Natural aloe emodin-hybridized sulfonamide aminophosphates as novel potential membrane-perturbing and DNA-intercalating agents against Enterococcus faecalis.

The dramatic rise in drug resistance accelerated the desire for new antibacterial agents to safeguard human health. This work constructed a novel type of aloe emodin-hybridized sulfonamide aminophosphates as unique potential antibacterial agents. The biological assay revealed that some target hybrids possessed potent inhibitory activity. Particularly, ethyl aminophosphate-hybridized sulfadiazine aloe emodin 7a (EASA-7a) not only displayed preponderant antibacterial efficiency against drug-resistant E. faecalis at low concentration as 0.25 µg/mL but also possessed strong bacteriostatic capacity and low propensity to develop resistance toward E. faecalis. The weak hemolysis toward human red blood cells and efficient biofilm-disruptive ability further implied the therapeutic potential of EASA-7a. Preliminary studies disclosed that the excellent antibacterial behavior of EASA-7a might be attributed to its capacity to permeate and depolarize the bacterial membrane, as well as promote ROS accumulation and intercalate with DNA. These findings manifested that EASA-7a was worthy of further development to combat life-threatening bacterial infections.

Aloe emodin-conjugated sulfonyl hydrazones as novel type of antibacterial modulators against S. aureus 25923 through multifaceted synergistic effects.

Aloe emodin-conjugated sulfonyl hydrazones were designed and synthesized as novel type of antibacterial modulators. Aloe emodin benzenesulfonyl hydrazone 5a (AEBH-5a) was preponderant for the treatment of S. aureus 25923 (MIC = 0.5 µg/mL) over norfloxacin and presented high selectivity between bacterial membranes and mammalian membranes. Especially, AEBH-5a could eliminate the formed biofilms and relieve the development of S. aureus 25923 resistance. The antibacterial mechanism of AEBH-5a from extracellularity to intracellularity illustrated that AEBH-5a could destroy bacterial membrane integrity, leading to the leakage of protein and nucleic acid. Besides, AEBH-5a could not only interact with DNA and induce oxidative stress but also inhibit lactate dehydrogenase (LDH) activity as well as render metabolic inactivation. In silico ADME studies prediction of AEBH-5a revealed a favorable bioavailability score and prominent drug-likeness profile. This research showed that the multifaceted synergistic effect initiated by aloe emodin-conjugated sulfonyl hydrazones is a reasonable and effective tactic to combat menacing bacterial infections.

A facile reaction to access novel structural sulfonyl-hybridized imidazolyl ethanols as potential DNA-targeting antibacterial agents.

A novel type of sulfonyl-hybridized imidazolyl ethanols as potential DNA-targeting antibacterial agents was constructed via the unique ring-opened reaction of oxiranes by imidazoles for the first time. Some developed target hybrids showed potential antimicrobial potency against the tested microbes. Especially, imidazole derivative 5f could strongly suppressed the growth of MRSA (MIC = 4 µg/mL), which was 2-fold and 16-fold more potent than the positive control sulfathiazole and norfloxacin. This compound exhibited quite low propensity to induce bacterial resistance. Antibacterial mechanism exploration indicated that compound 5f could embed in MRSA DNA to form steady 5f-DNA complex, which possibly hinder DNA replication to exert antimicrobial behavior. Molecular docking showed that molecule 5f could bind with dihydrofolate synthetase through hydrogen bonds. These results implied that imidazole derivative 5f could be served as a promising molecule for the exploration of novel antibacterial candidates.

Design and biological evaluation of a novel type of potential multi-targeting antimicrobial sulfanilamide hybrids in combination of pyrimidine and azoles.

This work explored a novel type of potential multi-targeting antimicrobial three-component sulfanilamide hybrids in combination of pyrimidine and azoles. The hybridized target molecules were characterized by 1H NMR, 13C NMR and HRMS spectra. Some of the developed target compounds exerted promising antimicrobial activity in comparison with the reference drugs norfloxacin and fluconazole. Noticeably, sulfanilamide hybrid 5c with pyrimidine and indole could effectively inhibit the growth of E. faecalis with MIC value of 1 µg/mL. The active molecule 5c showed low cell toxicity and did not obviously trigger the development of resistance towards the tested bacteria strains. Mechanism exploration indicated that compound 5c could not only exert efficient membrane permeability, but also intercalate into DNA of resistant E. faecalis to form 5c-DNA supramolecular complex, which might be responsible for its antimicrobial action. The further investigation showed that this molecule could be effectively transported by human serum albumins through hydrogen bonds and van der Waals force.

Novel purine benzimidazoles as antimicrobial agents by regulating ROS generation and targeting clinically resistant Staphylococcus aureus DNA groove.

A novel series of purine benzimidazole hybrids were designed and synthesized for the first time with the aim to circumvent the increasing antibiotic resistance. Hexyl appended hybrid 3c gave potent activities against most of the tested bacteria and fungi especially against multidrug-resistant strains Staphylococcus aureus (MIC = 4 µg/mL). Structure-activity relationships revealed that the benzimidazole fragment at the 9-position of purine played an important role in exerting potentially antibacterial activity. Both cell toxicity and ROS generation assays indicated that the purine derivative 3c showed low cytotoxicity and could be used as a safe agent. Molecular modeling suggested that hybrid 3c could bind with the residues of Topo IA through hydrogen bonds and electrostatic interactions. Quantum chemical studies were also performed on the target compound 3c to understand the structural features essential for activity. The active molecule 3c could effectively interact with S. aureus DNA to form 3c-DNA complex through groove binding mode, which might block DNA replication to display their powerful antimicrobial activity.

Azoalkyl ether imidazo[2,1-b]benzothiazoles as potentially antimicrobial agents with novel structural skeleton.

A series of new azoalkyl ether imidazo[2,1-b]benzothiazoles were developed via a convenient synthetic procedure. The antimicrobial assays showed that a good number of the prepared derivatives exhibited significant inhibitory properties against most of the tested strains. Especially 2-methyl-5-nitroimidazole derivative 5a presented superior inhibit activity against MRSA and B. typhi with MIC = 4 µg/mL and MIC = 1 µg/mL, respectively. The highly active compound 5a showed low toxicity against mammalian cells without obvious triggering of the development of bacterial resistance, and it also possessed rapid bactericidal efficacy. Molecular docking study exposed that the active molecule 5a could interact with the active site of S. aureus gyrase through hydrogen bond. Quantum chemical studies were also performed to explain the high antibacterial activity. Further investigation revealed that compound 5a could significantly associate with gyrase-DNA complex by mean of hydrogen bonds and could efficiently intercalate into MRSA DNA to form 5a-DNA supramolecular complex, which impart potent bioactivity.

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.

Discovery of Imidazole-Based Inhibitors of Plasmodium falciparum cGMP-Dependent Protein Kinase.

The discovery of new targets for the treatment of malaria, in particular those aimed at the pre-erythrocytic stage in the life cycle, advanced with the demonstration that orally administered inhibitors of Plasmodium falciparum cGMP-dependent protein kinase (PfPKG) could clear infection in a murine model. This enthusiasm was tempered by unsatisfactory safety and/or pharmacokinetic issues found with these chemotypes. To address the urgent need for new scaffolds, this paper presents initial structure-activity relationships in an imidazole scaffold at four positions, representative in vitro ADME, hERG characterization, and cell-based antiparasitic activity. This series of PfPKG inhibitors has good in vitro PfPKG potency, low hERG activity, and cell-based antiparasitic activity against multiple Plasmodium species that appears to be correlated with the in vitro potency.

Design and synthesis of aminothiazolyl norfloxacin analogues as potential antimicrobial agents and their biological evaluation.

A series of aminothiazolyl norfloxacin analogues as a new type of potential antimicrobial agents were synthesized and screened for their antimicrobial activities. Most of the prepared compounds exhibited excellent inhibitory efficiencies. Especially, norfloxacin analogue II-c displayed superior antimicrobial activities against K. pneumoniae and C. albicans with MIC values of 0.005 and 0.010 mM to reference drugs, respectively. This compound not only showed broad antimicrobial spectrum, rapid bactericidal efficacy and strong enzymes inhibitory potency including DNA gyrase and chitin synthase (CHS), low toxicity against mammalian cells and no obvious propensity to trigger the development of bacterial resistance, but also exerted efficient membrane permeability, and could effectively intercalate into K. pneumoniae DNA to form a steady supramolecular complex, which might block DNA replication to exhibit their powerful antimicrobial activity. Quantum chemical studies were also performed to explain the high antimicrobial activities. Molecular docking showed that compound II-c could bind with gyrase-DNA and topoisomerase IV-DNA through hydrogen bonds and π-π stacking.

Indole-nitroimidazole conjugates as efficient manipulators to decrease the genes expression of methicillin-resistant Staphylococcus aureus.

The biological resistance of methicillin-resistant staphylococcus aureus (MRSA) has pushed synthetic antibiotics to the forefront. To combat the resistance of MRSA, our new effort directed towards the development of novel structural candidates of enone-bridged indole nitroimidazole scaffolds, and wished to shed some light on the combination of some single pharmacophore with different biological activities. Bioassay revealed that the active compound 4b gave a satisfactory inhibition on MRSA (MIC = 1 µg/mL) and could effectively prevent the development of bacterial resistance. Mechanism exploration indicated that molecule 4b could not only intercalate into MRSA deoxyribonucleic acid (DNA), but also permeate MRSA membrane and bind with penicillin-binding protein 2a (PBP2a), then decreased the expression of three relevant genes in MRSA. Furthermore, it was able to be stored and carried by human serum albumin (HSA), and the participation of metal ions in 4b-HSA system was helpful to improve the supramolecular transport behavior. Hybrid 4b also exhibited low cytotoxicity towards normal lung epithelial cell line BEAS-2B.

A new exploration towards aminothiazolquinolone oximes as potentially multi-targeting antibacterial agents: Design, synthesis and evaluation acting on microbes, DNA, HSA and topoisomerase IV.

This work did a new exploration towards aminothiazolquinolone oximes as potentially multi-targeting antimicrobial agents. A class of novel hybrids of quinolone, aminothiazole, piperazine and oxime fragments were designed for the first time, conveniently synthesized as well as characterized by 1H NMR, 13C NMR and HRMS spectra. Biological activity showed that some of the synthesized compounds exhibited good antimicrobial activities in comparison with the reference drugs. Especially, O-methyl oxime derivative 10b displayed excellent inhibitory efficacy against MRSA and S. aureus 25923 with MIC values of 0.009 and 0.017 mM, respectively. Further studies indicated that the highly active compound 10b showed low toxicity toward BEAS-2B and A549 cell lines and no obvious propensity to trigger the development of bacterial resistance. Quantum chemical studies have also been conducted and rationally explained the structural features essential for activity. The preliminarily mechanism exploration revealed that compound 10b could not only exert efficient membrane permeability by interfering with the integrity of cells, bind with topoisomerase IV-DNA complex through hydrogen bonds and π-π stacking, but also form a steady biosupramolecular complex by intercalating into DNA to exert the efficient antibacterial activity. The supramolecular interaction between compound 10b and human serum albumin (HSA) was a static quenching, and the binding process was spontaneous, where hydrogen bonds and van der Waals force played vital roles in the supramolecular transportation of the active compound 10b by HSA.

Discovery of 2-aminothiazolyl berberine derivatives as effectively antibacterial agents toward clinically drug-resistant Gram-negative Acinetobacter baumanii.

Aminothiazolyl berberine derivatives as potentially antimicrobial agents were designed and synthesized in an effort to overcome drug resistance. The antimicrobial assay revealed that some target compounds exhibited significantly inhibitory efficiencies toward bacteria and fungi including drug-resistant pathogens, and the aminothiazole and Schiff base moieties were helpful structural fragments for aqueous solubility and antibacterial activity. Especially, aminothiazolyl 9-hexyl berberine 9c and 2,4-dichlorobenzyl derivative 18a exhibited good activities (MIC = 2 nmol/mL) against clinically drug-resistant Gram-negative Acinetobacter baumanii with low cytotoxicity to hepatocyte LO2 cells, rapidly bactericidal effects and quite slow development of bacterial resistance toward A. baumanii. Molecular modeling indicated that compounds 9c and 18a could bind with GLY-102, ARG-136 and/or ALA-100 residues of DNA gyrase through hydrogen bonds. It was found that compounds 9c and 18a were able to disturb the drug-resistant A. baumanii membrane effectively, and molecule 9c could not only intercalate but also cleave bacterial DNA isolated from resistant A. baumanii, which might be the preliminary antibacterial action mechanism of inhibiting the growth of A. baumanii strain. In particular, the combination use of compound 9c with norfloxacin could enhance the antibacterial activity, broaden antibacterial spectrum and overcome the drug resistance.

Discovery of Benzimidazole-Quinolone Hybrids as New Cleaving Agents toward Drug-Resistant Pseudomonas aeruginosa DNA.

A series of benzimidazole-quinolone hybrids as new potential antimicrobial agents were designed and synthesized. Bioactive assays indicated that some of the prepared compounds exhibited potent antibacterial and antifungal activities. Notably, 2-fluorobenzyl derivative 5 b (ethyl 7-chloro-6-fluoro-1-[[1-[(2-fluorophenyl)methyl]benzimidazol-2-yl]methyl]-4-oxo-quinoline-3-carboxylate) showed remarkable antimicrobial activity against resistant Pseudomonas aeruginosa and Candida tropicalis isolated from infected patients. Active molecule 5 b could not only rapidly kill the tested strains, but also exhibit low toxicity toward Hep-2 cells. It was more difficult to trigger the development of bacterial resistance of P. aeruginosa against 5 b than that against norfloxacin. Molecular docking demonstrated that 5 b could effectively bind with topoisomerase IV-DNA complexes, and quantum chemical studies theoretically elucidated the good antimicrobial activity of compound 5 b. Preliminary experimental reaction mechanism exploration suggested that derivative 5 b could not intercalate into DNA isolated from drug-resistant P. aeruginosa, but was able to cleave DNA effectively, which might further block DNA replication to exert powerful bioactivities. In addition, compound 5 b is a promising antibacterial agent with membrane disruption abilities.

Novel carbazole-triazole conjugates as DNA-targeting membrane active potentiators against clinical isolated fungi.

A series of carbazole-triazole conjugates were designed, synthesized and characterized by IR, NMR, and HRMS spectra. Biological assay showed that most of the synthesized compounds exhibited moderate and even strong antifungal activities, especially 3,6-dibromocarbazolyl triazole 5d displayed excellent inhibitory efficacy against most of the tested fungal strains (MIC = 2-32 µg/mL) and effectively fungicidal ability towards C. albicans, C. tropicals and C. parapsilosis ATCC 22019 (MFC = 4-8 µg/mL). Its combination use with fluconazole could enhance the antifungal efficacy, and compound 5d also did not obviously trigger the development of resistance in C. albicans even after 10 passages. Preliminary mechanism study revealed that the active molecule 5d could depolarize fungal membrane potential and intercalate into DNA to possibly block DNA replication, thus possibly exhibiting its powerful antifungal abilities. Conjugate 5d could interact with HSA, which was constructive for the further design, modification and screening of drug molecules. Docking investigation demonstrated a non-covalent binding of 5d with CYP51 through hydrogen bond and hydrophobicity. These results strongly suggested that compound 5d could act as a potential template for the development of promising antifungal drugs.

Novel organophosphorus aminopyrimidines as unique structural DNA-targeting membrane active inhibitors towards drug-resistant methicillin-resistant Staphylococcus aureus.

A series of novel unique structural organophosphorus aminopyrimidines were developed as potential DNA-targeting membrane active inhibitors through an efficient one-pot procedure from aldehydes, phosphonate and aminopyrimidine. The biological assay revealed that some of the prepared compounds displayed antibacterial activities. In particular, imidazole derivative 2c exhibited more potent inhibitory activity against MRSA with an MIC value of 4 µg mL-1 in comparison with the clinical drugs chloromycin and norfloxacin. Experiments revealed that the active molecule 2c had the ability to rapidly kill the tested strains without obviously triggering the development of bacterial resistance, showed low toxicity to L929 cells and could disturb the cell membrane. The molecular docking study discovered that compound 2c could bind with DNA gyrase via hydrogen bonds and other weak interactions. Further exploration disclosed that the active molecule 2c could also effectively intercalate into MRSA DNA and form a steady 2c-DNA supramolecular complex, which might further block DNA replication to exert powerful antibacterial effects.

Novel Naphthalimide Aminothiazoles as Potential Multitargeting Antimicrobial Agents.

A series of novel naphthalimide aminothiazoles were developed for the first time and evaluated for their antimicrobial activity. Some prepared compounds possessed good inhibitory activity against the tested bacteria and fungi. Noticeably, the piperazine derivative 4d displayed superior antibacterial activity against MRSA and Escherichia coli with MIC values of 4 and 8 µg/mL, respectively, to reference drugs. The most active compound 4d showed low toxicity against mammalian cells with no obvious triggering of the development of bacterial resistance, and it also possessed rapid bactericidal efficacy and efficient membrane permeability. Preliminarily investigations revealed that compound 4d could not only bind with gyrase-DNA complex through hydrogen bonds but could effectively intercalate into MRSA DNA to form 4d-DNA supramolecular complex, which might be responsible for the powerful bioactivity. Further transportation behavior evaluation indicated that molecule 4d could be effectively stored and carried by human serum albumin, and the hydrophobic interactions and hydrogen bonds played important roles in the binding process.