organocatalysts used in stereoselective organocatalyzed construction of β-ketoester-containing compounds.

Herein, we report a mild and efficient synthesis of a NODASA-functionalized peptide, which was initiated with a Michael addition reaction between monomethyl fumarate and 1,4,7-triazacyclononane.

Herein, we report an efficient, ligand-free, and additive-free Suzuki-Miyaura coupling that is compatible with the aromatic sulfonyl fluoride functional group. The protocol proceeds at room temperature, on water, and offers facile access to a wide range of biaryl sulfonyl fluorides as bioorthogonal "click" reagents.

Herein, we report a convenient synthesis of aryl-substituted (E)-vinylic NH-sulfoximines via the Horner–Wadsworth–Emmons reaction without the use of protection–deprotection group strategies.

The first synthesis and biological activity of a teixobactin analogue is reported. Substitution of the unusual L-allo-enduracididine residue by the naturally occurring L-arginine was achieved, and the analogue gave an activity trend similar to that of teixobactin (against Gram-postive bacteria) and meropenem, which was approved by the FDA in 1996. The synthetic route used allows for the synthesis of the natural product as well as the development of a program of medicinal chemistry.

Tigecycline (TIG), a derivative of minocycline, is the first in the novel class of glycylcyclines and is currently indicated for the treatment of complicated skin structure and intra-abdominal infections. A selective, accurate and reversed-phase high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) method was developed for the determination of TIG in rat brain tissues. Sample preparation was based on protein precipitation and solid phase extraction using Supel-Select HLB (30 mg/1 mL) cartridges. The samples were separated on a YMC Triart C18 column (150 mm x 3.0 mm. 3.0 µm) using gradient elution. Positive electrospray ionization (ESI+) was used for the detection mechanism with the multiple reaction monitoring (MRM) mode. The method was validated over the concentration range of 150-1200 ng/mL for rat brain tissue. The precision and accuracy for all brain analyses were within the acceptable limit. The mean extraction recovery in rat brain was 83.6%. This validated method was successfully applied to a pharmacokinetic study in female Sprague Dawley rats, which were given a dose of 25 mg/kg TIG intraperitoneally at various time-points. Copyright © 2015 John Wiley & Sons, Ltd.

This study explored the rearrangement process which occurred during Grignard reactions of the pentacycloundecane (PCU) dione, 1. This compound was reacted with vinyl and allyl magnesium bromide to afford PCU-vinyl cyclic ether, 2, and PCU-allyl cyclic ether, 4, which upon ozonolysis afforded compounds PCU dilactone, 3 and PCU-cyclic ether monoacid, 5 respectively. This resulted in the discovery of three novel cage compounds, 2, 4 and 5. The Baeyer-Villiger oxidation of 1 was proposed and investigated experimentally as an alternative synthetic route for the PCU dilactone. The unsymmetrical nature of compounds 2, 4 and 5 resulted in overlapping signals of the methine protons and carbons observed in the 1H and 13C NMR spectra, however, the complexity of the spectra was resolved by using 2D NMR techniques to successfully elucidate these compounds. Herein, the three novel cage compounds including compound 3 were fully characterized by IR and NMR spectroscopy, HRMS. Single crystal X-ray crystallography analysis was also performed on compounds 3 and 5.

Novel heterocyclic bioactive small molecules bearing thioether moiety, fluorine containing dihydro pyridine and dihydro pyran were synthesized and characterized using spectroscopic methods (FT-IR, 1H, 13C and 19F NMR), LC-MS and SC-XRD. The reaction conducted is highly environment-friendly involving d -α-Tocopherol polyethylene glycol succinate (TPGS) - Water binary solvent as reaction medium. All of the synthesized final compounds were evaluated against 2 g-negative [Escherichia coli (ATCC 25922) and Pseudomonas aeruginosa (ATCC 27853)] and 1 g-positive [Staphylococcus aureus (ATCC 29213)] bacterial strains by in vitro. Molecular docking experiments were carried out against p53-MDM2 tumor suppressor protein to gain more insights into the binding mode of the final compounds. In this study, we discovered potent p53-MDM2 inhibition by 2-thiobenzyl-3-formyl quinoline, 2-thio-1,2-dihydroquinoline-3-formyl N-substituted thiosemi-carbazone and fluorine substituted new pyridine and pyran derivatives by structure-based design.

To compare the concentrations of 13 different elements in nail samples from pre-eclamptic and normotensive pregnant women. The study site was a regional hospital in Durban, KwaZulu Natal. Nail samples were collected from normotensive (n = 33) and pre-eclamptic (n = 33) pregnant women. Approximately 0.02 g of nail samples were digested in 70% nitric acid and analyzed using inductively coupled plasma-optical emission spectrometry. Analytes of interest were the following essential elements calcium (Ca), chromium (Cr), cobalt (Co), copper (Cu), iron (Fe), magnesium (Mg), manganese (Mn), nickel (Ni), selenium (Se) and Zinc (Zn) as well as toxic elements, arsenic (As), cadmium (Cd) and lead (Pb). The observed concentrations of bioelements (mean, μg/g), Ca: normotensive (N) 3467 ± 197 vs (PE) 2897 ± 190; Mg: (N) 736 ± 61 vs (PE) 695 ± 59, were lower in pre-eclampsia albeit not statistically significant. Similarly, the observed concentrations of bioelements (mean, μg/g), Cd: (N) 3 ± 0.3 vs (PE) 2 ± 0.4; Co: (N) 3 ± 0.3 (PE) not detected; Mn: (N) 7 ± 1 (PE) 4 ± 0.8, were significantly lower in pre-eclampsia (p = 0.004, 0.0001 and 0.022, respectively). Therefore, this study demonstrated significantly lower levels of Cd, Co and Mn in pre-eclampsia which justifies the need for further research on these elements towards the effective management or prevention of pre-eclampsia which could ultimately also aid in establishing its pathogenesis.

Bedaquiline (BDQ) is the first-in-class United States Food and Drug Administration (US FDA) approved anti-tuberculosis (anti-TB) drug, which is a novel diarylquinoline antibiotic that has recently been utilized as an effective adjunct to existing therapies for multidrug-resistant tuberculosis (MDR-TB). BDQ is especially promising due to its novel mechanism of action, activity against drug-sensitive and drug-resistant tuberculosis (TB) in addition to having the potential to shorten treatment duration. Drug delivery to the central nervous system (CNS) is a major concern in TB chemotherapy, especially with the increasing cases of CNS-TB. In this study, we investigated the CNS penetration of BDQ in healthy rodent brain. Male Sprague-Dawley rats (n = 27; 100 ± 20 g) received a single 25 mg kg−1 b.w dose of BDQ via intraperitoneal (i.p.) administration, over a 24 h period. Liquid chromatography-tandem mass spectrometry (LC-MS/MS) was used to determine whole tissue drug concentrations and matrix-assisted laser desorption/ionization mass spectrometry imaging (MALDI MSI) was utilized to evaluate drug distribution in the brain. BDQ reached peak concentrations (Cmax) of 134.97 ng mL−1 in the brain at a Tmax of 4 h, which is within the range required for therapeutic efficacy. BDQ was widely distributed in the brain, with a particularly high intensity in the corpus callosum and associated subcortical white matter including the striatal, globus pallidus, corticofugal pathways, ventricular system, basal forebrain region and hippocampal regions. Using MALDI MSI, this study demonstrates that due to BDQ's distribution in the brain, it has the potential to target TB reservoirs within this organ.

C9H6FNO2S, triclinic, P1̄ (no. 2), a = 7.2786(2) Å, b = 8.1014(3) Å, c = 16.1084(5) Å, α = 76.320(1)°, β = 87.918(1)°, γ = 80.784(1)°, V = 911.00(5) Å3, Z = 4, R gt(F) = 0.0298, wR ref(F 2) = 0.0857, T = 100(2) K.

This is the first report of clofazimine (CFZ) penetration and distribution in normal mouse brain. Mice were administered 25 mg/kg CFZ or 100 mg/kg CFZ orally, daily for 2 weeks. Animals were sacrificed and blood and brain tissues were harvested. Liquid chromatography tandem mass spectrometry showed high concentrations of CFZ in homogenized brain, with 100 mg/kg dose having significantly higher concentration than 25 mg/kg. Matrix-assisted laser desorption/ionization spectrometric imaging of brain sections showed widespread tissue distribution of CFZ. Our results show dose dependent localization in brain.