Synthesis and antibacterial medicinal evaluation of carbothioamido hydrazonyl thiazolylquinolone with multitargeting antimicrobial potential to combat increasingly global resistance.

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 1H NMR, 13C 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.

A Unique Hybridization Route to Access Hydrazylnaphthalimidols as Novel Structural Scaffolds of Multitargeting Broad-Spectrum Antifungal Candidates.

This study developed a class of novel structural antifungal hydrazylnaphthalimidols (HNs) with multitargeting broad-spectrum potential via multicomponent hybridization to confront increasingly severe fungal invasion. Some prepared HNs exhibited considerable antifungal potency; especially nitrofuryl HN 4a (MIC = 0.001 mM) exhibited a potent antifungal activity against Candida albicans, which is 13-fold higher than that of fluconazole. Furthermore, nitrofuryl HN 4a displayed low cytotoxicity, hemolysis and resistance, as well as a rapid fungicidal efficacy. Preliminary mechanistic investigations revealed that nitrofuryl HN 4a could inhibit lactate dehydrogenase to decrease metabolic activity and promote the accumulation of reactive oxygen species, leading to oxidative stress. Moreover, nitrofuryl HN 4a did not exhibit membrane-targeting ability; it could embed into DNA to block DNA replication but could not cleave DNA. These findings implied that HNs are promising as novel structural scaffolds of potential multitargeting broad-spectrum antifungal candidates for treating fungal infection.

Unique aminothiazolyl coumarins as potential DNA and membrane disruptors towards Enterococcus faecalis.

Aminothiazolyl coumarins as potentially new antimicrobial agents were designed and synthesized in an effort to overcome drug resistance. Biological activity assay revealed that some target compounds exhibited significantly inhibitory efficiencies toward bacteria and fungi including drug-resistant pathogens. Especially, aminothiazolyl 7-propyl coumarin 8b and 4-dichlorobenzyl derivative 11b exhibited bactericidal potential (MBC/MIC = 2) toward clinically drug-resistant Enterococcus faecalis with low cytotoxicity to human lung adenocarcinoma A549 cells, rapidly bactericidal effects and no obvious bacterial resistance development against E. faecalis. The preliminary antibacterial action mechanism studies suggested that compound 11b was able to disturb E. faecalis membrane effectively, and interact with bacterial DNA isolated from resistant E. faecalis through noncovalent bonds to cleave DNA, thus inhibiting the growth of E. faecalis strain. Further molecular modeling indicated that compounds 8b and 11b could bind with SER-1084 and ASP-1083 residues of gyrase-DNA complex through hydrogen bonds and hydrophobic interactions. Moreover, compound 11b showed low hemolysis and in vivo toxicity. These findings of aminothiazolyl coumarins as unique structural scaffolds might hold a large promise for the treatments of drug-resistant bacterial infection.

Cyanomethylquinolones as a New Class of Potential Multitargeting Broad-Spectrum Antibacterial Agents.

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.

Discovery of indolylacryloyl-derived oxacins as novel potential broad-spectrum antibacterial candidates.

The emergence of serious bacterial resistance towards clinical oxacins poses a considerable threat to global public health, necessitating the development of novel structural antibacterial agents. Seven types of novel indolylacryloyl-derived oxacins (IDOs) were designed and synthesized for the first time from commercial 3,4-difluoroaniline via an eight-step procedure. The synthesized compounds were characterized by modern spectroscopic techniques. All target molecules were evaluated for antimicrobial activities. Most of the prepared IDOs showed a broad antibacterial spectrum and strong activities against the tested strains, especially ethoxycarbonyl IDO 10d (0.25-0.5 µg/mL) and hydroxyethyl IDO 10e (0.25-1 µg/mL) exhibited much superior antibacterial efficacies to reference drug norfloxacin. These highly active IDOs also displayed low hemolysis, cytotoxicity and resistance, as well as rapid bactericidal capacity. Further investigations indicated that ethoxycarbonyl IDO 10d and hydroxyethyl IDO 10e could effectively reduce the exopolysaccharide content and eradicate the formed biofilm, which might delay the development of drug resistance. Preliminary exploration of the antibacterial mechanism revealed that active IDOs could not only destroy membrane integrity, resulting in changes in membrane permeability, but also promote the accumulation of reactive oxygen species, leading to the production of malondialdehyde and decreased bacterial metabolism. Moreover, they exhibited the capability to bind with DNA and DNA gyrase, forming supramolecular complexes through various noncovalent interactions, thereby inhibiting DNA replication and causing bacterial death. All the above results suggested that the newly developed indolylacryloyl-derived oxacins should hold great promise as potential multitargeting broad-spectrum antibacterial candidates to overcome drug resistance.

Hydrazyl hydroxycoumarins as new potential conquerors towards Pseudomonas aeruginosa.

A class of unique hydrazyl hydroxycoumarins (HHs) as novel structural scaffold was developed to combat dreadful bacterial infections. Some HHs could effectively suppress bacterial growth at low concentrations, especially, pyridyl HH 7 exhibited a good inhibition against Pseudomonas aeruginosa 27853 with a low MIC value of 0.5 µg/mL, which was 8-fold more active than norfloxacin. Furthermore, pyridyl HH 7 with low hemolytic activity and low cytotoxicity towards NCM460 cells showed much lower trend to induce the drug-resistant development than norfloxacin. Preliminarily mechanism exploration indicated that pyridyl HH 7 could eradicate the integrity of bacterial membrane, result in the leakage of intracellular proteins, and interact with bacterial DNA gyrase via non-covalent binding, and ADME analysis manifested that compound 7 gave good pharmacokinetic properties. These results suggested that the newly developed hydrazyl hydroxycoumarins as potential multitargeting antibacterial agents should be worthy of further investigation for combating bacterial infection.

Novel aminothiazoximone-corbelled ethoxycarbonylpyrimidones with antibiofilm activity to conquer Gram-negative bacteria through potential multitargeting effects.

The emergence of drug-resistant microorganisms threatens human health, and it is usually exacerbated by the formation of biofilm, which forces the development of new antibacterial agents with antibiofilm activity. In this work, a novel category of aminothiazoximone-corbelled ethoxycarbonylpyrimidones (ACEs) was designed and synthesized, and some of the prepared ACEs showed potent bioactivity against the tested bacteria. In particular, imidazolyl ACE 6c showed better inhibitory activity towards Acinetobacter baumannii and Escherichia coli with MIC values both of 0.0066 mmol/L than norfloxacin. It was also revealed that imidazolyl ACE 6c not only possessed inconspicuous hemolytic rate and cytotoxicity, low drug resistance and no risk of penetrating the blood-brain barrier, but also exhibited obvious biofilm inhibition and eradication activities. The preliminary mechanism research suggested that imidazolyl ACE 6c could induce metabolic dysfunction by deactivating lactate dehydrogenase and promote the accumulation of reactive oxygen species to decrease the reduced glutathione and ultimately cause oxidative damage in bacteria. Furthermore, ACE 6c was also found that could insert into DNA to form the supramolecular complex of 6c-DNA and trigger cell death. The multidimensional effect might promote bacterial cell rupture, leading to the leakage of intracellular content. These findings manifested that novel imidazolyl ACE 6c as a potential multitargeting antibacterial agent with potent antibiofilm activity could provide new possibility for the treatment of refractory biofilm-intensified bacterial infections.

Discovery of benzopyridone cyanoacetates as new type of potential broad-spectrum antibacterial candidates.

Unique benzopyridone cyanoacetates (BCs) as new type of promising broad-spectrum antibacterial candidates were discovered with large potential to combat the lethal multidrug-resistant bacterial infections. Many prepared BCs showed broad antibacterial spectrum with low MIC values against the tested strains. Some highly active BCs exhibited rapid sterilization capacity, low resistant trend and good predictive pharmacokinetic properties. Furthermore, the highly active sodium BCs (NaBCs) displayed low hemolysis and cytotoxicity, and especially octyl NaBC 5g also showed in vivo potent anti-infective potential and appreciable pharmacokinetic profiles. A series of preliminary mechanistic explorations indicated that these active BCs could effectively eliminate bacterial biofilm and destroy membrane integrity, thus resulting in the leakage of bacterial cytoplasm. Moreover, their unique structures might further bind to intracellular DNA, DNA gyrase and topoisomerase IV through various direct noncovalent interactions to hinder bacterial reproduction. Meanwhile, the active BCs also induced bacterial oxidative stress and metabolic disturbance, thereby accelerating bacterial apoptosis. These results provided a bright hope for benzopyridone cyanoacetates as potential novel multitargeting broad-spectrum antibacterial candidates to conquer drug resistance.

Selective α-oxidation of amides via visible-light-driven iron catalysis.

Hydroxyl radicals (˙OH) as one of the highly reactive species can react unselectively with a wide range of chemicals. The ˙OH radicals are typically generated under harsh conditions. Herein, we report hydroxyl radical-induced selective N-α C(sp3)-H bond oxidation of amides under greener and mild conditions via an Fe(NO3)3·9H2O catalyst inner sphere pathway upon irradiation with a 30 W blue LED light strip (λ = 455 nm) using NaBrO3 as the oxidant. This protocol exhibited high chemoselectivity and excellent functional group tolerance. A preliminary mechanism investigation demonstrated that the iron catalyst afforded hydroxyl radicals via the visible-light-induced homolysis (VLIH) of iron complexes followed by a hydrogen atom transfer (HAT) process to realize this transformation.

Benzopyrone-mediated quinolones as potential multitargeting antibacterial agents.

A new type of benzopyrone-mediated quinolones (BMQs) was rationally designed and efficiently synthesized as novel potential antibacterial molecules to overcome the global increasingly serious drug resistance. Some synthesized BMQs effectively suppressed the growth of the tested strains, outperforming clinical drugs. Notably, ethylidene-derived BMQ 17a exhibited superior antibacterial potential with low MICs of 0.5-2 µg/mL to clinical drugs norfloxacin, it not only displayed rapid bactericidal performance and inhibited bacterial biofilm formation, but also showed low toxicity toward human red blood cells and normal MDA-kb2 cells. Mechanistic investigation demonstrated that BMQ 17a could effectually induce bacterial metabolic disorders and promote the enhancement of reactive oxygen species to disrupt the bacterial antioxidant defense system. It was found that the active molecule BMQ 17a could not only form supramolecular complex with lactate dehydrogenase, which disturbed the biological functions, but also effectively embed into calf thymus DNA, thus affecting the normal function of DNA and achieving cell death. This work would provide an insight into developing new molecules to reduce drug resistance and expand antibacterial spectrum.

Electrochemical trifluoroalkylation/annulation for the synthesis of CF3-functionalized tetrahydroquinolines and dihydroquinolinones.

Tuning the electronic structure of protecting groups on the nitrogen atom of substrates has emerged as an effective strategy to achieve the tandem trifluoromethylation/C(sp2)-H annulation using Langlois' reagent as the CF3 source for the electrochemical synthesis of functionalized tetrahydroquinolines and dihydroquinolinones.

Identification and Quantification of the Main Psychoactive Ingredients of Cannabis in Urine Using Excitation-Eemission Matrix Fluorescence Coupled with Parallel Factor Analysis.

Cannabis is the most prevalent abused substance after alcohol, and its consumption severely harms human health and thus adversely impacts society. The identification and quantification of cannabis in urine play important roles in practical forensics. Excitation-emission matrix (EEM) fluorescence spectroscopy coupled with parallel factor (PARAFAC) analysis was developed to identify and quantify the four main ingredients of cannabis in urine samples. The main ingredients of cannabis including Δ-9-tetrahydrocannabinol (THC), cannabidiol, cannabinol, and tetrahydrocannabinolic acid (THC-COOH) exhibited diverse fluorescence characteristics, and the concentrations of these compounds depicted a positive linear relationship with the fluorescence intensity at the ng/mL level. The EEM/PARAFAC method adequately characterized and discriminated the four ingredients in calibration and prediction samples with a low root-mean-square error of prediction (RMSEP; 0.03-0.07 µg/mL) and limit of quantitation (LOQ; 0.26-0.71 µg/mL). The prediction results of the EEM/PARAFAC method well correlated with that of GC-MS with a low RMSEP range (0.01-0.05 µg/mL) and LOQ range (0.07-0.44 µg/mL) in urine samples. The EEM spectroscopic investigation coupled with the PARAFAC algorithm results in an organic, solvent-less, fast, reliable tool to perform accurate and rapid screening of cannabis abusers.

Identification of unique indolylcyanoethylenyl sulfonylanilines as novel structural scaffolds of potential antibacterial agents.

The increasing incidence of antibiotic resistance has forced the development of unique antimicrobials with novel multitargeting mechanisms to combat infectious diseases caused by multidrug-resistant pathogens. Structurally unique indolylcyanoethylenyl sulfonylanilines (ISs) were exploited as novel promising antibacterial agents to confront stubborn drug resistance. Some prepared ISs possessed favorable bacteriostatic action towards the tested bacteria. Especially, hydroxyethyl IS 14a exerted 8-fold more potent inhibitory efficacy against multidrug-resistant A. baumannii and E. coli 25922 with the low MIC of 0.5 µg/mL than norfloxacin, and showed low cell toxicity and rapid bactericidal property. Moreover, this compound also possessed obvious effect of eradicating bacterial biofilm, which could effectually relieve the development of drug resistance. A preliminary assessment of the antibacterial mechanism indicated that compound 14a could disintegrate membrane integrity leading to the leakage of intracellular protein, inactivation of lactate dehydrogenase and metabolism inhibition. Hydroxyethyl IS 14a mediated the accumulation of excess reactive oxygen species, which further contributed to reducing glutathione, resulting in oxidative damage to bacteria. Furthermore, IS 14a could intercalate into DNA to hinder the biological function of DNA. Quantum chemical study disclosed that IS 14a with the lowest energy gap was conducive to displaying high bioactivity. These findings demonstrated that hydroxyethyl IS 14a as a prospective antimicrobial candidate for combating A. baumannii and E. coli 25922 would be a promising starting point.

Unexpected Cascade Sequence Forming the C(sp3)-N/C(sp2)-C(sp2) Bond: Direct Access to γ-Lactam-Fused Pyridones with Anticancer Activity.

An unexpected Ugi cascade reaction was developed for the facile construction of γ-lactam-fused pyridone derivatives with high tolerance of substrates. A C(sp3)-N bond and a C(sp2)-C(sp2) bond were formed together, accompanied by a chromone ring-opening in Ugi adducts, under the basic conditions without any metal catalyst for the whole process. Screening data of several difficult-to-inhibit cancer cell lines demonstrated that 7l displayed a high cytotoxicity against HCT116 cells (IC50 = 5.59 ± 0.78 µM). Taken together, our findings revealed new insights into the molecular mechanisms underlying compound 7l and provided potential usage of this scaffold for cancer therapeutics.

Comprehensive Insights into Medicinal Research on Imidazole-Based Supramolecular Complexes.

The electron-rich five-membered aromatic aza-heterocyclic imidazole, which contains two nitrogen atoms, is an important functional fragment widely present in a large number of biomolecules and medicinal drugs; its unique structure is beneficial to easily bind with various inorganic or organic ions and molecules through noncovalent interactions to form a variety of supramolecular complexes with broad medicinal potential, which is being paid an increasing amount of attention regarding more and more contributions to imidazole-based supramolecular complexes for possible medicinal application. This work gives systematical and comprehensive insights into medicinal research on imidazole-based supramolecular complexes, including anticancer, antibacterial, antifungal, antiparasitic, antidiabetic, antihypertensive, and anti-inflammatory aspects as well as ion receptors, imaging agents, and pathologic probes. The new trend of the foreseeable research in the near future toward imidazole-based supramolecular medicinal chemistry is also prospected. It is hoped that this work provides beneficial help for the rational design of imidazole-based drug molecules and supramolecular medicinal agents and more effective diagnostic agents and pathological probes.

Thiazolyl hydrazineylidenyl indolones as unique potential multitargeting broad-spectrum antimicrobial agents.

The emergence of pathogenic and drug-resistant microorganisms seriously threatens public safety. This work constructed a unique type of thiazolyl hydrazineylidenyl indolones (THIs) to combat global microbial multidrug-resistance. Bioactive evaluation discovered that some target THIs displayed much superior antimicrobial efficacy than clinical chloromycetin, norfloxacin, cefdinir or fluconazole against the tested strains. Eminently, butyl THI 6c displayed a broad antimicrobial spectrum with low MICs of 0.25-1 µg/mL. The highly active THI 6c not only showed low cytotoxicity and hemolysis, rapidly bactericidal ability, good antibiofilm activity and promising pharmacokinetic properties, but also could significantly impede the development of bacterial resistance. Preliminary exploration of antibacterial mechanism revealed that THI 6c could effectively penetrate the cell membrane of MRSA and embed DNA to form 6c‒DNA supramolecular complex and thus hinder DNA replication. Moreover, THI 6c could reduce cell metabolic activity, which might be attributed to the fact that THI 6c could target the pyruvate kinase of MRSA and interfere with the function of the enzyme. These results provided powerful information for further developing thiazolyl hydrazineylidenyl indolones as new broad-spectrum antimicrobial agents.

Highly potent Platinum(IV) complexes with multiple-bond ligands targeting mitochondria to overcome cisplatin resistance.

The efficacy and resistance of cisplatin-based compounds are very intractable problems at present. This study reports a series of platinum(IV) compounds containing multiple-bond ligands, which exhibited better tumor cell inhibitory activity and antiproliferative and anti-metastasis activities than cisplatin. The meta-substituted compounds 2 and 5 were particularly excellent. Further research showed that compounds 2 and 5 possessed appropriate reduction potential and performed significantly better than cisplatin in cellular uptake, reactive oxygen species response, the up-regulation of apoptosis and DNA lesion-related genes, and drug-resistant cell activity. The title compounds exhibited better antitumor potential and fewer side effects than cisplatin in vivo. Multiple-bond ligands were introduced into cisplatin to form the title compounds in this study, which not only enhanced their absorption and overcame drug resistance but also demonstrated the potential to target mitochondria and inhibit the detoxification of tumor cells.

Azolylpyrimidinediols as Novel Structural Scaffolds of DNA-Groove Binders against Intractable Acinetobacter baumannii.

A unique class of antibacterial azolylpyrimidinediols (APDs) and their analogues were developed. Some synthesized compounds showed excellent bacteriostatic potency; especially, triazolylpyrimidinediol (triazolyl PD) 7a exhibited good anti-Acinetobacter baumannii potential with a low MIC of 0.002 mmol/L. Triazolyl PD 7a with inconspicuous cytotoxicity and hemolytic activity could eradicate the established biofilm, showed low resistance, and exhibited favorable drug-likeness. Mechanistic explorations revealed that compound 7a without membrane-targeting ability could decrease metabolic activity, interact with DNA through groove binding action to block DNA replication rather than intercalate into and cleave DNA, and thus inhibit bacterial growth. Further computations displayed that the low EHOMO and large energy gap might help triazolyl PD 7a binding to biological targets more easily. Moreover, compound 7a gave appreciable in vivo pharmacokinetic properties and pharmacodynamics. These findings of azolylpyrimidinediols as novel structural scaffolds of DNA-groove binders might imply a large promise for the treatments of Acinetobacter baumannii infection.

Benzenesulfonyl thiazoloimines as unique multitargeting antibacterial agents towards Enterococcus faecalis.

New efficient antimicrobial agents are urgently needed to combat invasive multidrug-resistant pathogens infections. Structurally unique benzenesulfonyl thiazoloimines (BSTIs) were exploited as novel potential antibacterial victors to confront terrific drug resistance. Some developed BSTIs exerted effectively antimicrobial efficacy against the tested strains. Notably, 2-pyridyl BSTI 14d exhibited good antibacterial activity against E. faecalis with MIC value of 1 µg/mL, which was superior to sulfathiazole and norfloxacin. The most active compound 14d not only showed rapid bactericidal properties and impeded E. faecalis biofilm formation to effectually relieve the development of drug resistance, but also performed low toxicity toward human red blood cells, human normal squamous epithelial cells and human non-neoplastic colon epithelial cells. Mechanistic investigation demonstrated that molecule 14d could exert efficient membrane destruction leading to the leakage of intracellular materials and metabolism inhibition, cause oxidative damage of E. faecalis through accumulation of excess reactive oxygen species and reduction of glutathione activity, and intercalate into DNA to hinder replication of DNA. Molecular docking indicated that the formation of 14d-dihydrofolate synthetase supramolecular complex could hinder the function of this enzyme. ADME analysis displayed that compound 14d possessed promising pharmacokinetic properties. These findings suggested that the newly developed benzenesulfonyl thiazoloimines with multitargeting antibacterial potential provided a new possibility for evading resistance.

New Efforts toward Aminothiazolylquinolones with Multitargeting Antibacterial Potential.

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.