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The global microbial resistance is a serious threat to human health, and multitargeting compounds are considered to be promising to combat microbial resistance. In this work, a series of new thiazolylquinolones with multitargeting antimicrobial potential were developed through multi-step reactions using triethoxymethane and substituted anilines as start materials. Their structures were confirmed by 1 H NMR, 13 C NMR and HRMS spectra. Antimicrobial evaluation revealed that some of the target compounds could effectively inhibit microbial growth. Especially, carbothioamido hydrazonyl aminothiazolyl quinolone 8a showed strong inhibitory activity toward drug-resistant Staphylococcus aureus with MIC value of 0.0047 mM, which was 5-fold more active than that of norfloxacin. The highly active compound 8a exhibited negligible hemolysis, no significant toxicity in vitro and in vivo, low drug resistance, as well as rapidly bactericidal effects, which suggested its favorable druggability. Furthermore, compound 8a was able to effectively disrupt the integrity of the bacterial membrane, intercalate into DNA and inhibit the activity of topoisomerase IV, suggesting multitargeting mechanism of action. Compound 8a could form hydrogen bonds and hydrophobic interactions with DNA-topoisomerase IV complex, indicating the insertion of aminothiazolyl moiety was beneficial to improve antibacterial efficiency. These findings indicated that the active carbothioamido hydrazonyl aminothiazolyl quinolone 8a as a chemical therapeutic candidate demonstrated immense potential to tackle drug-resistant bacterial infections., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Masson SAS. All rights reserved.)

Cyclopenta[g]quinolones of type 4 were designed with the aim to bioisosterically replace the phenol of potent GluN2B ligands such as ifenprodil and Ro 25-6981 by the quinolone system and to restrict the conformational flexibility of the aminopropanol substructure in a cyclopentane system. The designed ligands were synthesized in an eight-step sequence starting with terephthalaldehyde (5). Key steps pf the synthesis were the intramolecular Friedel-Crafts acylation of propionic acids 10 to yield the cyclopenta[g]quinolinediones 11 and the Mannich reaction of diketone 11a followed by conjugate addition at the α,β-unsaturated ketone 12a. Although the quinolones 13a, 15a, and 16a contain an H-bond donor group (secondary lactam) as ifenprodil and Ro 25-6981, they show only moderate GluN2B affinity (K i  > 410 nM). However, the introduction of lipophilic substituents at the quinolone N-atom resulted in more than 10-fold increased GluN2B affinity of the benzyl and benzyloxymethyl derivatives cis-13c (K o  = 36 nM) and 13e (K o  = 27 nM). All compounds are selective over the phencyclidine (PCP) binding site of the N-methyl-D-aspartate (NMDA) receptor. The benzyl derivative 13c showed six- and threefold selectivity over σ 1 and σ 2 receptors, respectively., (© 2024 The Author(s). Archiv der Pharmazie published by Wiley‐VCH GmbH on behalf of Deutsche Pharmazeutische Gesellschaft.)

Southern root-knot nematodes are among the most pernicious phytoparasites; they are responsible for substantial yield losses in agricultural crops worldwide. The limited availability of nematicides for the prevention and control of plant-parasitic nematodes necessitates the urgent development of novel nematicides. Natural products have always been a key source for the discovery of pesticides. Waltherione A, an alkaloid, exhibits potent nematocidal activity. In this study, we designed and synthesized a series of quinoline and quinolone derivatives from Waltherione A, leveraging a strategy of structural simplification. Bioassays have revealed that the quinoline derivatives exhibit better activity than quinolone derivatives in terms of both nematocidal and fungicidal activities. Notably, compound D1 demonstrated strong nematocidal activity, with a 72 h LC 50 of 23.06 μg/mL, and it effectively controlled the infection of root-knot nematodes on cucumbers. The structure-activity relationship suggests that the quinoline moiety is essential for the nematocidal efficacy of Waltherione A. Additionally, compound D1 exhibited broad-spectrum fungicidal activity, with an EC 50 of 2.98 μg/mL against Botrytis cinerea . At a concentration of 200 μg/mL, it significantly inhibited the occurrence of B. cinerea on tomato fruits, with an inhibitory effect of 96.65%, which is slightly better than the positive control (90.30%).

Asperalins represent a novel class of viridicatin natural products with potent inhibitory activities against fish pathogens. In this study, we elucidated the biosynthesis of asperalins in the Aspergillus oryzae NSAR1 heterologous host and identified the FAD-dependent monooxygenase AplB stereoselectively hydroxylates viridicatin to yield a unique 3 R ,4 S configuration. The monomodular NRPS AplJ catalyzes a rare intramolecular ester bond formation reaction using dihydroquinoline as a nucleophile. Subsequent modifications by cytochrome P450 AplF, chlorinase AplN, and prenyltransferase AplE tailor the anthranilic acid portion, leading to the formation of asperalins. Additionally, we explored the potential of AplB for the hydroxylation of viridicatin analogs, demonstrating its relaxed substrate specificity. This finding suggests that AplB could be developed as a biocatalyst for the synthesis of viridicatin derivatives.

NADPH oxidases (NOXs) are the sole enzyme in the human body that can directly produce reactive oxygen species. Recent studies have shown that NOXs is a very promising target for the treatment of diabetic nephropathy (DN). Here, a series of quinoline(quinolinone) derivatives have been designed based on pharmacophore strategy, synthesized and evaluated. Among them, 19d exhibits potent antiproliferative and NOXs inhibitory activities, and is worthy for further investigation., (© 2024 John Wiley & Sons Ltd.)

A series of N-glycosyl- 6BrCaQ conjugates was synthesized through a Pd-catalyzed cross-coupling reaction between brominated N-glycosyl quinolin-2-one derivatives and various nitrogen nucleophiles. Antiproliferative assays revealed that this new series of analogues represents a promising class of antitumor compounds as illustrated by the high biological activity observed for several derivatives towards different cancer cell lines compared to the non-glycosylated congeners., (© 2024 The Authors. ChemMedChem published by Wiley-VCH GmbH.)

In order to improve the drug-likeness qualities, the antimalarial endochin-like quinolone (ELQ) scaffold has been modified by replacing the 4-(trifluoromethoxy)phenyl portion with an isoidide unit that is further adjustable by varying the distal O-substituents. As expected, the water solubilities of the new analogs are greatly improved, and the melting points are lower. However, the antimalarial potency of the new analogs is reduced to EC 50 > 1 millimolar, a result ascribable to the hydrophilic nature of the new substitution.

GPR41, a G protein-coupled receptor, serves as a sensor for short-chain fatty acids and plays a crucial role in regulating multiple physiological processes such as the maintenance of metabolic and immune homeostasis. Therefore, the modulation of GPR41 has garnered attention as a potential strategy for the treatment of various disorders. We conducted a structure-activity relationship study on a lead tetrahydroquinolone derivative bearing a 2-(trifluoromethoxy)benzene group that displayed antagonistic activity toward GPR41. Modification of the aryl group attached to the furan moiety revealed that derivatives containing di- or trifluorobenzene, instead of 2-(trifluoromethoxy)benzene, exhibited agonistic activity toward GPR41, comparable with the reported agonistic modulator AR420626. These results suggest that the aryl group plays a pivotal role in regulating the activity of compounds toward GPR41, providing valuable insights for the design of GPR41 modulators., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

ELQ-300 is a potent antimalarial drug with activity against blood, liver, and vector stages of the disease. A prodrug, ELQ-331 , exhibits reduced crystallinity and improved in vivo efficacy in preclinical testing, and currently, it is in the developmental pipeline for once-a-week dosing for oral prophylaxis against malaria. Because of the high cost of developing a new drug for human use and the high risk of drug failure, it is prudent to have a back-up plan in place. Here we describe ELQ-596 , a member of a new subseries of 3-biaryl-ELQs, with enhanced potency in vitro against multidrug-resistant Plasmodium falciparum parasites. ELQ-598 , a prodrug of ELQ-596 with diminished crystallinity, is more effective vs murine malaria than its progenitor ELQ-331 by 4- to 10-fold, suggesting that correspondingly lower doses could be used to protect and cure humans of malaria. With a longer bloodstream half-life in mice compared to its progenitor, ELQ-596 highlights a novel series of next-generation ELQs with the potential for once-monthly dosing for protection against malaria infection. Advances in the preparation of 3-biaryl-ELQs are presented along with preliminary results from experiments to explore key structure-activity relationships for drug potency, selectivity, pharmacokinetics, and safety.

The cystic fibrosis transmembrane conductance regulator (CFTR) is a crucial ion channel whose loss of function leads to cystic fibrosis, whereas its hyperactivation leads to secretory diarrhea. Small molecules that improve CFTR folding (correctors) or function (potentiators) are clinically available. However, the only potentiator, ivacaftor, has suboptimal pharmacokinetics and inhibitors have yet to be clinically developed. Here, we combine molecular docking, electrophysiology, cryo-EM, and medicinal chemistry to identify CFTR modulators. We docked ∼155 million molecules into the potentiator site on CFTR, synthesized 53 test ligands, and used structure-based optimization to identify candidate modulators. This approach uncovered mid-nanomolar potentiators, as well as inhibitors, that bind to the same allosteric site. These molecules represent potential leads for the development of more effective drugs for cystic fibrosis and secretory diarrhea, demonstrating the feasibility of large-scale docking for ion channel drug discovery., Competing Interests: Declaration of interests B.K.S. and P.G. are founders of Epiodyne. B.K.S. is a co-founder of BlueDolphin and Deep Apple Therapeutics, as is J.J.I., and serves on the SRB of Genentech and the SABs of Vilya Therapeutics and Umbra Therapeutics and consults for Great Point Ventures and Levator Therapeutics. A patent on the discovery of positive and negative allosteric regulators for CFTR has been filed. The authors declare no other competing interests., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Acute myelogenous leukemia (AML), a heterogeneous disease of the blood and bone marrow, is characterized by the inability of myeloblasts to differentiate into mature cell types. Dihydroorotate dehydrogenase (DHODH) is an enzyme well-known in the pyrimidine biosynthesis pathway and preclinical findings demonstrated that DHODH is a metabolic vulnerability in AML as inhibitors can induce differentiation across multiple AML subtypes. As a result of virtual screening and structure-based drug design approaches, a novel series of isoquinolinone DHODH inhibitors was identified. Further lead optimization afforded JNJ-74856665 as an orally bioavailable, potent, and selective DHODH inhibitor with favorable physicochemical properties selected for clinical development in patients with AML and myelodysplastic syndromes (MDS).

Background: Antibiotics residues can accelerate the growth of drug-resistant bacteria and harm the ecological environment. Under the effect of enrichment and biomagnification, the emergence of drug-resistant pathogenic bacteria may eventually lead to humans being ineffective to drugs in the face of bacterial or fungal disease infections in the future. It is urgent to develop an efficient separation medium and analytical method for simultaneous extraction and determination of antibiotics in the water environment., Results: This work doped 2,6-Di-O-methyl-β-cyclodextrin, randomly methyl-β-cyclodextrin, 2-hydroxypropyl-β-cyclodextrin with thymol:fatty acid respectively to construct non-covalent interaction-dominated pH-responsive ternary supramolecular deep eutectic solvents (SUPRADESs), which can undergo a hydrophilic/hydrophobic transition with aqueous phase to achieve an efficient microextraction. Semi-empirical method illustrated that SUPRADESs have a wide range of hydrogen bond receptor sites. We developed a SUPRADES-based analytical method combined with liquid chromatography-triple quadrupole mass spectrometry for the extraction and determination of trace quinolones and sulfonamides in wastewater. The overall limits of detection of the method were 0.0021-0.0334 ng mL -1 and the limits of quantification were 0.0073-0.1114 ng mL -1 . The linearity maintained good in the spiked level of 0.01-100 ng mL -1  (R 2  > 0.99). The overall enrichment factors of the method were 157-201 with lower standard deviations (≤8.7)., Significance: The method gave an extraction recovery of 70.1-115.3 % for 28 antibiotics in livestock farming wastewater samples from Zhejiang, China, at trace levels (minimum 0.5 ng mL -1 ). The results demonstrated that inducing the phase transition between SUPRADES and aqueous phase by adjusting pH for extraction is a novel and efficient pretreatment strategy. To our knowledge, this is the first application of cyclodextrin-based ternary SUPRADESs with pH-responsive reversible hydrophobicity-hydrophilicity transition behavior in wastewater analysis., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

In this communication, we explored the synthesis of novel alkoxy-functionalised dihydropyrimido[4,5- b ]quinolinones using a microwave-assisted multicomponent reaction. All the synthesized molecules were screened for anti-proliferative and anti-invasive activity against glioblastoma cells. 5c shows the most potent anti-proliferative activity with a half maximal effective concentration of less than 3 μM against primary patient-derived glioblastoma cells. 5c effectively inhibited invasion and tumor growth of 3D primary glioma cultures in a basement membrane matrix. This suggests that the novel compounds could inhibit both the proliferation and invasive spread of glioma and they were selected for further study.

This study aimed to present a selective and effective method for analyzing quinolones (QNs) in food matrix. Herein, a NiFe 2 O 4 -based magnetic sodium disulfonate covalent organic framework (NiFe 2 O 4 /COF) was prepared using a simple solvent-free grinding method, and was adopted as a selective adsorbent for magnetic solid phase extraction of QNs. Coupled with UHPLC-Q-Orbitrap HRMS, an efficient method for simultaneous detection of 18 kinds of QNs was established. The method exhibited good linearity (0.01-100 ng g -1 ), high sensitivity (LODs ranging from 0.0011 to 0.0652 ng g -1 ) and precision (RSDs below 9.5%). Successful extraction of QNs from liver and kidney samples was achieved with satisfactory recoveries ranging from 82.2% to 108.4%. The abundant sulfonate functional groups on NiFe 2 O 4 /COF facilitated strong affinity to QNs through electrostatic and hydrogen bonding interactions. The proposed method provides a new idea for the extraction of contaminants with target selectivity., Competing Interests: Declaration of competing interest The authors declare that none of the work presented in this study may have been impacted by any known competing financial interests or personal ties., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Ketolides (3-keto) such as TE-802 and acylides (3-O-acyl) like TEA0929 are ineffective against constitutively resistant pathogens harboring erythromycin ribosomal methylation (erm) genes. Following our previous work on alkylides (3-O-alkyl), we explored the structure-activity relationships of hybrids combining (R/S) 3-descladinosyl erythromycin with 6/7-quinolone motifs, featuring extended ether-linked spacers, with a focus on their efficacy against pathogens bearing constitutive erm gene resistance. Optimized compounds 17a and 31f not only reinstated efficacy against inducibly resistant pathogens but also demonstrated significantly augmented activities against constitutively resistant strains of Streptococcus pneumoniae and Streptococcus pyogenes, which are typically refractory to existing C-3 modified macrolides. Notably, hybrid 31f (coded ZN-51) represented a pioneering class of agents distinguished by its dual modes of action, with ribosomes as the primary target and topoisomerases as the secondary target. As a novel chemotype of macrolide-quinolone hybrids, alkylide 31f is a valuable addition to our armamentarium against macrolide-resistant bacteria., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: [The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Jian-Hua Liang reports financial support was provided by Sichuan Science and Technology Program. Jian-Hua Liang reports financial support was provided by the National Natural Science Foundation of China. Jian-Hua Liang has patent #CN2024109090844 pending to China national intellectual property Administration. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper]., (Copyright © 2024 Elsevier Inc. All rights reserved.)

This work identified a class of cyanomethylquinolones (CQs) and their carboxyl analogues as potential multitargeting antibacterial candidates. Most of the prepared compounds showed high antibacterial activities against most of the tested bacteria, exhibiting lower MIC values (0.125-2 μg/mL) than those of clinical norfloxacin, ciprofloxacin, and clinafloxacin. The low hemolysis, drug resistance, and cytotoxicity, as well as good predictive pharmacokinetics of active CQs and carboxyl analogues revealed their development potential. Furthermore, they could eradicate the established biofilm, facilitating bacterial exposure to these antibacterial candidates. These active compounds could induce bacterial death through multitargeting effects, including intercalating into DNA, up-regulating reactive oxygen species, damaging membranes directly, and impeding metabolism. Moreover, the highly active cyclopropyl CQ 15 exhibited more effective in vivo anti-MRSA potency than ciprofloxacin. These findings highlight the potential of CQs and their carboxyl analogues as multitargeting broad-spectrum antibacterial candidates for treating intractable bacterial infections.

Breast cancer stands as one of the foremost cause of cancer-related deaths globally, characterized by its varied molecular subtypes. Each subtype requires a distinct therapeutic strategy. Although advancements in treatment have enhanced patient outcomes, significant hurdles remain, including treatment toxicity and restricted effectiveness. Here, we explore the anticancer potential of novel 1,4-naphthoquinone/4-quinolone hybrids on breast cancer cell lines. The synthesized compounds demonstrated selective cytotoxicity against Luminal and triple-negative breast cancer (TNBC) cells, which represent the two main molecular types of breast cancer that depend most on cytotoxic chemotherapy, with potency comparable to doxorubicin, a standard chemotherapeutic widely used in breast cancer treatment. Notably, these derivatives exhibited superior selectivity indices (SI) when compared to doxorubicin, indicating lower toxicity towards non-tumor MCF10A cells. Compounds 11a and 11b displayed an improvement in IC 50 values when compared to their precursor, 1,4-naphthoquinone, for both MCF-7 and MDA-MB-231 and a comparable value to doxorubicin for MCF-7 cells. Also, their SI values were superior to those seen for the two reference compounds for both cell lines tested. Mechanistic studies revealed the ability of the compounds to induce apoptosis and inhibit clonogenic potential. Additionally, the irreversibility of their effects on cell viability underscores their promising therapeutic utility. In 3D-cell culture models, the compounds induced morphological changes indicative of reduced viability, supporting their efficacy in a more physiologically relevant model of study. The pharmacokinetics of the synthesized compounds were predicted using the SwissADME webserver, indicating that these compounds exhibit favorable drug-likeness properties and potential as antitumor agents. Overall, our findings underscore the promise of these hybrid compounds as potential candidates for breast cancer chemotherapy, emphasizing their selectivity and efficacy.

The enhancer of zeste homologue 2 (EZH2) is the core catalytic subunit of polycomb repressive complex 2, which catalyzes lysine 27 methylation of histone H3. Herein, a series of quinolinone derivatives were designed and synthesized based on the structure of Tazemetostat as the lead compound. Compound 9l (EZH2 WT IC 50  = 0.94 nM) showed stronger antiproliferative activity in HeLa cells than the lead compound. Moreover, compound 9e (EZH2 WT IC 50  = 1.01 nM) significantly inhibited the proliferation and induced apoptosis in A549 cells., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier Ltd.)

Twenty N-substituted pyrrolo[3,4-c]quinoline-1,3-diones 3a-t were synthesized by a cyclization reaction of Pfitzinger's quinoline ester precursor with the selected aromatic, heteroaromatic and aliphatic amines. The structures of all derivatives were confirmed by IR, 1 H NMR, 13 C NMR and HRMS spectra, while their purity was determined using HPLC techniques. Almost all compounds were identified as a new class ofpotent inhibitors against hDHODH among which 3a and 3t were the most active ones with the same IC 50 values of 0.11 μM, about seven times better than reference drug leflunomide. These two derivatives also exhibited very low cytotoxic effects toward healthy HaCaT cells and the optimal lipophilic properties with logP value of 1.12 and 2.07 respectively, obtained experimentally at physiological pH. We further evaluated the comparative differences in toxicological impact of the three most active compounds 3a, 3n and 3t and reference drug leflunomide. The rats were divided into five groups and were treated intraperitoneally, control group (group I) with a single dose of leflunomide (20 mg/kg) group II and the other three groups, III, IV and V were treated with 3a, 3n and 3t (20 mg/kg bw) separately. The investigation was performed in liver, kidney and blood by examining serum biochemical parameters and parameters of oxidative stress., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Purpose: Toxoplasmosis is caused by the parasite Toxoplasma gondii (T. gondii). In immunocompetent individuals, the infection is often asymptomatic; however, in expectant mothers and those with immune system deficiencies, complications may arise. Consequently, there is a need for new drugs that cause minimal damage to host cells. The purpose of this study was to investigate the in vitro antiparasitic efficacy of quinolone-coumarin hybrids QC1-QC12, derived from quinolone antibacterials and novobiocin, against T. gondii., Methods: The derivatives were compared with novobiocin and ciprofloxacin during testing, with pyrimethamine used as a positive control. We conducted the MTT assay to examine the anti-toxoplasmic effects of the test compounds and novobiocin. Evaluation included the infection and proliferation indices, as well as the size and number of plaques, based on the viability of both healthy and infected cells., Results: The in vitro assays revealed that QC1, QC3, QC6, and novobiocin, with selectivity indices (SIs) of 7.27, 13.43, and 8.23, respectively, had the least toxic effect on healthy cells and the highest effect on infected cells compared to pyrimethamine (SI = 3.05). Compared to pyrimethamine, QC1, QC3, QC6, and novobiocin Without having a significant effect on cell viability, demonstrated a significant effect on reducing in both infection index and proliferation index, in addition to reducing the quantity and dimensions of plaques ( P < 0.05)., Conclusion: Based on our results, QC1, QC3, QC6, and novobiocin due to their significant therapeutic effects could be considered as potential new leads in the development of novel anti-Toxoplasma agents., (© 2024. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Four erbium(III) complexes with the fluoroquinolones enrofloxacin, levofloxacin, flumequine and sparfloxacin as ligands were synthesized and characterized by a wide range of physicochemical and spectroscopic techniques as well as single-crystal X-ray crystallography. The compounds were evaluated for their activity against the bacterial strains Staphylococcus aureus, Bacillus subtilis, Escherichia coli and Xanthomonas campestris, which was higher than that of the corresponding free quinolones. The interaction mode of the complexes with calf-thymus DNA is via intercalation, as suggested by diverse studies such as UV-vis spectroscopy, DNA-viscosity measurements and competitive studies with ethidium bromide. Fluorescence emission spectroscopy revealed the high affinity of the complexes for bovine and human serum albumin and the determined binding constants suggested a tight and reversible binding of the compounds with both albumins., Competing Interests: Declaration of competing interest There are no conflicts to declare., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Quinolones, a widely used class of antibiotics, present significant environmental and health concerns if they excessively remain in the environment and in food. Aptamers specific to quinolones can be applied as bioreceptors for the detection of quinolone residues in the environment and food. The quinolone family contains dozens of different individuals that share the same core structure coupled with various substituents at six different positions. The diversity and complexity of the substitution sites make it a challenge to choose a set of representative molecules that encompass all the desired sites and preserve the core molecular framework for the screening of quinolone-specific aptamers via systematic evolution of ligands by exponential enrichment (SELEX). To address this challenge, we introduce a novel parallel-series strategy guided by Liebig's law for isolating quinolone-specific cross-reactive aptamers by using the library-immobilized SELEX method. Through this approach, we successfully identified 5 aptamers (Apt.AQ01-Apt.AQ05) with high binding affinity and excellent specificity to 24 different quinolone individuals. Among them, Apt.AQ03 showcased optimal performance with affinities ranging from 0.14 to 1.07 μM across the comprehensive set of 24 quinolones, exhibiting excellent specificity against nontarget interferents. The binding performance of Apt.AQ03 was further characterized with microscale thermophoresis, circular dichroism spectra, and an exonuclease digestion assay. By using Apt.AQ03 as a bioreceptor, a fluorescence resonance energy transfer (FRET) aptasensor was developed for the detection of 24 quinolones in milk, achieving a remarkable detection limit of 14.5-21.8 ng/mL. This work not only establishes a robust and effective strategy for selecting cross-reactive aptamers applicable to other small-molecule families but also provides high-quality aptamers for developing various high-throughput and reliable methods for the detection of multiple quinolone residues in food.

Metallo-β-lactamases (MBL) deactivate β-lactam antibiotics through a catalytic reaction caused by two zinc ions at the active center. Since MBLs deteriorate a wide range of antibiotics, they are dangerous factors for bacterial multidrug resistance. In this work, organic synthesis, computational design, and crystal structure analysis were performed to obtain potent MBL inhibitors based on a previously identified hit compound. The hit compound comprised 3,4-dihydro-2(1H)-quinolinone linked with a phenyl-ether-methyl group via a thiazole ring. In the first step, the thiazole ring was replaced with a tertiary amine to avoid the planar structure. In the second step, we virtually modified the compound by keeping the quinolinone backbone. Every modified compound was bound to a kind of MBL, imipenemase-1 (IMP-1), and the binding pose was optimized by a molecular mechanics calculation. The binding scores were evaluated for the respective optimized binding poses. Given the predicted binding poses and calculated binding scores, candidate compounds were determined for organic syntheses. The inhibitory activities of the synthesized compounds were measured by an in vitro assay for two kinds of MBLs, IMP-1 and New Delhi metallo-β-lactamase (NDM-1). A quinolinone connected with an amine bound with methyl-phenyl-ether-propyl and cyclohexyl-ethyl showed a 50% inhibitory concentration of 4.8 μM. An X-ray crystal analysis clarified the binding structure of a synthesized compound to IMP-1. The δ-lactam ring of quinolinone was hydrolyzed, and the generated carboxyl group was coordinated with zinc ions. The findings on the chemical structure and binding pose are expected to be a base for developing MBL inhibitors.

Malaria continues to be a serious and debilitating disease. The emergence and spread of high-level resistance to multiple antimalarial drugs by Plasmodium falciparum has brought about an urgent need for new treatments that will be active against multidrug resistant malaria infections. One such treatment, ELQ-331 (MMV-167), an alkoxy carbonate prodrug of 4(1H)-quinolone ELQ-300, is currently in preclinical development with the Medicines for Malaria Venture. Clinical development of ELQ-331 or similar compounds will require the availability of isotopically labeled analogs. Unfortunately, a suitable method for the deuteration of these important compounds was not found in the literature. Here, we describe a facile and scalable method for the deuteration of 4(1H)-quinolone ELQ-300, its alkoxycarbonate prodrug ELQ-331, and their respective N-oxides using deuterated acetic acid., (© 2024 John Wiley & Sons Ltd. This article has been contributed to by U.S. Government employees and their work is in the public domain in the USA.)

Three newly synthesized triphenyltin(IV) compounds, Ph3SnL1 (L1- = 3-(4-methyl-2-oxoquinolin-1(2 H )-yl)propanoato), Ph3SnL2 (L2- = 2-(4-methyl-2-oxoquinolin-1(2 H )-yl)ethanoato), and Ph3SnL3 (L3- = 2-(4-hydroxy-2-oxoquinolin-1(2 H )-yl)ethanoato), were characterized by elemental microanalysis, FT-IR spectroscopy and multinuclear ( 1 H, 13 C and 119 Sn) NMR spectroscopy. A single X-ray diffraction study indicates that compounds Ph3SnL1 and Ph3SnL2 exhibit a 1D zig-zag chain polymeric structure, which in the case of Ph3SnL2 is additionally stabilized by π-interactions. In addition, the synthesized compounds were further examined using density functional theory and natural bond orbital analysis. The compounds have been evaluated for their in vitro anticancer activity against three human cell lines: MCF-7 (breast adenocarcinoma), A375 (melanoma), HCT116 (colorectal carcinoma), and three murine cell lines: 4T1 (breast carcinoma), B16 (melanoma), CT26 (colon carcinoma) using MTT and CV assays. The IC 50 values fall in the nanomolar range, indicating that these compounds possess better anticancer activity than cisplatin. The study of the effect of the newly developed drug Ph 3 SnL1 showed its plasticity in achieving an antitumor effect in vitro , which depends on the specificity of the phenotype and the redox status of the malignant cell line and ranges from the initiation of apoptotic cell death to the induction of differentiation to a more mature cell form. In the syngeneic model of murine melanoma, Ph3SnL1 showed the potential to reduce the tumor volume similar to cisplatin, but in a well-tolerated form and with low systemic toxicity, representing a significant advantage over the conventional drug.

Quinolone synthase from Aegle marmelos (AmQNS) is a type III polyketide synthase that yields therapeutically effective quinolone and acridone compounds. Addressing the structural and molecular underpinnings of AmQNS and its substrate interaction in terms of its high selectivity and specificity can aid in the development of numerous novel compounds. This paper presents a high-resolution AmQNS crystal structure and explains its mechanistic role in synthetic selectivity. Additionally, we provide a model framework to comprehend structural constraints on ketide insertion and postulate that AmQNS's steric and electrostatic selectivity plays a role in its ability to bind to various core substrates, resulting in its synthetic diversity. AmQNS prefers quinolone synthesis and can accommodate large substrates because of its wide active site entrance. However, our research suggests that acridone is exclusively synthesized in the presence of high malonyl-CoA concentrations. Potential implications of functionally relevant residue mutations were also investigated, which will assist in harnessing the benefits of mutations for targeted polyketide production. The pharmaceutical industry stands to gain from these findings as they expand the pool of potential drug candidates, and these methodologies can also be applied to additional promising enzymes., (© 2024. The Author(s).)

With the rising incidence of various diseases in China and the constant development of the pharmaceutical industry, there is a growing demand for floxacin-type antibiotics. Due to the large-scale production and high cost of waste treatment, the parent drug and its metabolites constantly enter the water environment through domestic sewage, production wastewater, and other pathways. In recent years, the pollution of the aquatic environment by floxacin has become increasingly serious, making the technology to degrade floxacin in the aquatic environment a research hotspot in the field of environmental science. Metal-organic frameworks (MOFs), as a new type of porous material, have attracted much attention in recent years. In this paper, four photocatalytic materials, MIL-53(Fe), NH 2 -MIL-53(Fe), MIL-100(Fe), and g-C 3 N 4 , were synthesised and applied to the study of the removal of ofloxacin and enrofloxacin. Among them, the MIL-100(Fe) material exhibited the best photocatalytic effect. The degradation efficiency of ofloxacin reached 95.1% after 3 h under visible light, while enrofloxacin was basically completely degraded. The effects of different materials on the visible photocatalytic degradation of the floxacin were investigated. Furthermore, the photocatalytic mechanism of enrofloxacin and ofloxacin was revealed by the use of three trappers (▪O 2 - , h + , and ▪OH), demonstrating that the role of ▪O 2 - promoted the degradation effect of the materials under photocatalysis.

Since synovial hypoxic microenvironment significantly promotes the pathological progress of rheumatoid arthritis (RA), hypoxia-inducible factor 1 (HIF-1) has been emerged as a promising target for the development of novel therapeutic agents for RA treatment. In this study, we designed and synthesized a series of diaryl substituted isoquinolin-1(2H)-one derivatives as HIF-1 signaling inhibitors using scaffold-hopping strategy. By modifying the substituents on N-atom and 6-position of isoquinolin-1-one, we discovered compound 17q with the most potent activities against HIF-1 (IC 50  = 0.55 μM) in a hypoxia-reactive element (HRE) luciferase reporter assay. Further pharmacological studies revealed that 17q concentration-dependently blocked hypoxia-induced HIF-1α protein accumulation, reduced inflammation response, inhibited cellular invasiveness and promoted VHL-dependent HIF-1α degradation in human RA synovial cell line. Moreover, 17q improved the pathological injury of ankle joints, decreased angiogenesis and attenuated inflammation response in the adjuvant-induced arthritis (AIA) rat model, indicating the promising therapeutic potential of compound 17q as an effective HIF-1 inhibitor for RA therapy., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Masson SAS. All rights reserved.)

The structural optimization of B14, an antibacterial agent we previously obtained, has led to the discovery of a new class of CH 2 -linked quinolone-aminopyrimidine hybrids with potent anti-MRSA activities. Surprisingly, the hybrids lacking a C-6 fluoro atom at the quinolone nucleus showed equal or even stronger anti-MRSA activities than their corresponding 6-fluoro counterparts, despite the well-established structure-activity relationships (SARs) indicating that the 6-fluoro substituent enhances the antibacterial activity in conventional fluoroquinolone antibiotics. Moreover, these new hybrids, albeit structurally related to conventional fluoroquinolones, showed no cross-resistance with fluoroquinolone drugs. The most active compound, 15m, exhibited excellent activities with a MIC value of 0.39 μg/mL against both fluoroquinolone-sensitive strain USA500 and -resistant MRSA isolate Mu50. Further resistance development studies indicated MRSA is unlikely to acquire resistance against 15m. Moreover, 15m displayed favorable in vivo half-life and safety profiles. These findings suggest a rationale for further evolution of quinolone antibiotics with a high barrier to resistance., Competing Interests: Declaration of competing interest The authors declare no competing financial interest., (Copyright © 2024 Elsevier Masson SAS. All rights reserved.)

Nagana and Human African Trypanosomiasis (HAT), caused by (sub)species of Trypanosoma, are diseases that impede human and animal health, and economic growth in Africa. The few drugs available have drawbacks including suboptimal efficacy, adverse effects, drug resistance, and difficult routes of administration. New drugs are needed. A series of 20 novel quinolone compounds with affordable synthetic routes was made and evaluated in vitro against Trypanosoma brucei and HEK293 cells. Of the 20 compounds, 12 had sub-micromolar potencies against the parasite (EC 50 values=0.051-0.57 μM), and most were non-toxic to HEK293 cells (CC 50 values>5 μM). Two of the most potent compounds presented sub-micromolar activities against other trypanosome (sub)species (T. cruzi and T. b. rhodesiense). Although aqueous solubility is poor, both compounds possess good logD values (2-3), and either robust or poor microsomal stability profiles. These varying attributes will be addressed in future reports., (© 2024 The Authors. ChemMedChem published by Wiley-VCH GmbH.)

Traditional spiking methods for preparing matrix reference material of aquatic products is difficult to control the drug content in the matrix, especially one matrix containing multiple drugs. Minced fish is commonly used for the preparation of matrix reference materials in aquatic products, which is a relatively complex matrix with stickiness and difficult handling. Drug loading capacity is a key factor affecting the effectiveness of matrix reference materials. Here, we proposed a new spiking approach to improve the drug loading capacity of seven quinolones based on microfluidics, simultaneously. Fresh grass carp tissue underwent grinding, fine filtration, centrifugation and reconstituted in distilled water to form a liquid sample, which was subsequently mixed with a sodium alginate solution (1 %) at a ratio of 1:1.2. The mixed solution was supplemented with seven quinolones of equal concentration, followed by the preparation of uniform fish gel microspheres using microfluidic technology. The results indicated that the recoveries of seven quinolones ranged from 82.54 % to 114.17 %, demonstrating a significant improvement in the drug loading capacity of these quinolones compared to traditional methods. Moreover, the drug concentration in the matrix can be precisely controlled. A strong linear relationship was observed between the concentration of seven quinolones in the matrix and its initial concentration, which could serve as a reference for the development of other matrix reference materials., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Herein, we report the development of a diastereoselective and efficient route to construct sugar-derived pyrano[3,2-c]quinolones utilizing 1-C-formyl glycal and 4-hydroxy quinolone annulation. This methodology will open a route to synthesize nature inspired pyrano[3,2-c]quinolones. This is the first report for the stereoselective synthesis of sugar-derived pyrano[3,2-c]quinolones, where 100% stereoselectivity was observed. A total of sixteen compounds have been synthesized in excellent yields with 100% stereoselectivity. The molecular docking of the synthesized novel natural product analogues demonstrated their binding modes within the active site of type II topoisomerase. The results of the in-silico studies displayed more negative binding energies for the all the synthesized compounds in comparison to the natural product huajiosimuline A, indicating their affinity for the active pocket. Ten out of the sixteen novel synthesized compounds were found to have comparative or relatively more negative binding energy in comparison to the standard anti-cancer drug, doxorubicin. Additionally, the scalability and viability of this protocol was illustrated by the gram scale synthesis., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Streptomide (1), a new amide analogue, streptomynone (2), a new quinolinone, and ten known compounds including three aliphatic acids (3-5), two amides (6-7), four cyclic dipeptides (8-11), and an adenosine (12) were isolated from the fermentation broth of Streptomyces sp. YIM S01983 isolated from a sediment sample collected in Bendong Village, Huadong Town, Chuxiong, China. Their structures were determined by analysis of the 1D/2D-NMR and HR-ESI-MS spectra. Compound 12 presented weak antimicrobial activities against Candida albicans and Aligenes faecalis (MIC=64 μg/mL). Compounds 7 and 12 showed weak cytotoxic activity against MHCC97H., (© 2024 Wiley-VHCA AG, Zurich, Switzerland.)

Penicilloneines A ( 1 ) and B ( 2 ) are the first reported quinolone-citrinin hybrids. They were isolated from the starfish-derived fungus Penicillium sp. GGF16-1-2, and their structures were elucidated using spectroscopic, chemical, computational, and single-crystal X-ray diffraction methods. Penicilloneines A ( 1 ) and B ( 2 ) share a common 4-hydroxy-1-methyl-2(1 H )-quinolone unit; however, they differ in terms of citrinin moieties, and these two units are linked via a methylene bridge. Penicilloneines A ( 1 ) and B ( 2 ) exhibited antifungal activities against Colletotrichum gloeosporioides , with lethal concentration 50 values of 0.02 and 1.51 μg/mL, respectively. A mechanistic study revealed that 1 could inhibit cell growth and promote cell vacuolization and consequent disruption of the fungal cell walls via upregulating nutrient-related hydrolase genes, including putative hydrolase, acetylcholinesterase, glycosyl hydrolase, leucine aminopeptidase, lipase, and beta-galactosidase, and downregulating their synthase genes 3-carboxymuconate cyclase, pyruvate decarboxylase, phosphoketolase, and oxalate decarboxylase.

To formulate and optimize Ozenoxacin nano-emulsion using Quality by Design (QbD) concept by means of Box-Behnken Design (BBD) and converting it to a gel to form Ozenoxacin nano-emulgel followed by physico-chemical, in-vitro, ex-vivo and in-vivo evaluation. This study demonstrates the application of QbD methodology for the development and optimization of an effective topical nanoemulgel formulation for the treatment of Impetigo focusing on the selection of appropriate excipients, optimization of formulation and process variables, and characterization of critical quality attributes. BBD was used to study the effect of "% of oil, % of S mix and homogenization speed" on critical quality attributes "globule size and % entrapment efficiency" for the optimisation of Ozenoxacin Nano-emulsion. Ozenoxacin loaded nano-emulgel was characterized for "description, identification, pH, specific gravity, amplitude sweep, viscosity, assay, organic impurities, antimicrobial effectiveness testing, in-vitro release testing, ex-vivo permeation testing, skin retention and in-vivo anti-bacterial activity". In-vitro release and ex-vivo permeation, skin retention and in-vivo anti-bacterial activity were found to be significantly (p < 0.01) higher for the nano-emulgel formulation compared to the innovator formulation (OZANEX™). Antimicrobial effectiveness testing was performed and found that even at 70% label claim of benzoic acid is effective to inhibit microbial growth in the drug product. The systematic application of QbD principles facilitated the successful development and optimization of a Ozenoxacin Nano-Emulsion. Optimised Ozenoxacin Nano-Emulgel can be considered as an effective alternative and found to be stable at least for 6 months at 40 °C / 75% RH and 30 °C / 75% RH., (© 2024. The Author(s), under exclusive licence to American Association of Pharmaceutical Scientists.)

Quinolone is a heterocyclic compound containing carbonyl at the C-2 or C-4 positions with nitrogen at the C-1 position. The scaffold was first identified for its antibacterial properties, and the derivatives were known to possess many pharmacological activities, including anticancer. In this review, the quinolin-2(H)-one and quinolin-4(H)-one derivatives were identified to inhibit several various proteins and enzymes involved in cancer cell growth, such as topoisomerase, microtubules, protein kinases, phosphoinositide 3-kinases (PI3K) and histone deacetylase (HDAC). Hybrids of quinolone with curcumin or chalcone, 2-phenylpyrroloquinolin-4-one and 4-quinolone derivatives have demonstrated strong potency against cancer cell lines. Additionally, quinolones have been explored as inhibitors of protein kinases, including EGFR and VEGFR. Therefore, this review aims to consolidate the medicinal chemistry of quinolone derivatives in the pipeline and discuss their similarities in terms of their pharmacokinetic profiles and potential target sites to provide an understanding of the structural requirements of anticancer quinolones., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Eye drops, including solutions and suspensions, are essential dosage forms to treat ophthalmic diseases, with poorly water-soluble drugs typically formulated as ophthalmic suspensions. In addition to low bioavailability, suspensions exhibit limited efficacy, safety, and usability due to the presence of drug particles. Improving bioavailability can reduce the drug concentrations and the risk of problems associated with suspended drug particles. However, practical penetration enhancers capable of improving bioavailability remain elusive. Herein, we focused on penetratin (PNT), a cell-penetrating peptide (CPP) that promotes active cellular transport related to macromolecule uptake, such as micropinocytosis. According to the in vitro corneal uptake study using a reconstructed human corneal epithelial tissue model, LabCyte CORNEA-MODEL24, PNT enhanced the uptake of Fluoresbrite ® YG carboxylate polystyrene microspheres without covalent binding. In an ex vivo porcine eye model, the addition of 10 µM PNT to rebamipide ophthalmic suspension markedly improved the corneal uptake of rebamipide; however, the addition of 100 µM PNT was ineffective due to potentially increased particle size by aggregation. This article provides basic information on the application of PNT as a penetration enhancer in ophthalmic suspensions, including the in vitro and ex vivo studies mentioned above, as well as the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) cytotoxicity assay and storage stability at different pH values.

Background: The estimated number of cancer cases in India for the year 2022 was found to be 14,61,427. The development of chemotherapeutic agents has reduced the mortality rate, however, they have high toxicity which is a disadvantage. Many researchers have found out that quinolin-2- one possesses anticancer activity, with this background we thought of synthesizing the quinolin-2-one derivatives., Objective: This study aimed to carry out docking, synthesis, characterization, and evaluation of 2-(2- (4-Hydroxy-2-oxoquinolin-1(2H)-yl)phenyl/ substituted phenyl)-3-(phenylamino) thiazolidon-4-one derivatives (IVa-g) as an anticancer agent., Method: Diphenylamine and malonic acid treated with phosphoryl chloride gave compound I, which on formylation afforded compound II, which on reaction with various substituted aromatic phenylhydrazine derivatives gave compounds IIIa-g, which on further reaction with thioglycolic acid and anhydrous zinc chloride yielded the compounds IVa-g., Result: Among all the synthesized novel derivatives, compounds IV a-d showed 50% lysis in the IC 50 range of 25-50μg for the A549 cell line, and compounds IVa, and IVb showed 50% lysis in the IC 50 range of 25-50μg for the MDA-MB cell line. The compound, 3-((4-fluorophenyl)amino)-2-(2-(4- hydroxy-2-oxoquinolin-1(2H)-yl)phenyl)thiazolidin-4-one (IVg) was found to be the most active against both the cell line, A549 and MDA-MB with IC 50 value of 0.0298μmol and 0.0338μmol respectively. The docking results revealed that the synthesized compounds exhibited well-conserved hydrogen bonding with one or more amino acid residues in the active pocket of EGFR tyrosine kinase domain with 4-anilinoquinazoline inhibitor erlotinib (PDB ID:1M17). Compound IVg showed the highest MolDock score of -137.813 compared to the standard drug Imatinib having a MolDock score of -119.354., Conclusion: Compound IVg showed the highest MolDock score and was also found to be most potent against both the cell line, A549, and MDA-MB., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Lead molecules containing 1,4-quinone moiety are intriguing novel compounds that can be utilized to treat cancer owing to their antiproliferative activities. Nine previously reported quinolinequinones (AQQ1-9) were studied to better understand their inhibitory profile to produce potent and possibly safe lead molecules. The National Cancer Institute (NCI) of Bethesda chose all quinolinequinones (AQQ1-9) based on the NCI Developmental Therapeutics Program and tested them against a panel of 60 cancer cell lines. At a single dose and five further doses, AQQ7 significantly inhibited the proliferation of all leukemia cell lines and some breast cancer cell lines. We investigated the in vitro cytotoxic activities of the most promising compounds, AQQ2 and AQQ7, in MCF7 and T-47D breast cancer cells, DU-145 prostate cancer cells, HCT-116 and COLO 205 colon cancer cell lines, and HaCaT human keratinocytes using the MTT assay. AQQ7 showed particularly high cytotoxicity against MCF7 cells. Further analysis showed that AQQ7 exhibits anticancer activity through the induction of apoptosis without causing cell cycle arrest or oxidative stress. Molecular docking simulations for AQQ2 and AQQ7 were conducted against the COX, PTEN, and EGFR proteins, which are commonly overexpressed in breast, cervical, and prostate cancers. The in vitro ADME and in vivo PK profiling of these compounds have also been reported., (© 2023 John Wiley & Sons Ltd.)

Antibiotic resistance is a global threat to public health, and the search for new antibacterial therapies is a current research priority. The aim of this in silico study was to test nine new fluoroquinolones previously designed with potential leishmanicidal activity against Campylobacter jejuni , Escherichia coli , Neisseria gonorrhoeae , Pseudomonas aeruginosa , and Salmonella typhi , all of which are considered by the World Health Organization to resistant pathogens of global concern, through molecular docking and molecular dynamics (MD) simulations using wild-type (WT) and mutant-type (MT) DNA gyrases as biological targets. Our results showed that compound 9FQ had the best binding energy with the active site of E. coli in both molecular docking and molecular dynamics simulations. Compound 9FQ interacted with residues of quinolone resistance-determining region (QRDR) in GyrA and GyrB chains, which are important to enzyme activity and through which it could block DNA replication. In addition to compound 9FQ , compound 1FQ also showed a good affinity for DNA gyrase. Thus, these newly designed molecules could have antibacterial activity against Gram-negative microorganisms. These findings represent a promising starting point for further investigation through in vitro assays, which can validate the hypothesis and potentially facilitate the development of novel antibiotic drugs.

Bioorganometallic complexes have attracted considerable interest and have shown promise for potential application in the treatment and diagnosis of cancer, as well as bioimaging agents, some acting as theranostic agents. The series of novel ferrocene, benzimidazo[1,2- a ]quinoline and fluorescein derivatives with bidentate pyridyl-1,2,3-triazole and 2,2'-dipyridylamine and their tricarbonylrhenium(I) complexes was prepared and fully characterised by NMR, single-crystal X-ray diffraction, UV-Vis and fluorescence spectroscopy in biorelevant conditions. The fluorescein and benzimidazo[1,2- a ]quinoline ligands and their complexes with Re(I) showed interactions with ds-DNA/RNA and HSA, characterised by thermal denaturation measurements, fluorimetric and circular dichroism titrations. The binding constants revealed that addition of Re(I) increases the affinity of fluorescein but decreases the affinity of benzimidazo[1,2- a ]quinoline. The complexation of Re(I) had the opposite effect on fluorescein and benzimidazo[1,2- a ]quinoline ligands' fluorimetric sensitivity upon biomacromolecule binding, Re(I) fluorescein complex emission being strongly quenched by DNA/RNA or HSA, while emission of Re(I) benzimidazo[1,2- a ]quinolone complex was enhanced, particularly for HSA, making it a promising fluorescent probe. Some mono- and heterobimetallic complexes showed considerable antiproliferative activity on colon cancer cells (CT26 and HT29), with ferrocene dipyridylamine complexes exhibiting the best inhibitory activity, comparable to cisplatin. The correlation of the cytotoxicity data with the linker type between the ferrocene and the 1,2,3-triazole ring suggests that direct binding of the metallocene to the 1,2,3-triazole is favourable for antitumor activity. The Re(I) benzimidazo[1,2- a ]quinolone complex showed moderate antiproliferative activity, in contrast to the Re(I) fluorescein complex, which exhibited weak activity on CT26 cells and no activity on HT29 cells. The accumulation of the Re(I) benzimidazo[1,2- a ]quinolone complex in the lysosomes of CT26 cells indicates the site of its bioactivity, thus making this complex a potential theranostic agent.

Organic dyes have been actively studied as useful photocatalysts because they allow access to versatile structural flexibility and green synthetic applications. The identification of a new class of robust organic chromophores is, therefore, in high demand to increase structural diversity and variability. Although coumarins and quinolinones have long been acknowledged as organic chromophores, their ability to participate in photoinduced transformations is somewhat less familiar. Fascinated by their chromophoric features and adaptable platform, our group is interested in the identification of fluorescent bioactive molecules and in the development of new photoinduced synthetic methods using coumarins and quinolinones as photocatalysts. This account provides an overview of our recent progress in the discovery and application of light-absorbing coumarin and quinolinone derivatives in photochemistry and medicinal chemistry., (© 2023 The Chemical Society of Japan & Wiley-VCH GmbH.)

Four new oxepine-containing pyrazinopyrimidine alkaloids, versicoxepines A - D (1-4), two quinolinone alkaloid analogs including 3-hydroxy-6-methoxy-4-phenylquinolin-2(1H)-one (5) and 3-methoxy-6-hydroxy-4-phenylquinolin-2(1H)-one (6) which were new naturally occurring compounds, together with two known compounds (7 and 8) were isolated from Aspergillus versicolor AS-212, an endozoic fungus isolated from the deep-sea coral Hemicorallium cf. imperiale, which was collected from the Magellan Seamounts in the Western Pacific Ocean. Their structures were determined by extensive analysis of the spectroscopic and X-ray crystallographic data as well as by chiral HPLC analysis, ECD calculation, and DP4+ probability prediction. Structurally, versicoxepines B and C (2 and 3) represent the first example of a new oxepine-containing pyrazinopyrimidine alkaloid whose cyclic dipeptide moiety is composed of the same type of amino acid (Val or Ile). Compound 5 displayed antibacterial activity against aquatic pathogens, Vibrio harveyi and V. alginolyticus, with MICs of 8 μg/mL., Competing Interests: Declaration of Competing Interest The authors declare no competing financial interest., (Copyright © 2023 Elsevier B.V. All rights reserved.)

The discovery of nalidixic acid is one pinnacle in medicinal chemistry, which opened a new area of research that has led to the discovery of several life-saving antimicrobial agents (generally referred to as fluoroquinolones) for over decades. Although fluoroquinolones are frequently encountered in the literature, the utility of quinolone compounds extends far beyond the applications of fluoroquinolones. Quinolone-based compounds have been reported for activity against malaria, tuberculosis, fungal and helminth infections, etc. Hence, the quinolone scaffold is of great interest to several researchers in diverse disciplines. This article highlights the versatility of the quinolone pharmacophore as a therapeutic agent beyond the fluoroquinolone profile., (© 2022. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

An improved method for the synthesis of a new quinolone class of antibiotics, which are exceptionally potent against gram-positive bacteria, has been developed and the structure confirmed by single-crystal X-ray analysis. In the course of synthesis, using either Chan-Lam coupling or Buchwald-Hartwig amination, we have shown that the careful choice of protecting group at the C4 position of the quinoline is required for selective amination at the C5 position and subsequent deprotection to avoid the formation of a novel pyrido[4,3,2- de ]quinazoline tetracycle.

The human African trypanosomiasis is a devastating parasitic infection, which is caused by the protozoan Trypanosoma brucei and transmitted by the bite of the tsetse fly. An untreated infection usually results in death and only few drugs with significant drawbacks are currently available for treatment. Previous investigations revealed the quinolone amide MB007 as a lead compound with an excellent selectivity for T. b. brucei. Here, new quinolone amides were synthesized for deeper insights into the structure-activity relationship. Furthermore, the aqueous solubility of the compounds was analyzed, as the poor solubility of previous quinolone amides impeded in vivo studies for target identification. The biological evaluation led to the new lead structure 9f, which exhibits a promising in vitro activity against T. b. brucei (IC 50  = 22 nM) and showed no cytotoxicity against macrophages. Moreover, compounds 10b and 10c were discovered, which possessed an improved solubility combined with a decent selectivity., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Masson SAS. All rights reserved.)

Hydrogen-bonding catalytic reactions have gained great interest. Herein, a hydrogen-bond-assisted three-component tandem reaction for the efficient synthesis of N -alkyl-4-quinolones is described. This novel strategy features the first proof of polyphosphate ester (PPE) as a dual hydrogen-bonding catalyst and the use of readily available starting materials for the preparation of N -alkyl-4-quinolones. The method provides a diversity of N -alkyl-4-quinolones in moderate to good yields. The compound 4h demonstrated good neuroprotective activity against N -methyl-ᴅ-aspartate (NMDA)-induced excitotoxicity in PC12 cells.

New antibacterial 3-(aminothiazolyl)quinolones (ATQs) were designed and efficiently synthesized to counteract the growing multidrug resistance in animal husbandry. Bioactive assays manifested that N , N -dicyclohexylaminocarbonyl ATQ 10e and methyl ATQ 17a , respectively, showed better antibacterial behavior against Staphylococcus aureus ATCC 29213 and Pseudomonas aeruginosa than reference drug norfloxacin. Notably, highly active ATQ 17a with low hemolysis, negligible mammalian cytotoxicity, and good pharmacokinetic properties displayed low trends to induce resistance and synergistic combinations with norfloxacin. Preliminary mechanism exploration implied that representative ATQ 17a could inhibit the formation of biofilms and destroy bacterial membrane integrity, further binding to intracellular DNA and DNA gyrase to hinder bacterial DNA replication. ATQ 17a could also induce the production of excess reactive oxygen species and reduce bacterial metabolism to accelerate bacterial death. These results provided a promise for 3-(aminothiazolyl)quinolones as new potential multitargeting antibacterial agents to treat bacterial infection of animals.

Fluoroquinolones are an important class of antibacterials, and rising levels of resistance threaten their clinical efficacy. Gaining a more full understanding of their mechanism of action against their target enzymes-the bacterial type II topoisomerases gyrase and topoisomerase IV-may allow us to rationally design quinolone-based drugs that overcome resistance. As a step toward this goal, we investigated whether the water-metal ion bridge that has been found to mediate the major point of interaction between Escherichia coli topoisomerase IV and Bacillus anthracis topoisomerase IV and gyrase, as well as Mycobacterium tuberculosis gyrase, exists in E. coli gyrase. This is the first investigation of the water-metal ion bridge and its function in a Gram-negative gyrase. Evidence suggests that the water-metal ion bridge does exist in quinolone interactions with this enzyme and, unlike the Gram-positive B. anthracis gyrase, does use both conserved residues (serine and acidic) as bridge anchors. Furthermore, this interaction appears to play a positioning role. These findings raise the possibility that the water-metal ion bridge is a universal point of interaction between quinolones and type II topoisomerases and that it functions primarily as a binding contact in Gram-positive species and primarily as a positioning interaction in Gram-negative species. Future studies will explore this possibility.

Three previously unreported quinolinone alkaloids: melicodenines J-L ( 1 - 3 ) and six known compounds ( 4 - 9 ), were isolated from the leaves of Melicope denhamii (Seem) T.G. Hartley. The structures of three quinolinone alkaloids were identified based on HRESIMS and NMR spectra. Compounds 1-9 were assayed in three cancer cells (MCF-7, HeLa, and P-388). Compounds 1 and 5 showed high cytotoxic activity against HeLa cells with IC 50 values of 1.8 and 0.8 µM, respectively.