Coadministration of bedaquiline and pyrifazimine reduce exposure to toxic metabolite N-desmethyl bedaquiline.

Background: A new, effective anti-tuberculosis (TB) regimen containing bedaquiline (BDQ) and pyrifazimine (TBI-166) has been recommended for a phase IIb clinical trial. Preclinical drug-drug interaction (DDI) studies of the combination of BDQ and TBI-166 have been designed to support future clinical trials. In this study, we investigated whether a DDI between BDQ and TBI-166 affects the pharmacokinetics of BDQ. Methods: We performed in vitro quantification of the fractional contributions of the fraction of drug metabolism by individual CYP enzymes (f m) of BDQ and the inhibition potency of key metabolic pathways of TBI-166. Furthermore, we conducted an in vivo steady-state pharmacokinetics study in a murine TB model and healthy BALB/c mice. Results: The in vitro f m value indicated that the CYP3A4 pathway contributed more than 75% to BDQ metabolism to N-desmethyl-bedaquiline (M2), and TBI-166 was a moderate (IC50 2.65 µM) potential CYP3A4 inhibitor. Coadministration of BDQ and TBI-166 greatly reduced exposure to metabolite M2 (AUC0-t 76310 vs 115704 h ng/mL, 66% of BDQ alone), whereas the exposure to BDQ and TBI-166 did not changed. The same trend was observed both in healthy and TB model mice. The plasma concentration of M2 decreased significantly after coadministration of BDQ and TBI-166 and decreased further during treatment in the TB model. Conclusions: In conclusion, our results showed that the combination of BDQ and TBI-166 significantly reduced exposure to the toxic metabolite M2 by inhibiting the activity of the CYP3A4 pathway. The potential safety and efficacy benefits demonstrated by the TB treatment highly suggest that coadministration of BDQ and TBI-166 should be studied further.

Imidazo[1,2-a]pyridine derivatives synthesis from lignin ß-O-4 segments via a one-pot multicomponent reaction.

The catalytic conversion of lignin into N-containing chemicals is of great significance for the realization of value-added biorefinery concept. In this article, a one-pot strategy was designed for the transformation of lignin ß-O-4 model compounds to imidazo[1,2-a]pyridines in yields up to 95% using 2-aminopyridine as a nitrogen source. This transformation involves highly coupled cleavage of C-O bonds, sp3C-H bond oxidative activation, and intramolecular dehydrative coupling reaction to construction of N-heterobicyclic ring. With this protocol, a wide range of functionalized imidazo[1,2-a]pyridines sharing the same structure skeleton as those commercial drug molecules, such as Zolimidine, Alpidem, Saripidem, etc., were synthesized from different lignin ß-O-4 model compounds and one ß-O-4 polymer, emphasizing the application feasibility of lignin derivatives in N-heterobicyclic pharmaceutical synthesis.

Efficacy of Replacing Linezolid with OTB-658 in Anti-Tuberculosis Regimens in Murine Models.

Linezolid (LZD) was the first oxazolidinone approved for treating drug-resistant tuberculosis. A newly approved regimen combining LZD with bedaquiline (BDQ) and pretomanid (PMD) (BPaL regimen) is the first 6-month oral regimen that is effective against multidrug- and extensively drug-resistant tuberculosis. However, LZD toxicity, primarily due to mitochondrial protein synthesis inhibition, may undermine the efficacy of LZD regimens, and oxazolidinones with higher efficacy and lower toxicity during prolonged administration are needed. OTB-658 is an oxazolidinone anti-TB candidate derived from LZD that could replace LZD in TB treatment. We previously found that OTB-658 had better anti-TB activity and safety than LZD in vitro and in vivo. In the present work, two murine TB models were used to evaluate replacing LZD with OTB-658 in LZD-containing regimens. In the C3HeB/FeJ murine model, replacing 100 mg/kg LZD with 50 mg/kg OTB-658 in the BDQ + PMD backbone significantly reduced lung and spleen CFU counts (P < 0.05), and there were few relapses at 8 weeks of treatment. Replacing 100 mg/kg LZD with 50 or 100 mg/kg OTB-658 in the pyrifazimine (previously called TBI-166) + BDQ backbone did not change the anti-TB efficacy and relapse rate. In BALB/c mice, replacing 100 mg/kg LZD with 100 mg/kg OTB-658 in the TBI-166 + BDQ backbone resulted in no culture-positive lungs at 4 and 8 weeks of treatment, and there were no significant differences in relapses rate between the groups. In conclusion, OTB-658 is a promising clinical candidate that could replace LZD in the BPaL or TBI-166 + BDQ + LZD regimens and should be studied further in clinical trials.

Synthesis and comparison study of electrochemiluminescence from mononuclear and corresponding heterodinuclear Ir-Ru complexes via an amide bond as a bridge.

A mononuclear iridium-based complex with a primary amine group (named Ir-NH2), a mononuclear ruthenium-based complex with a butanoic acid group (named Ru-COOH) and the corresponding heterodinuclear complex containing an iridium and ruthenium center via an amide bond bridge (named Ir-Ru) were designed and successfully synthesized in this study. The photophysical and electrochemical properties and ECL performances of these three metal complexes under various experimental conditions were well characterized. For the first time, the insights from this comprehensive comparison study indicate that the two metal-based subunits with comparable luminescent properties are significant in the design of bimetallic-based multicolor luminophores at the molecular level, which helps us to further understand the emission performances of bimetallic complexes and to rationally design more efficient corresponding organometallic luminophores with multicolor emission for wide applications in the future.

Successive Cleavage and Reconstruction of Lignin ß-O-4 Models and Polymer to Access Quinoxalines.

The construction of N-heterocyclic compounds from lignin remains a great challenge due to the complex lignin structure and the involvement of multiple steps, including the cleavage of lignin C-O linkages and the formation of heterocyclic aromatic rings. Herein, the first example of KOH mediated sustainable synthesis of quinoxaline derivatives from lignin ß-O-4 model compounds in a one-pot fashion under transition-metal-free conditions has been achieved. Mechanistic studies suggested that this transformation includes highly coupled cascade steps of cleavage of C-O bonds, dehydrative condensation, sp3 C-H bond oxidative activation, and intramolecular dehydrative coupling reaction. With this protocol, a wide range of functionalized quinoxalines, including an important drug compound AG1295, were synthesized from lignin ß-O-4 model compounds and ß-O-4 polymer, showcasing the application potential of lignin in pharmaceutical synthesis.

Superior Efficacy of a TBI-166, Bedaquiline, and Pyrazinamide Combination Regimen in a Murine Model of Tuberculosis.

TBI-166, derived from riminophenazine analogues, shows more potent anti-TB activity than clofazimine and is being assessed against tuberculosis (TB) in a phase IIa clinical trial in China. Preclinical regimen studies containing TBI-166 will support the phase IIb clinical trials of TBI-166. In the present study, we compared the efficacy in three murine TB models of an all-oral drug-resistant TB drug regimen of TBI-166 with bedaquiline (BDQ) and pyrazinamide (PZA) with the first-line regimen of isoniazid (INH) with rifampin (RFP) and PZA (HRZ regimen), the most effective reported TBI-166-containing regimen of TBI-166 with BDQ and linezolid (LZD), and the Nix-TB clinical trial regimen of BDQ with pretomanid and LZD (BPaL regimen). In the C3HeB/FeJ murine TB model, for the TBI-166+BDQ+PZA regimen, the lungs of mice were culture negative at 4 weeks, and there were no relapses at 8 weeks of treatment. The reduction in bacterial burden and relapse rate were greater than those of the HRZ regimen and the TBI-166+BDQ+LZD regimen. Compared with the BPaL regimen, the TBI-166+BDQ+PZA regimen had similar or stronger early bactericidal activity, bactericidal activity, and sterilizing activity in the BALB/c murine TB model. The bacterial burden in the TBI-166+BDQ+PZA regimen group decreased significantly more than that in the BPaL regimen group and was almost or totally relapse free (<13.33% after 8 weeks). In conclusion, oral short-course three-drug regimens, including TBI-166 with high efficacy, were identified. The TBI-166+BDQ+PZA regimen is recommended for further study in a TBI-166 phase IIb clinical trial.

Transition-Metal-Free Synthesis of Functionalized Quinolines by Direct Conversion of ß-O-4 Model Compounds.

Direct production of heterocyclic aromatic compounds from lignin ß-O-4 models remains a huge challenge due to the incompatible catalysis for aryl ether bonds cleavage and heterocyclic ring formation. Herein, the first example of quinoline synthesis from ß-O-4 model compounds by a one-pot cascade reaction is reported in yields up to 89 %. The reaction pathway involves selective cleavage of C-O bonds, dehydrogenation, aldol condensation, C-N bond formation along with heterocyclic aromatic ring construction. The control experiments suggest that both imine and chalcone were identified as the key intermediates, and the rate determining step as well as the preferred pathway were experimentally clarified and supported by density functional theory (DFT) calculations. Based on this protocol, the conversion of ß-O-4 polymer delivered 56 wt % yield of quinoline derivative in three steps. This transformation provides a potential petroleum-independent choice for heterocyclic aromatic chemicals.

Relevance of gene polymorphisms of NAT2 and NR1I2 to anti-tuberculosis drug-induced hepatotoxicity.

The recommended treatment regimen for tuberculosis is a combination of agents with antitubercular activity, during which hepatotoxicity is one of the most common side effects. In addition to the N-acetyltransferase 2 (NAT2) genotype, rs3814055 in nuclear receptor subfamily 1, group I, member 2 (NR1I2) has been demonstrated to be associated with anti-tuberculosis drug-induced hepatotoxicity (ATDH), but previous results have been inconsistent.A retrospective nested hospital-based case-control study was performed to investigate the association between genetic polymorphisms and the risk of ATDH. Fifteen genetic variants (13 SNPs and two null genotypes) in cytochrome P450 2E1, NR1I2, UDP-glucuronosyltransferase 1A1, NAT2, superoxide dismutase 1, superoxide dismutase 2, and glutathione S-transferases (GSTT1, GSTM1, GSTP1) were genotyped. Odds ratios with 95% confidence intervals were calculated with drug doses, body mass index comorbidity of diabetes mellitus, and baseline alanine transaminase value as covariates.Conditional logistic regression demonstrated that the NAT2 slow acetylation genotype and the T allele of rs3814055 in NR1I2 may contribute to susceptibility to ATDH.Stratified association analysis demonstrated that in NAT2 non-slow acetylators, the T allele of rs3814055 was a risk factor for ATDH, whereas the T allele did not increase the susceptibility to ATDH in slow acetylators.

Iridium solvent complex as a new sensitive probe to detect benzimidazole pesticides based on photoluminescent signals "switch-on" via coordination mechanism.

An iridium solvent complex (abbreviated as Ir-probe) has been synthesized and reported as a new photoluminescent "switch-on" probe to detect benzimidazole pesticides via coordination mechanism in this work. This new probe could successfully distinguish benzimidazole pesticides from other kinds of common pesticides widely used in agriculture activities. Thiabendazole (TBZ) and carbendazim (CBZ) as the representative benzimidazole pesticides, this probe exhibited good analytical performance with the linear ranges of 0.05 µM to 20 µM for TBZ and 3 µM to 40 µM for CBZ, and the corresponding limit of detection (LOD, 3σ/S) is 0.03 µM and 0.5 µM for analyzing TBZ and CBZ, respectively. In addition, the proposed method in this work also has good recoveries in analyzing TBZ and CBZ residues in the real samples.

Linezolid Pharmacokinetics/Pharmacodynamics-Based Optimal Dosing for Multidrug-Resistant Tuberculosis.

OBJECTIVES: Linezolid can significantly impact drug-resistant tuberculosis (DR-TB) patient outcomes. However, the long-term use of this drug for TB treatment has been limited by adverse reactions and uncertainty regarding optimal dosage regimens for balancing drug efficacy and safety across different populations. This study attempted to find the optimal dosing regimen of linezolid in different populations. METHODS: A total of 355 blood samples were collected from 126 DR-TB patients. Population pharmacokinetic analysis (using a one-compartment model) and dose simulations were conducted using NONMEM and R software. The ratio between the area under the free drug plasma concentration-time curve to the MIC (fAUC/MIC) of > 119 and trough concentration (Cmin) ≤ 2 mg/L served as efficacy and safety targets, respectively, toward the formulation of optimal dosage regimens based on a ≥ 90% cumulative fraction of response. RESULTS: Body weight and blood urea nitrogen levels were the most significant covariates of apparent volume, while creatinine clearance and haemoglobin level significantly influenced apparent clearance. The probability of target attainment for different dosage regimens was evaluated via Monte Carlo simulation. For subjects with MICs of 0.125, 0.25 and 0.5 mg/L, specific total daily doses of ≥ 300 mg, ≥ 450 mg and ≥ 900 mg were required to reach the target, respectively. Subjects with body weight ≤ 70 kg and MIC ≥ 1 mg/L received a total 1200 mg daily dose to reach the probability of target attainment target. Notably, single dosing was safer than multiple dosing at the same daily dose. The optimal dosage regimens for subjects with body weight < 50 kg and ≥ 50 kg were 450 mg/d and 600 mg/d (once daily), respectively. CONCLUSION: Optimal dosage regimens for patients weighing < 50 kg and ≥ 50 kg were 450 mg/d and 600 mg/d, respectively. A single dose was safer than multiple doses.

Efficient NIR electrochemiluminescent dyes based on ruthenium(II) complexes containing an N-heterocyclic carbene ligand.

Three new ruthenium(ii) complexes containing an N-heterocyclic carbene (NHC) ligand (RuNHC) have been successfully synthesized and proved to be efficient near-infrared (NIR) ECL (electrogenerated chemiluminescence) luminophores. In addition to the advantages of the lower-charge main motif (+1), the much lower oxidation potentials, and the longer metal to ligand charge transfer (MLCT) absorption bands, most importantly, these RuNHC complexes show higher, or at least comparable, ECL efficiency compared with Ru(bpy)32+ under the same experimental conditions; this demonstrates their great potential for applications in the NIR ECL imaging field in the future.

Effects of ABCG2 and SLCO1B1 gene variants on inflammation markers in patients with hypercholesterolemia and diabetes mellitus treated with rosuvastatin.

PURPOSE: Dysregulation of angiogenesis and inflammation play important roles in the development of atherosclerosis. Rosuvastatin (RST) was widely used in atherosclerosis therapy. Genetic variations of transporters may affect the rosuvastatin concentration in plasma and reflect different clinical treatment. The aim of this study was to explore the drug transport related single-nucleotide polymorphisms (SNPs) on RST pharmacokinetic and the further on pro-angiogenic and pro-inflammatory factors. METHODS: A total of 269 Chinese patients with hypercholesterolemia and diabetes mellitus were enrolled. They were treated with RST to lower cholesterol. The plasma concentration of RST was determined using a validated UPLC-MS/MS method. Seven single-nucleotide polymorphisms (SNPs) in six genes were genotyped using the Sanger dideoxy DNA sequencing method. The serum concentrations of inflammation markers were determined using ELISA kits. RESULTS: ABCG2 421C > A (rs2231142) and SLCO1B1 521 T > C (rs4149056) variations were highly associated with plasma concentrations of RST (P < 0.01, FDR < 0.05). The serum MCP-1, sVCAM-1, and TNF-α levels were significantly different between the ABCG2 421C > A and SLCO1B1 521 T > C genetic variation groups (P < 0.01). RST concentration was negatively correlated with sVCAM-1 concentration (r = 0.150, P = 0.008). CONCLUSION: ABCG2 421C > A (rs2231142) and SLCO1B1 521 T > C (rs4149056) genetic variants affect RST concentration significantly and potentially affect serum levels of pro-inflammatory and pro-angiogenic markers. The effects on anti-inflammation might not be related to high plasma exposure of RST.

Synthesis and Structural Optimization of Iridium(III) Solvent Complex for Electrochemiluminescence Labeling of Histidine-Rich Protein and Immunoassay Applications for CRP Detection.

The reaction between an iridium(III) solvent complex and the histidine site of biomolecules as one kind of novel bioconjugation approaches has received much attention during the past few years. To extend this novel bioconjugation approach into electrochemiluminescence (ECL) immunoassay and optimize the performances, three iridium(III) solvent complexes with different C∧N bidentate main ligands have been designed and synthesized in this work. Bovine serum albumin (BSA) as the standard histidine-rich protein is initially employed to evaluate the labeling performances by comparing the ECL intensity of the same amount of BSA labeled by different iridium(III) solvent complexes. Importantly, a magnetic beads-based sandwich immunoassay platform using Ir-dmpq (iridium(III) acetonitrile complex with 2-(3,5-dimethylphenyl)quinoline as the main ligand) as a structurally optimized labeling agent has been successfully constructed to detect C-reactive protein (CRP, an important biomarker of systemic inflammation in clinic), and the limit of detection based on this novel labeling agent could reach below 1 ng/mL, which may further pave the way for applications of the iridium(III) solvent complex in histidine-rich protein ECL labeling beyond fluorescence labeling.

Investigation of Metal-Organic Framework-5 (MOF-5) as an Antitumor Drug Oridonin Sustained Release Carrier.

Oridonin (ORI) is a natural active ingredient with strong anticancer activity. But its clinical use is restricted due to its poor water solubility, short half-life, and low bioavailability. The aim of this study is to utilize the metal organic framework material MOF-5 to load ORI in order to improve its release characteristics and bioavailability. Herein, MOF-5 was synthesized by the solvothermal method and direct addition method, and characterized by Scanning Electron Microscopy (SEM), X-Ray Diffraction (XRD), Fourier Transform Infrared Spectrometer (FTIR), Thermogravimetric Analysis (TG), Brunauer-Emmett-Teller (BET), and Dynamic Light Scattering (DLS), respectively. MOF-5 prepared by the optimal synthesis method was selected for drug-loading and in vitro release experiments. HepG2 cells were model cells. MTT assay, 4',6-diamidino-2-phenylindole (DAPI) staining and Annexin V/PI assay were used to detect the biological safety of blank carriers and the anticancer activity of drug-loaded materials. The results showed that nano-MOF-5 prepared by the direct addition method had complete structure, uniform size and good biocompatibility, and was suitable as an ORI carrier. The drug loading of ORI@MOF-5 was 52.86% ± 0.59%. The sustained release effect was reliable, and the cumulative release rate was about 87% in 60 h. ORI@MOF-5 had significant cytotoxicity (IC50:22.99 µg/mL) and apoptosis effect on HepG2 cells. ORI@MOF-5 is hopeful to become a new anticancer sustained release preparation. MOF-5 has significant potential as a drug carrier material.