Piperazines are important heterocycles in drug compounds. We report the asymmetric synthesis of arylpiperazines by photocatalytic decarboxylative arylation (metallaphotoredox catalysis) then kinetic resolution using n-BuLi/(+)-sparteine. This gave a range of piperazines with very high enantioselectivities. Further functionalizations gave enantioenriched 2,2-disubstituted piperazines, and either N-substituent can be removed selectively. Late-stage functionalizations of enantioenriched piperazine derivatives were demonstrated, including synthesis of a drug compound with glycogen synthase kinase (GSK)-3β inhibitor activity with potential for treating Alzheimer's disease.
ABSTRACT Precise control of intracellular redox status, i.e., maintenance of physiological level of reactive oxygen species (ROS) for mediating normal cellular functions (oxidative eustress) while evading the excess ROS stress (distress) is central to the concept of redox medicine. In this regard, engineered nanoparticles with unique ROS generation, transition, or depletion functions have the potential to be the choice of redox therapeutics. However, it is always challenging to estimate whether ROS-induced intracellular events are beneficial or deleterious to the cell. Here, we propose the concept of redox buffering capacity as a therapeutic index of engineered nanomaterials. As a steady redox state is maintained for normal functioning cells, we hypothesize that the ability of a nanomaterial to preserve this homeostatic condition will dictate its therapeutic efficacy. Additionally, the redox buffering capacity is expected to provide information about the nanoparticle toxicity. Here, using citrate functionalized trimanganese tetroxide nanoparticles (C-Mn 3 O 4 NPs) as a model nanosystem we explored its redox buffering capacity in erythrocytes. Furthermore, we went on to study the chronic toxic effect (if any) of this nanomaterial in animal model in order to co-relate with the experimentally estimated redox buffering capacity. This study could function as a framework for assessing the capability of a nanomaterial as redox medicine (whether maintains eustress or damages by creating distress), thus orienting its application and safety for clinical use.
Abstract Whole genome sequence analysis of the Mycobacterium tuberculosis (Mtb) isolates show correlation to their drug resistance phenotype which may also reflect in their global metabolome. In this report, clinical Mtb isolates (S1, S4, S5, S6, S7, S10) harvested from the sputum of tuberculosis patients were characterized using drug sensitive test (DST), electron microscope, whole genome sequencing (WGS) and metabolomics. Majority of these Mtb isolates showed similar size (length: 1.0–3.2 μm; width: 0.32–0.52 μm) to the H37Rv Mtb strain whereas significant variations were observed in their growth kinetics, WGS and metabolome profiles. In-silico drug resistance prediction, from the WGS data (single-nulceotide polymorphisms (SNP) pattern) of these Mtb isolates showed resistance to tuberculosis drugs and matched with DST results. Differences in the genes involved in stress response, pathogenicity, drug efflux pumps were observed between isolates but genes of the central carbon metabolic pathways and amino acid metabolism were conserved. Gas chromatography and mass spectrometry (GC-MS) based metabolite profiling of these clinical isolates identified 291 metabolites involved in various metabolic pathways and a sub set of these metabolites (glutamic acid, aspartic acid and serine) contributed to the drug resistance patterns. These clinical Mtb isolates could be useful as alternate reagent for understanding host pathogen interaction and the pipeline used for WGS analysis could be used to predict drug resistance pattern of new Mtb isolates.
Introduction: Interscalene Brachial Plexus Block (ISBPB) block provides optimal analgesia for shoulder and upper arm surgery. However, higher incidence of phrenic nerve palsy limits the application of ISBPB for patients with limited pulmonary reserve. The Supplemented Suprascapular Nerve Block (SSNB) is a landmark based technique that is believed to block the sensory fibres supplying major part of shoulder joint, as well as, supraspinatus and infraspinatus muscles. Aim: To compare the analgesic effect and duration of sensory block in interscalene versus interscalene with SSNB block for shoulder and upper arm surgery. Materials and Methods: This double-blinded randomised controlled study was conducted in a Tertiary Care Institute, from April 2021 to march 2022. Eighty patients posted for shoulder and upper arm surgery were divided into two equal groups (group A and B). In group A (n=40), 30 mL 0.5% levobupivacaine in ISBPB and in group B (n=40), 15 mL 0.5% levobupivacaine in ISBPB+15 mL 0.5% levobupivacaine in SSNB were administered. Demographic data, sensory and motor block, onset times and durations, time to administer first rescue analgesic, total analgesic requirement, indications of upper arm surgeries, surgical bleeding and surgeon’s satisfaction score, postoperative Visual Analogue Scale (VAS) score were recorded for each patient. Results: The onset and duration of sensory and motor block was significantly faster and longer in group B. Consequently, time to administer first rescue analgesic in group A vs group B (325.88±33.23 vs. 348.34±37.12) minutes were significantly delayed and in lesser in amount in group B respectively. On the other hand, suprascapular block reduced the odds of block-related respiratory (group A vs group B are 14 and 10, respectively) complications. In group B postoperative VAS score at 24 hour was significantly lower (p-value <0.05) than group A was (3.5 vs 4.5). Intraoperative haemodynamic parameters were comparable among two groups throughout the study period. Conclusion: SSNB when supplemented with Interscalene Block (ISB) could be an effective adjunct for shoulder and upper arm surgery. This combination prolongs the sensory blockade duration, reduces requirement of analgesics and side-effects in postoperative period.
A series of chiral dimeric ligands 1A–C, 2A–B, 3A–B and 4A derived from (S)/(R) 1,1′-bi(2-naphthol)-bis-aldehyde/piperazine-bis-aldehyde and various aminoalcohols viz., (1R,2S)-(−)-2-aminodiphenylethanol, (1S,2R)-(−)-2-aminodiphenylethanol, (1R,2S)-1-amino-2,3-dihydro-1H-inden-2-ol and (R)-valinol were synthesized. In situ generated complexes 1A–C–, 2A–B–, 3A–B–, 4A–Cu(II)/Cu(I) of dimeric chiral ligands with different copper salts were used as catalysts for the asymmetric aza-Henry reaction of a variety of N-tosylimines as substrates with different nitroalkanes at RT to afford good yields of aza-Henry products (80% with respect to the imines) with excellent enantioselectivity (ee > 99%) in 24 h with nitromethane and high syn selective products with excellent enantioselectivity with nitroethane. The dimeric chiral Cu(II) complex 1A–Cu(II) retained its performance at the gram level and was expediently recycled for a number of times. The enantio-pure aza-Henry product was further used for the synthesis of (S)-levamisole (an anthelminthic agent) in good yield and ee in three steps.
Photoresponsive polymers, typically activated with direct excitation of an azobenzene moiety, are an intriguing class of materials for application as adaptive structures. Here, we introduce triplet excited state sensitization as a mechanism to harness light in a stilbene-based photopolymer (i.e., the carbon analogue of azobenzene). While the undoped film shows no response, the sensitized film exhibits polarization dependent bending under 445 nm irradiation via (1) sensitizer excitation, (2) triplet energy transfer, (3) stilbene isomerization, and (4) subunit reorientation. This work is the first to demonstrate stilbene-based photopolymers and triplet sensitization as a low energy light harvesting mechanism in photomechanics.
Background In an endeavor to find an orally active and affordable antileishmanial drug, we tested the efficacy of a cationic amphiphilic drug, imipramine, commonly used for the treatment of depression in humans. The only available orally active antileishmanial drug is miltefosine with long half life and teratogenic potential limits patient compliance. Thus there is a genuine need for an orally active antileishmanial drug. Previously it was shown that imipramine, a tricyclic antidepressant alters the protonmotive force in promastigotes, but its in vivo efficacy was not reported. Methodology/Principal Findings Here we show that the drug is highly active against antimony sensitive and resistant Leishmania donovani in both promastigotes and intracellular amastigotes and in LD infected hamster model. The drug was found to decrease the mitochondrial transmembrane potential of Leishmania donovani (LD) promastigotes and purified amastigotes after 8 h of treatment, whereas miltefosine effected only a marginal change even after 24 h. The drug restores defective antigen presenting ability of the parasitized macrophages. The status of the host protective factors TNF α, IFN γ and iNOS activity increased with the concomitant decrease in IL 10 and TGF β level in imipramine treated infected hamsters and evolution of matured sterile hepatic granuloma. The 10-day therapeutic window as a monotherapy, showing about 90% clearance of organ parasites in infected hamsters regardless of their SSG sensitivity. Conclusions This study showed that imipramine possibly qualifies for a new use of an old drug and can be used as an effective orally active drug for the treatment of Kala-azar.
Cu(ii) Schiff base complexes Cu(ii)- and Cu(ii)- based on 2-acetyl pyridine with both (1R,2R)-1,2-diaminocyclohexane and (1S,2S)-1,2-diaminocyclohexane were synthesized in a single step. Subsequent reduction of ligands and with NaBH4 followed by complexation with Cu(OTf)2 resulted in generation of two more additional chiral centers in complexes Cu(ii)- and Cu(ii)-. The ligands and their corresponding complexes were well characterized by several spectral techniques like (1)H-NMR, (13)C-NMR, LC-MS, CD, UV-Vis spectroscopy and microanalysis. The respective Cu(ii) complexes derived from ligands and were investigated using both the solution and solid state EPR spectra. The particular orientation of the reduced complex with Cu(OTf)2 was confirmed by the X-ray crystal structure of the corresponding complex. All the catalytic protocols were applied in the asymmetric aza-Henry reaction to evaluate the catalytic properties of the Cu(ii) complexes in the present study.
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