Piperazine Moiety Research Articles

The preclinical pharmacokinetics of Tolinapant-A dual cIAP1/XIAP antagonist with invivo efficacy.

AT-IAP (1-{6-[(4-fluorophenyl)methyl]-3,3-dimethyl-1H,2H,3H-pyrrolo[3,2-b]pyridin-1-yl}-2-[(2R,5R)-5-methyl-2-{[(3R)-3-methylmorpholin-4-yl]methyl}piperazin-1-yl]ethan-1-one) was identified as a novel potent non-alanine small molecule dual inhibitor of cIAP1/XIAP protein. AT-IAP was assessed in preclinical species, demonstrating favorable bioavailability in rodent species and oral efficacy at 30 mg/kg in MDA-MB-231 mouse xenograft models. The major metabolic route of AT-IAP was identified to be CYP3A driven, resulting in low oral exposure in non-human primate (NHP) studies, given the comparatively high expression of equivalent CYP3A. AT-IAP metabolite identification studies determined ring opening of the morpholino or piperazine moiety. An extensive campaign of optimisation resulted in increased polarity by the addition of a hydroxymethyl, which led to the identification of tolinapant (1-(6-[(4-Fluorophenyl)methyl]-5-(hydroxymethyl)-3,3-dimethyl-1 H,2 H,3 H-pyrrolo[3,2- b]pyridin-1-yl)-2-[(2 R,5 R)-5-methyl-2-([(3R)-3-methylmorpholin-4-yl]methyl)piperazin-1-yl]ethan-1-one) with reduced CYP3A metabolism. Tolinapant showed oral bioavailability in rodents and NHP in the range 12-34% at 5 mg/kg. Non-linear pharmacokinetics in NHP were observed at oral doses in the range 5-75 mg/kg. Pharmacodynamic modulation and efficacy were demonstrated in A375 mouse xenograft models at dose ranges between 5 and 20 mg/kg. On-target engagement, as measured by reduction of cIAP 1 protein levels, was confirmed in NHP surrogate tissues and applied to target activity assessments in tolinapant phase1/2 clinical trials.

Antibacterial and antibiofilm agents in the group of xanthone derivatives with piperazine moiety active against drug-resistant Helicobacter pylori strains

Helicobacter pylori (H. pylori) cause chronic inflammation of the gastric mucosa which can lead to epithelial atrophy and metaplasia resulting in peptic ulcer disease and gastric cancer. The increasing resistance of H. pylori to antibiotics and chemotherapeutics used to treat the infection is a serious problem. However, it has been confirmed that the introduction of effective anti-H. pylori therapy can prevent the progression to cancerous changes. This problem calls for the search for new and effective therapies. Xanthones are a group of compounds with extensive biological activities, including antibacterial activity, also against H. pylori. Addressing this issue, the aim of the study was to evaluate the potential of a group of 13 xanthone derivatives against susceptible and resistant H. pylori strains. Moreover, our objective was to conduct tests aimed at determining their ability to inhibit biofilm formation.The antimicrobial evaluation revealed that benzylpiperazine coupled at the C-2 position to xanthone (compounds C11 and C12) had good selective bacteriostatic activity against reference and clinical H. pylori strains (MBC/MIC ratio >4) but with no activity against other bacteria such as Staphylococcus aureus, Escherichia coli, and Lactobacillus paracasei. Analysis of the activity of compounds C11 and C12 against the biofilm formed by H. pylori strain ATCC 700684, and the clinical strain showed that these compounds caused a significant reduction in the amount of biofilm produced (5–20×). Moreover, cell viability analysis confirmed a 3–4× reduction in the viability of cells forming biofilm after treatment with C11 and C12. Finally,both compounds did not impair human fibroblast viability at tested concentrations and were not mutagenic in the Ames test. Therefore, they could be promising leads as antibacterial candidates for multidrug-resistant strains of H. pylori.

Studies on the synthesis, crystal structures, biological activities and molecular docking of novel natural methylxanthine derivatives containing piperazine moiety.

A series of novel methylxanthine Mannich base derivatives containing substituted piperazine groups were synthesized through Mannich reaction. The structures of these new compounds were confirmed by NMR, HRMS or elemental analyses, and X-ray single crystal diffraction. Bioassay results showed that some of the compounds exhibit favorable fungicidal and insecticidal potentials. Particularly, compounds IIk, IIq, IIs and compounds If, IIk against Physalospora piricola and Rhizoctonia cerealis, respectively, were comparable with Azoxystrobin and Chlorothalonil; compound Ik exhibited higher potency than Triflumuron against Plutella xylostella L., suggesting its potential as a lead compound for further development in insecticidal applications. Despite possessing weak herbicidal activities, the target compounds, especially the methylxanthine S-Mannich base derivatives I displayed remarkable inhibitory activities toward ketol-acid reductoisomerase (KARI); compounds Ib, If, and Ik which had Ki values of 2.41-8.08 µmol/L can be novel potent KARI inhibitors for deeper exploration. The SARs were analyzed in detail. The molecular docking studies on the highly active inhibitors with KARI provided possible binding modes between inhibitor and the target enzyme. The physicochemical parameter predictions indicated that compounds Ik, IIk, IIq and IIs have "druglike structure" features. The research results in this article may bring a new inspiration to the extensive explorations on new methylxanthine derivatives in pesticide area.

Synthesis, In Vivo, ADME Determination, and Molecular Docking Studies of 1,3,4‐Oxadiazoles Containing Pyridine and Piperazine Moieties as New Diuretic Agents

AbstractA series of 1‐(piperazin‐1‐yl)‐2‐((5‐(pyridin‐4‐yl)‐1,3,4‐oxadiazol‐2‐yl)thio)ethan‐1‐one derivatives (9a–l) were prepared using a multistep reaction between 2‐chloro‐1‐(piperazin‐1yl)ethan‐1‐one derivatives (4a–l) and 5‐(pyridine‐4‐yl)‐1,3,4‐oxadiazole‐2‐thiol (8) and studied their diuretic potential by following established in vivo and in silico protocols. The data obtained from the experimental rat animal model in vivo diuretic studies indicated that synthesized derivatives 9d, 9e, 9g, 9i, and 9j possess excellent diuretic potential. The results obtained from in vivo study were also reinforced by the data of in silico studies performed using AutoDock (1.5.7) software. The molecular docking involved interactions of synthesized molecules with two target proteins, that is, human carbonic anhydrase II protein (hCA‐II, PDB ID: 3HS4) and human NKCCl K289NA492E protein (NKCCl, PDB ID: 7S1Y). The ADME properties of the synthesized molecules have also been determined using pkCSM software that established that the synthesized molecules are good candidates for oral absorption. All the data of in vivo and in silico studies synergized the results that state that the diuretic activity of all synthesized compounds is greater than that of the standard drug (furosemide), whereas compounds 9d, 9e, 9g, 9i, and 9j show excellent activity with values of 1.32, 1.33, 1.35, 1.39, and 1.35, respectively.

Development of Imidazo[1,2-a]pyridines Containing Sulfonyl Piperazines as Potential Antivirals against Tomato Spotted Wilt Virus.

Mesoionic structures have become important advancements in recent agrochemical design. However, their potential beyond serving as excellent insecticides remains unexplored with limited reports available. Herein, a series of imidazo[1,2-a]pyridine mesoionics were developed by structurally incorporating sulfonyl piperazine moieties into imidazo[1,2-a]pyridines. Many of the obtained derivatives demonstrated bioactivity against tomato spotted wilt virus (TSWV) in bioassays. In particular, compound Z40, identified via three-dimensional quantitative structure activity relation models, displayed encouraging protective performance (half-maximal effect concentration = 252 μg/mL) compared to the positive controls ningnanmycin (332 μg/mL) and vanisulfane (523 μg/mL). Through defense enzyme assays, real-time quantitative polymerase chain reaction, and proteomics analysis, Z40 was identified as a plant immunomodulator that promotes defense enzyme activity and the mediates oxidative phosphorylation pathway, enabling plants to resist TSWV. We expect this study to help expand the possibilities of mesoionic compounds.

Some heterocycles connected to substituted piperazine by 1,3,4-oxadiazole linker: Design, synthesis, anticholinesterase and antioxidant activity

AD is a multifactorial neurodegenerative disease that has caused morbidity and mortality on a global scale. Currently, there are only a few drugs used in the treatment of AD. Although many compounds that aim at new targets have reached clinical trials, none have been approved. However, discovering efficient drugs for AD treatment is one of the biggest challenges for pharmaceutical research and requires strong support. In this paper, we aim to design a series of indole, benzothiophene, and thiophene bearing 1,3,4-oxadiazole linker to the piperazine basic center and evaluate for their antioxidant and inhibitory activity against both cholinesterase enzymes. Among the compounds, 6a, 7b, and 8b exhibited moderate cationic radical scavenging activities with IC50 values ranging from 20.39 to 30.10 μM. The inhibitory activity results revealed that compounds 5c (IC50 for AChE = 53.91 μM and for BChE = 55.81 μM) and 6c (IC50 for AChE = 54.42 μM and BChE = 45.82 μM) bearing 2-fluorophenyl piperazine moiety showed both AChE and BChE inhibition with moderate IC50 values. To explore the binding properties of the target compounds into the active site of the enzyme, a molecular docking study was carried out using MOE software. The docking study showed that compound 6c targeted both the catalytic active site (CAS) and the peripheral anionic site (PAS) of AChE/BChE and formed important interactions with key residues. Moreover, theoretical physicochemical properties of the best active compound 6c were calculated by the SwissADME web service. It obeyed Lipinski's rule of five and had high GI absorption (gastrointestinal absorption) and good permeating to the blood-brain barrier (BBB). The compound 6c can be considered a promising compound and provides us directions for further research of anti-AD agent development.

Laccase mediated transformation of fluoroquinolone antibiotics: Analyzing degradation pathways and assessing algal toxicity

Improper waste disposal or inadequate wastewater treatment can result in pharmaceuticals reaching water bodies, posing environmental hazards. In this study, crude extracts containing the laccase enzyme from Pleurotus florida, Pleurotus eryngii, and Pleurotus sajor caju were used to degrade the fluoroquinolone antibiotics (FQs) levofloxacin (LEV), norfloxacin (NOR), ciprofloxacin (CIP), ofloxacin (OFL), and enrofloxacin (ENR) in aqueous solutions. The results for the fungi derived laccase extracts were compared with those obtained using commercially sourced laccase. Proteomics analysis of the crude extracts confirmed the presence of laccase enzyme across all three tested species, with proteins matching those found in Trametes versicolor and Pleurotus ostreatus. In vivo studies were conducted using species pure lines of fungal whole cells. The highest degradation efficiency observed was 77.7% for LEV in the presence of P. sajor caju after 25 days of treatment. Degradation efficiencies ranged from approximately 60-72% for P. florida, 45–76% for P. eryngii, and 47–78% for P. sajor caju. A series of in vitro experiments were also conducted using crude extracts from the three species and outcomes compared with those obtained when commercial laccase was used confirmed laccase as the enzyme responsible for antibiotic removal. The degradation efficiencies in vitro surpassed those measured in vivo, ranging from approximately 91-98% for commercial laccase, 77–92% for P. florida, 76–92% for P. eryngii, and 78–88% for P. sajor caju. Liquid chromatography–high-resolution mass spectrometry (LC-MS/MS) identified the degradation products, indicating a consistent enzymatic degradation pathway targeting the piperazine moiety common to all tested FQs, irrespective of the initial antibiotic structure. Phytoplankton toxicity studies with Dunaliella tertiolecta were performed to aid in understanding the impact of emerging contaminants on ecosystems, and by-products were analysed for ecotoxicity to assess treatment efficacy. Laccase-mediated enzymatic oxidation shows promising results in reducing algal toxicity, notably with Pleurotus eryngii extract achieving a 97.7% decrease for CIP and a 90% decrease for LEV. These findings suggest the potential of these naturally sourced extracts in mitigating antibiotic contamination in aquatic ecosystems.

In silico molecular modeling and invitro biological screening of novel benzimidazole-based piperazine derivatives as potential acetylcholinesterase and butyrylcholinesterase inhibitors.

New series of benzimidazole incorporating piperazine moieties in single molecular framework has been reported. The structures of the synthesized derivatives were assigned by 1H-NMR, 13C-NMR, and HR-MS techniques. The hybrid derivatives were evaluated for their acetylcholinesterase and butyrylcholinesterase inhibition effect. All the synthesized analogs showed good to moderate inhibitory effect ranging from IC50 value 0.20±0.01 µM to 0.50±0.10 µM for acetylcholinesterase and from IC50 value 0.25±0.01 µM to0.70±0.10 µM for butyrylcholinesterase except one thatshowed least potency with IC50 value 1.05±0.1 µM and 1.20±0.1 µM. The differences in inhibitory potential of synthesized compounds were due to the nature and position of substitution attached to the main ring. Additionally, molecular docking study was carried out for most active inorder to explore the binding interactions established byligand (active compounds) with the active residues of targeted AChE & BuChE enzyme.

Novel mandelic acid derivatives containing piperazinyls as potential candidate fungicides against Monilinia fructicola: Design, synthesis and mechanism study

Brown rot of stone fruit, a disease caused by the ascomycete fungus Monilinia fructicola, has caused significant losses to the agricultural industry. In order to explore and discover potential fungicides against M. fructicola, thirty-one novel mandelic acid derivatives containing piperazine moieties were designed and synthesized based on the amide skeleton. Among them, target compound Z31 exhibited obvious in vitro antifungal activity with the EC50 value of 11.8 mg/L, and significant effects for the postharvest pears (79.4 % protective activity and 70.5 % curative activity) at a concentration of 200 mg/L. Antifungal activity for the target compounds was found to be significantly improved by the large steric hindrance of the R1 groups and the electronegative of the piperazines in the molecular structure, according to a three-dimensional quantitative structure–activity relationship (3D-QSAR) analysis. Further mechanism studies have demonstrated that the compound Z31 can disrupt cell membrane integrity, resulting in increased membrane permeability, release of intracellular electrolytes, and affect the normal growth of hyphae. Additional, morphological study also indicated that Z31 may disrupt the integrity of the membrane by inducing generate excess endogenous reactive oxygen species (ROS) and resulting in the peroxidation of cellular lipids, which was further verified by the detection of malondialdehyde (MDA) content. These studies have provided the basis for the creation of novel fungicides to prevent brown rot in stone fruits.

Synthesis of Piperazine-containing Derivatives and their Antimicrobial, Antimycobacterial, Antimalarial and Antioxidant Activities

Background: One of the most crucial heterocycles is piperazine for the creation of novel medication candidates with a variety of medicinal applications. The piperazine moiety is a cyclic compound with four carbon atoms and two nitrogen atoms in positions 1 and 4. Objective: The objective of this studty is the development of 1-((3,4-dimethoxyphenyl) (substitutedphenyl) substituted -piperazine (A1-A10) analogs via the one-pot synthesis method and evaluation for their preliminary antibacterial, antifungal, antimycobacterial, antioxidant, and antimalarial activity. Methods: Desired piperazine derivatives were obtained in a single step reaction using piperazine, aldehydes, and boronic acid derivatives. The structures of all newly synthesized compounds have been established based on analytical and spectral data. An in silico molecular docking study was carried out for the series. Results: The spectral data using IR, 1 H NMR, and 13C NMR and mass spectra confirmed the structure of the synthesized compounds. Compounds A6 and A10 were found to be the most promising agents for antimalarial activity. A1-A10 showed a higher IC50 value and found less antioxidant activity. Some of the compounds showed higher potency when compared to the standard drugs in this antimicrobial study. Conclusion: The structure-activity study showed that changes in substituents either on aldehyde, piperazine, or boronic acid derivatives can lead to potential active compounds. These facts make the compounds interesting candidates for further evaluation of their efficacy in the treatment of microbial, tubercular and malarial diseases.

Novel Octahedral Nickel (II) Complex with Flexible Piperazinyl Moiety Exhibits Potent Cytotoxic Effect Along with Anti-Migratory and Anti-Metastatic Effect on Human Cancer Cells.

Synthesis of non-platinum transition metal complexes with N,O donor chelating ligand for application against pathogenesis of cancer with higher efficacy and selectivity is currently an important field of research. We assessed the anti-cancer effect of a mixed ligand Ni(II) complex on human breast and lung cancer cell lines in this investigation. Mononuclear mixed ligand octahedral Ni(II) complex [NiIIL(NO3)(MeOH)] complex (1), with tri-dentate phenol-based ligand 2,4-dichloro-6-((4-methylpiperazin-1-yl) methyl) phenol (HL) along with methanol and nitrate as ancillary ligand was prepared. Piperazine moiety of the ligand exists as boat conformation in this complex as revealed from single crystal X-ray study. UV-visible spectrum of complex (1) exhibits three distinct d-d bands due to spin-allowed 3 A2 g→3T1 g (P), 3 A2 g→3T1 g(F) and 3 A2 g→3T2 g(F) transitions as expected in an octahedral d8 system. Our study revealed that Complex (1) induces apoptotic cell death in mouse and human cancer cells such as mcf-7, A549 and MDA-MB-231 through transactivation of p53 and its pro-apoptotic downstream targets in a dose dependent manner. Furthermore, complex (1) was able to slow the migratory rate of MDA-MB-231 cells' in vitro as well as epithelia -mesenchymal transition (EMT), the key step for metastatic transition and malignancy. Over all our results suggest complex (1) as a potential agent in anti-tumor treatment regimen showing both cytotoxic and anti-metastatic activity against malignant neoplasia.

Solar-light-driven photocatalytic degradation and detoxification of ciprofloxacin using sodium niobate nanocubes decorated g-C3N4 with built-in electric field

Simultaneous degradation and detoxification during pharmaceutical and personal care product removal are important for water treatment. In this study, sodium niobate nanocubes decorated with graphitic carbon nitride (NbNC/g-C3N4) were fabricated to achieve the efficient photocatalytic degradation and detoxification of ciprofloxacin (CIP) under simulated solar light. NaNbO3 nanocubes were in-situ transformed from Na2Nb2O6•H2O via thermal dehydration at the interface of g-C3N4. The optimized NbNC/g-C3N4-1 was a type-I heterojunction, which showed a high conduction band (CB) level of −1.68 eV, leading to the efficient transfer of photogenerated electrons to O2 to produce primary reactive species, •O2−. Density functional theory (DFT) calculations of the density of states indicated that C 2p and Nb 3d contributed to the CB, and 0.37 e– transferred from NaNbO3 to g-C3N4 in NbNC/g-C3N4 based on the Mulliken population analysis of the built-in electric field intensity. NbNC/g-C3N4-1 had 3.3- and 2.3-fold of CIP degradation rate constants (k1 = 0.173 min−1) compared with those of pristine g-C3N4 and NaNbO3, respectively. In addition, N24, N19, and C5 in CIP with a high Fukui index were reactive sites for electrophilic attack by •O2−, resulting in the defluorination and ring-opening of the piperazine moiety of the dominant degradation pathways. Intermediate/product identification, integrated with computational toxicity evaluation, further indicated a substantial detoxification effect during CIP degradation in the photocatalysis system.

Pharmaceutical Studies on Piperazine-Based Compounds Targeting Serotonin Receptors and Serotonin Reuptake Transporters.

Depression is a debilitating mental illness that has a significant impact on an individual's psychological, social, and physical life. Multiple factors, such as genetic factors and abnormalities in neurotransmitter levels, contribute to the development of depression. Monoamine oxidase inhibitors, tricyclic antidepressants, serotonin reuptake inhibitors (SSRIs), serotonin-noradrenaline reuptake inhibitors, and atypical and new-generation antidepressants are well-known drug classes. SSRIs are the commonly prescribed antidepressant medications in the clinic. Genetic variations impacting serotonergic activity in people can influence susceptibility to diseases and response to antidepressant therapy. Gene polymorphisms related to 5-hydroxytryptamine (5-HT) signaling and subtypes of 5-HT receptors may play a role in the development of depression and the response to antidepressants. SSRIs binding to 5-HT reuptake transporters help relieve depression symptoms. Research has been conducted to identify a biomarker for detecting depressive disorders to identify new treatment targets and maybe offer novel therapy approaches. The pharmacological potentials of the piperazine-based compounds led researchers to design new piperazine derivatives and to examine their pharmacological activities. Structure-activity relationships indicated that the first aspect is the flexibility in the molecules, where a linker of typically a 2-4 carbon chain joins two aromatic sides, one of which is attached to a piperazine/phenylpiperazine/benzyl piperazine moiety. Newly investigated compounds having a piperazine core show a superior antidepressant effect compared to SSRIs in vitro/in vivo.

Synthesis, Biological Evaluation and Molecular Docking Study of Novel Benzhydryl Piperazine‐1,2,3‐Triazoline Hybrids

AbstractHerein, a novel series of 1,5‐disubstituted‐1,2,3‐triazolines containing 1‐(4‐chlorobenzhydryl) piperazine moiety (8–18) were synthesised and evaluated for their anticancer activity across eight human tumor cell lines. Remarkably, compound 11 substituted with 3‐acetylphenyl group was the most potent anticancer agent against three selected human cancer cell lines (HL‐60, Z138, and DND‐41) with IC50 values of 16.80, 18.50, and 19.20 μM, respectively. In contrast, analogue 10 demonstrated activity against HL‐60, Z138, and DND‐41 cell lines, with IC50 values of 19.90, 18.00, and 18.50 μM, respectively. Moreover, derivative 13 substituted with 4‐bromophenyl moiety displayed activity with IC50=19.90 μM against the DND‐41 cell line. However, all analogues showed IC50 values ranging from 22.95 to 58.45 μM when tested against other investigated cancer cell lines. These findings suggest that derivative 11 holds promise as a potential candidate for synthesizing novel anticancer agents. Furthermore, compounds 8–18 were screened for their antioxidant activity. Molecular docking studies of compound 11 on crystal structures of two proteins, CDK2/cyclin A2 (PDB: 7B7S) and kinase Akt1 PKB alpha (PDB: 4GV1) have been studied.

Degradation of enrofloxacin with natural manganese oxides and enhancement by manganese oxidizing bacteria

Natural manganese oxides (n-MnOx) widely exist in the nature and may contribute to the elimination of organic contaminants. The present study investigated the degradation of frequently detected fluoroquinolone antibiotic enrofloxacin (EFX) and the degradation kinetics were analyzed. During the reaction, the valence of Mn in n-MnOx changed with the release of Mn ions. It was also found that combing manganese oxidizing bacteria with n-MnOx can enhance the degradation of EFX and alter the degradation pathway as well. The transformation products of EFX were analyzed with UPLC-MS/MS, which revealed seven products. Based on them, it is proposed that the degradation may start with the dehydrogenation from the piperazine moiety that was further broken down. Respirometry tests demonstrated that the degradation with n-MnOx significantly reduced the toxicity of EFX. This study proved the oxidation with n-MnOx as a simple and effective technology to remediate the contamination of enrofloxacin and other fluoroquinolones and the potential of combing the special capacity of microorganisms.

Zirconium-based hydrophobic-MOFs as innovative electrode modifiers for flibanserin determination: Exploring the electrooxidation mechanism using a comprehensive spectroelectrochemical study.

Threedifferent types of Zr-based MOFs derived from benzene dicarboxylic acid (BDC) and naphthalene dicarboxylic acid as organic linkers (ZrBDC, 2,6-ZrNDC, and 1,4-ZrNDC) were synthesized. They were characterized using X-ray diffraction analysis (XRD), X-ray photoelectron spectroscopy (XPS), Fourier-transform IR spectroscopy (FT-IR), and Transmission electron microscopy (TEM). Their hydrophilic/hydrophobic nature was investigated via contact angle measurements; ZrBDC MOF was hydrophilic and the other two (ZrNDC) MOFs were hydrophobic. The three MOFs were combined with MWCNTs as electrode modifiers for the determinationof a hydrophobic analyte, flibanserin (FLB), as a proof-of-concept analyte. Under the optimized experimental conditions, a significant enhancement in the oxidation peak current of FLB was observed when utilizing 2,6-ZrNDC and 1,4-ZrNDC, being the highest when using 1,4-ZrNDC. Furthermore, a thorough investigation of the complex oxidation pathway of FLB was performed by carrying out simultaneous spectroelectrochemical measurements. Based on the obtained results, it was verified that the piperazine moiety of FLB is the primary site for electrochemical oxidation. The fabricated sensor based on 1,4-ZrNDC/MW/CPE showed an oxidation peak of FLB at 0.8V vs Ag/AgCl. Moreover, it showed excellent linearity for the determinationof FLB in the range 0.05 to 0.80μmol L-1 with a correlation coefficient (r) = 0.9973 and limit of detection of 3.0nmol L-1. The applicability of the developed approach was demonstrated by determinationof FLB in pharmaceutical tablets and human urine samples with acceptable repeatability (% RSD values were below 1.9% and 2.1%, respectively) and reasonable recovery values (ranged between 97 and 103% for pharmaceutical tablets and between 96 and 102% for human urine samples). The outcomes of the suggested methodology can be utilized for the determinationof other hydrophobic compounds of pharmaceutical or biological interest with the aim of achieving low detection limits of these compounds in various matrices.

Clinical translation of a novel FAPI dimer [68Ga]Ga-LNC1013.

Three new FAPI dimers were synthesized by linking two quinoline-based FAPIs with different spacers. The in vitro binding affinity and preclinical small animal PET imaging of the compounds were compared with their monomeric counterparts, FAPI-04 and FAPI-46. The lead compound, [68Ga]Ga -LNC1013, was then evaluated in a pilot clinical PET imaging study involving seven patients with gastrointestinal cancer. The three newly synthesized FAPI homodimers had high binding affinity and specificity in vitro and in vivo. Small animal PET imaging and biodistribution studies showed that [68Ga]Ga-LNC1013 had persistent tumor retention for at least 4h, also higher uptake than the other two dimers and the monomer counterparts, making it the lead compound to enter clinical investigation. In the pilot clinical PET imaging study, seven patients were enrolled. The effective dose of [68Ga]Ga-LNC1013 was 8.24E-03mSv/MBq. The human biodistribution of [68Ga]Ga-LNC1013 demonstrated prominent tumor uptake and good tumor-to-background contrast. [68Ga]Ga-LNC1013 PET imaging showed potential in capturing primary and metastatic lesions and outperforming 18F-FDG PET in detecting pancreatic and esophageal cancers. The SUVmax for lesions with [68Ga]Ga-FAPI-46 decreased over time, whereas [68Ga]Ga-LNC1013 exhibited persistently high tumor uptake from 1 to 4h post-injection. Dimerization is an effective strategy to produce FAPI derivatives with favorable tumor uptake, long tumor retention, and imaging contrast over its monomeric counterpart. We demonstrated that [68Ga]Ga-LNC1013, the lead compound without any piperazine moiety, had superior diagnostic potential over [68Ga]Ga-FAPI-46 and 18F-FDG, suggesting the future potential of LNC1013 for radioligand therapy of FAP-positive cancers.

Mechanistic study of the electrochemical oxidation of fluoroquinolones: Ciprofloxacin, danofloxacin, enoxacin, levofloxacin and lomefloxacin

The fluoroquinolones ciprofloxacin, danofloxacin, enoxacin, levofloxacin and lomefloxacin, occur in water bodies worldwide and therefore pose a threat to the aquatic environment. Advanced purification procedures, such as electrochemical oxidation, may act as a remedy since they contribute to eliminating contaminants and prevent micropollutants from entering open water bodies. By electrochemical treatment in a micro-flow reactor equipped with a boron-doped diamond (BDD) electrode, the fluoroquinolones were efficiently degraded. A total of 15 new products were identified using high-performance high-resolution chromatography coupled with high-resolution multifragmentation mass spectrometry. The ecotoxicity of the emerging transformation products was estimated through in silico quantitative structure activity relationship analysis. Almost all transformation products were predicted less ecotoxic than the initial compounds. The fluoroquinolone degradation followed three major mechanisms depending on the voltage during the electrochemical oxidation. At approximately 1 V, the reactions started with the elimination of molecular hydrogen from the piperazine moiety. At approx. 1.25 V, methyl and methylene groups were eliminated. At 1.5 V, hydroxyl radicals, generated at the BDD electrode, led to substitution at the piperazine ring. This novel finding of the three reactions depending on voltage contributes to the mechanistic understanding of electrochemical oxidation as potential remedy against fluoroquinolones in the aquatic environment.

A novel enrofloxacin-degrading fungus, Humicola sp. KC0924g, isolated from the rhizosphere sediment of the submerged macrophyte Vallisneria spiralis L.

A novel enrofloxacin-degrading fungus was isolated from a rhizosphere sediment of the submerged macrophyte Vallisneria spiralis L.. The isolate, designated KC0924g, was identified as a member of the genus Humicola based on morphological characteristics and tandem conserved sequence analysis. The optimal temperature and pH for enrofloxacin degradation by strain KC0924g were 28°C and 9.0, respectively. Under such condition, 98.2% of enrofloxacin with an initial concentration of 1mg L-1 was degraded after 72h of incubation, with nine possible degradation products identified. Four different metabolic pathways were proposed, which were initiated by cleavage of the piperazine moiety, hydroxylation of the aromatic ring, oxidative decarboxylation, or defluorination. In addition to enrofloxacin, strain KC0924g also degraded other fluoroquinolone antibiotics (ciprofloxacin, norfloxacin, and ofloxacin), malachite green (an illegal additive in aquaculture), and leucomalachite green. Pretreatment of cells of strain KC0924g with Cu2+ accelerated ENR degradation. Furthermore, it was speculated that a flavin-dependent monooxygenase was involved in ENR degradation, based on the increased transcriptional levels of these two genes after Cu2+ induction. This work enriches strain resources for enrofloxacin remediation and, more importantly, would facilitate studies on the molecular mechanism of ENR degradation with degradation-related transcriptome available.

Synthesis,Antidiabetic and Antitubercular Evaluation of Quinoline-pyrazolopyrimidine hybrids and Quinoline-4-Arylamines.

Two libraries of quinoline-based hybrids 1-(7-chloroquinolin-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine and 7-chloro-N-phenylquinolin-4-amine were synthesized and evaluated for their α-glucosidase inhibitory and antioxidant properties. Compounds with 4-methylpiperidine and para-trifluoromethoxy groups, respectively, showed the most promising α-glucosidase inhibition activity with IC50=46.70 and 40.84 μM, compared to the reference inhibitor, acarbose (IC50=51.73 μM). Structure-activity relationship analysis suggested that the cyclic secondary amine pendants and para-phenyl substituents account for the variable enzyme inhibition. Antioxidant profiling further revealed that compounds with an N-methylpiperazine and N-ethylpiperazine ring, respectively, have good DPPH scavenging abilities with IC50=0.18, 0.58 and 0.93 mM, as compared to ascorbic acid (IC50=0.05 mM), while the best DPPH scavenger is NO2-substituted compound (IC50=0.08 mM). Also, compound with N-(2-hydroxyethyl)piperazine moiety emerged as the best NO radical scavenger with IC50=0.28 mM. Molecular docking studies showed that the present compounds are orthosteric inhibitors with their quinoline, pyrimidine, and 4-amino units as crucial pharmacophores furnishing α-glucosidase binding at the catalytic site. Taken together, these compounds exhibit dual potentials; i. e., potent α-glucosidase inhibitors and excellent free radical scavengers. Hence, they may serve as structural templates in the search for agents to manage Type 2 diabetes mellitus. Finally, in preliminary assays investigating the anti-tubercular potential of these compounds, two pyrazolopyrimidine series compounds and a 7-chloro-N-phenylquinolin-4-amine hybrid showed sub-10 μM whole-cell activities against Mycobacterium tuberculosis.