Publications by authors named "Cheng-He Zhou"

104 Publications

Isatin-derived azoles as new potential antimicrobial agents: Design, synthesis and biological evaluation.

Bioorg Med Chem Lett 2021 Apr 8;41:128030. Epub 2021 Apr 8.

Institute of Bioorganic & Medicinal Chemistry, Key Laboratory of Luminescence Analysis and Molecular Sensing, Ministry of Education, School of Chemistry and Chemical Engineering, Southwest University, Chongqing 400715, PR China. Electronic address:

Novel antibiotics are forced to be developed on account of multidrug-resistant bacteria with serious threats to human health. This work developed isatin-derived azoles as new potential antimicrobial agents. Bioactive assay revealed that isatin hybridized 1,2,4-triazole 7a exhibited excellent inhibitory activity against E. coli ATCC 25,922 with an MIC value of 1 µg/mL, which was 8-fold more potent than reference drug norfloxacin. The active molecule 7a possessed the ability to kill some bacteria and fungi as well as displayed low propensity to induce resistance towards E. coli ATCC25922. Preliminary mechanism investigation indicated that hybrid 7a might block deoxyribonucleic acid (DNA) replication by intercalating with DNA and possibly interacting with DNA polymerase III, thus exerting its antimicrobial potency.
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http://dx.doi.org/10.1016/j.bmcl.2021.128030DOI Listing
April 2021

Pyrimidinetrione-imidazoles as a Unique Structural Type of Potential Agents towards Candida Albicans: Design, Synthesis and Biological Evaluation.

Chem Asian J 2021 Apr 8. Epub 2021 Apr 8.

Institute of Bioorganic & Medicinal Chemistry', Key Laboratory of Luminescence Analysis and Molecular Sensing (Ministry of Education), School of Chemistry and Chemical Engineering, Southwest University, Chongqing, 400715, P. R. China.

Substantial morbidity and mortality of fungal infections have aroused concerns all over the world, and common Candida spp. currently bring about severe systemic infections. A series of pyrimidinetrione-imidazole conjugates as potentially antifungal agents were developed. Bioassays manifested that 4-fluobenzyl pyrimidinetrione imidazole 5 f exerted favorable inhibition towards C. albicans (MIC=0.002 mM), being 6.5 folds more active than clinical antifungal drug fluconazole (MIC=0.013 mM). Preliminary mechanism research indicated that compound 5 f could not only depolarize membrane potential but also permeabilize the membrane of C. albicans. Molecular docking was operated to simulate the interaction mode between molecule 5 f and CYP51. In addition, hybrid 5 f might form 5 f-DNA supramolecular complex via intercalating into DNA. The interference of membrane and DNA might contribute to its fungicidal capacity with no obvious tendency to induce the resistance against C. albicans. Conjugate 5 f endowed good blood compatibility as well as low cytotoxicity towards HeLa and HEK-293T cells.
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http://dx.doi.org/10.1002/asia.202100146DOI Listing
April 2021

Unique para-aminobenzenesulfonyl oxadiazoles as novel structural potential membrane active antibacterial agents towards drug-resistant methicillin resistant Staphylococcus aureus.

Bioorg Med Chem Lett 2021 Mar 26;41:127995. Epub 2021 Mar 26.

Institute of Bioorganic & Medicinal Chemistry, Key Laboratory of Luminescence Analysis and Molecular Sensing, Ministry of Education, Southwest University, Chongqing 400715, PR China. Electronic address:

A class of structurally unique para-aminobenzenesulfonyl oxadiazoles as new potential antimicrobial agents was designed and synthesized from acetanilide. Some target para-aminobenzenesulfonyl oxadiazoles showed antibacterial potency. Noticeably, hexyl derivative 8b (MIC = 1 μg/mL) was more active than norfloxacin against drug resistant MRSA. Compound 8b was able to disturb the membrane effectively and intercalate into deoxyribonucleic acid (DNA) to form a steady 8b-DNA complex, which might be responsible for bacterial metabolic inactivation. Molecular docking indicated that 8b could interact with DNA topoisomerase IV through noncovalent interactions to form a supramolecular complex and hinder the function of this enzyme. These results indicated that hexyl derivative 8b deserved further investigation as a new lead compound.
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http://dx.doi.org/10.1016/j.bmcl.2021.127995DOI Listing
March 2021

Membrane active 7-thiazoxime quinolones as novel DNA binding agents to decrease the genes expression and exert potent anti-methicillin-resistant Staphylococcus aureus activity.

Eur J Med Chem 2021 May 10;217:113340. Epub 2021 Mar 10.

Institute of Bioorganic & Medicinal Chemistry, Key Laboratory of Luminescence Analysis and Molecular Sensing (Southwest University), Ministry of Education, School of Chemistry and Chemical Engineering, Southwest University, Chongqing, 400715, PR China. Electronic address:

A novel class of 7-thiazoxime quinolones was developed as potential antimicrobial agents for the sake of bypassing resistance of quinolones. Biological assays revealed that some constructed 7-thiazoxime quinolones possessed effective antibacterial efficiency. Methyl acetate oxime derivative 6l exhibited 32-fold more active than ciprofloxacin against MRSA, which also possessed rapidly bactericidal ability and low toxicity towards mammalian cells. The combination use of 7-thiazoxime quinolone 6l and ciprofloxacin was able to improve antibacterial potency and effectively alleviate bacterial resistance. The preliminarily mechanism exploration revealed that compound 6l could destroy the cell membrane and insert into MRSA DNA to bind with DNA gyrase, then decrease the expression of gyrB and femB genes. The above results strongly suggested that methyl acetate oxime derivative 6l held a promise for combating MRSA infection.
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http://dx.doi.org/10.1016/j.ejmech.2021.113340DOI Listing
May 2021

Aerobic Copper-Catalyzed Salicylaldehydic C -H Arylations with Arylboronic Acids.

Chemistry 2021 Feb 26;27(10):3278-3283. Epub 2021 Jan 26.

Institute of Bioorganic & Medicinal Chemistry, Key Laboratory of Luminescence Analysis and Molecular Sensing, Ministry of Education, School of Chemistry and Chemical Engineering, Southwest University, Chongqing, 400715, P. R. China.

We report a challenging copper-catalyzed C -H arylation of salicylaldehydes with arylboronic acids that involves unique salicylaldehydic copper species that differ from reported salicylaldehydic rhodacycles and palladacycles. This protocol has high chemoselectivity for the C -H bond compared to the phenolic O-H bond involving copper catalysis under high reaction temperatures. This approach is compatible with a wide range of salicylaldehyde and arylboronic acid substrates, including estrone and carbazole derivatives, which leads to the corresponding arylation products. Mechanistic studies show that the 2-hydroxy group of the salicylaldehyde substrate triggers the formation of salicylaldehydic copper complexes through a Cu /Cu /Cu catalytic cycle.
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http://dx.doi.org/10.1002/chem.202004810DOI Listing
February 2021

An unexpected discovery toward novel membrane active sulfonyl thiazoles as potential MRSA DNA intercalators.

Future Med Chem 2020 10 8;12(19):1709-1727. Epub 2020 Oct 8.

Institute of Bioorganic & Medicinal Chemistry, School of Chemistry & Chemical Engineering, Southwest University, Tiansheng Street 2, Beibei District, Chongqing, 400715, PR China.

With the increasing emergence of drug-resistant bacteria, the need for new antimicrobial agents has become extremely urgent. This work was to develop sulfonyl thiazoles as potential antibacterial agents. Novel hybrids of sulfonyl thiazoles were developed from commercial acetanilide and acetylthiazole. Hybrids and displayed excellent inhibitory efficacy against clinical methicillin-resistant (MRSA) (minimum inhibitory concentration = 1 μg/ml) without obvious toxicity toward normal mammalian cells (RAW 264.7). The combination uses were found to improve the antimicrobial ability. Further preliminary antibacterial mechanism experiments showed that the active molecule could effectively interfere with MRSA membrane and insert into MRSA DNA. Compounds and could serve as potential DNA-targeting templates toward the development of promising antimicrobial agents.
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http://dx.doi.org/10.4155/fmc-2019-0303DOI Listing
October 2020

Synthesis of monofluorooxazoles with quaternary C-F centers through photoredox-catalyzed radical addition of methylene-2-oxazolines.

Org Biomol Chem 2020 03;18(12):2223-2226

College of Pharmacy, National & Local Joint Engineering Research Center of Targeted and Innovative Therapeutics, Chongqing Key Laboratory of Kinase Modulators as Innovative Medicine, Chongqing University of Arts and Sciences, Chongqing 402160, China.

A novel photoredox-catalyzed radical addition of methylene-2-oxazolines has been developed under visible light irradiation to synthesize monofluorooxazoles with a quaternary carbon center using 2-bromo-2-fluoro-3-oxo-3-phenylpropionates as radical source. This method with a simple protocol, scalability and high yield offers a facile path to get diverse monofluorinated oxazoles with quaternary C-F centers, which are a class of highly valuable motifs and synthons.
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http://dx.doi.org/10.1039/d0ob00267dDOI Listing
March 2020

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

Bioorg Med Chem Lett 2020 03 20;30(6):126982. Epub 2020 Jan 20.

Institute of Bioorganic & Medicinal Chemistry, Key Laboratory of Applied Chemistry of Chongqing Municipality, School of Chemistry and Chemical Engineering, Southwest University, Chongqing 400715, China. Electronic address:

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 H NMR, C 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.
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http://dx.doi.org/10.1016/j.bmcl.2020.126982DOI Listing
March 2020

Pd-Catalyzed Remote Site-Selective and Stereoselective C(Alkenyl)-H Alkenylation of Unactivated Cycloalkenes.

J Org Chem 2020 Jan 24;85(2):774-787. Epub 2019 Dec 24.

Key Laboratory of Luminescent and Real-Time Analytical Chemistry, Ministry of Education, Institute of Bioorganic & Medicinal Chemistry, School of Chemistry and Chemical Engineering , Southwest University , Chongqing 400715 , P. R. China.

A palladium-catalyzed alkenylation involving remote δ-position C(alkenyl)-H activation of cycloalkenes reacting with electron-deficient alkenes is described. This method features excellent site selectivity and stereoselectivity to efficiently afford only -selective highly substituted 1,3-diene derivatives with extra-ligand-free and good functional group tolerance including estrone and free N-H tryptamine under weakly alkaline conditions. Mechanistic studies suggest that picolinamide as a bidentate directing group enables the formation of unique alkenyl palladacycle intermediates.
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http://dx.doi.org/10.1021/acs.joc.9b02797DOI Listing
January 2020

Ethylenic conjugated coumarin thiazolidinediones as new efficient antimicrobial modulators against clinical methicillin-resistant Staphylococcus aureus.

Bioorg Chem 2020 01 19;94:103434. Epub 2019 Nov 19.

Institute of Bioorganic & Medicinal Chemistry, Key Laboratory of Luminescent and Real-Time Analytical Chemistry (Southwest University), Ministry of Education, School of Chemistry and Chemical Engineering, Southwest University, Tiansheng Street 2, Beibei District, Chongqing 400715, PR China. Electronic address:

In an effort for the development of novel antimicrobial agents, ethylenic conjugated coumarin thiazolidinediones as potential multi-targeting new antimicrobial compounds were synthesized through convenient procedures from commercially available resorcinol and were evaluated for their antimicrobial potency. Bioactive evaluation revealed that some of the prepared compounds showed strong antimicrobial activities towards the tested microorganisms including clinically drug-resistant strains. Especially, propargyl derivative 12b exhibited effective anti-MRSA potency with MIC value of 0.006 μmol/mL, which was highly advantageous over clinical antibacterial drug norfloxacin. Compound 12b showed rapid killing effect, low toxicity against hepatocyte LO2 cell line, and no obvious drug resistance development against MRSA. Preliminary exploration of action mechanism manifested that molecule 12b acted upon MRSA through forming stable supramolecular complex with bacterial DNA which might impede DNA replication. Molecular docking showed that compound 12b could bind with DNA-gyrase through hydrogen bonds.
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http://dx.doi.org/10.1016/j.bioorg.2019.103434DOI Listing
January 2020

Merging Visible Light with Cross-Coupling: The Photochemical Direct C-H Difluoroalkylation of Imidazopyridines.

Org Lett 2019 Oct 20;21(20):8169-8173. Epub 2019 Aug 20.

International Academy of Targeted Therapeutics and Innovation , Chongqing University of Arts and Sciences , 319 Honghe Avenue , Yongchuan , Chongqing 402160 , China.

A transition-metal-free protocol for the difluoroalkylation of imidazopyridines with bromodifluoroaryl ketones promoted by visible light irradiation is presented. This protocol is distinguished by simple, mild, and catalyst-free reaction conditions with a wide reaction scope, which is complementary to existing difluoroalkylation strategies by photoredox scenarios. Additionally, this protocol potentially offers a new way for streamlining the synthesis of compounds containing the difluoro moiety.
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http://dx.doi.org/10.1021/acs.orglett.9b02487DOI Listing
October 2019

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

Eur J Med Chem 2019 Oct 2;179:723-735. Epub 2019 Jul 2.

Key Laboratory of Applied Chemistry of Chongqing Municipality, Institute of Bioorganic & Medicinal Chemistry, School of Chemistry and Chemical Engineering, Southwest University, Chongqing, 400715, China. Electronic address:

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.
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http://dx.doi.org/10.1016/j.ejmech.2019.06.093DOI Listing
October 2019

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

Eur J Med Chem 2019 Oct 19;179:166-181. Epub 2019 Jun 19.

Institute of Bioorganic & Medicinal Chemistry, Key Laboratory of Applied Chemistry of Chongqing Municipality, School of Chemistry and Chemical Engineering, Southwest University, Chongqing, 400715, China. Electronic address:

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 H NMR, C 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.
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http://dx.doi.org/10.1016/j.ejmech.2019.06.046DOI Listing
October 2019

Identification of novel imidazole flavonoids as potent and selective inhibitors of protein tyrosine phosphatase.

Bioorg Chem 2019 07 9;88:102900. Epub 2019 Apr 9.

Laboratory of Bioorganic & Medicinal Chemistry, School of Chemistry and Chemical Engineering, Southwest University, Chongqing 400715, People's Republic of China.

A series of imidazole flavonoids as new type of protein tyrosine phosphatase inhibitors were synthesized and characterized. Most of them gave potent protein phosphatase 1B (PTP1B) inhibitory activities. Especially, compound 11a could effectively inhibit PTP1B with an IC value of 0.63 μM accompanied with high selectivity ratio (9.5-fold) over T-cell protein tyrosine phosphatase (TCPTP). This compound is cell permeable with relatively low cytotoxicity. The high binding affinity and selectivity was disclosed by molecular modeling and dynamics studies. The structural features essential for activity were confirmed by quantum chemical studies.
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http://dx.doi.org/10.1016/j.bioorg.2019.03.074DOI Listing
July 2019

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

Eur J Med Chem 2019 Apr 4;167:105-123. Epub 2019 Feb 4.

Institute of Bioorganic & Medicinal Chemistry, Key Laboratory of Applied Chemistry of Chongqing Municipality, School of Chemistry and Chemical Engineering, Southwest University, Chongqing, 400715, PR China. Electronic address:

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.
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http://dx.doi.org/10.1016/j.ejmech.2019.01.072DOI Listing
April 2019

Sulfonamide-Derived Four-Component Molecular Hybrids as Novel DNA-Targeting Membrane Active Potentiators against Clinical Escherichia coli.

Mol Pharm 2019 03 30;16(3):1036-1052. Epub 2019 Jan 30.

Institute of Bioorganic & Medicinal Chemistry, Key Laboratory of Applied Chemistry of Chongqing Municipality, School of Chemistry and Chemical Engineering , Southwest University , Chongqing 400715 , China.

Novel sulfonamide-based four-component molecular hybrids as potential DNA-targeting antimicrobial agents were developed from marketed acetanilide through convenient procedures. Biological assays indicated that a few of the target compounds showed significant inhibitory efficiencies toward the tested bacteria and fungi. Noticeably, metronidazole hybrid 6a exhibited a lower minimum inhibitory concentration (MIC) value of 0.019 mM against clinical drug-resistant Escherichia coli ( E. coli), which showed to be 84-fold more active than clinical norfloxacin and had no obvious toxicity toward human breast cancer MCF-7 cells. Synergistic combinations of compound 6a with clinical antibacterial or antifungal drugs could improve the antimicrobial efficiency. Further molecular modeling indicated that the active molecule 6a could bind with THR-199, HIS-64, and GLN-92 residues of human carbonic anhydrase isozyme II through hydrogen bonds and was also able to insert into base-pairs of the DNA hexamer duplex by forming hydrogen bonds. The preliminary exploration of the antibacterial mechanism suggested that compound 6a was capable of disturbing the E. coli membrane effectively and intercalating into clinical resistant E. coli bacterial DNA through noncovalent bonds to form a supramolecular complex, thus exerting its powerful antimicrobial activity. This might suggest a great possibility for hybrid 6a to be a DNA-targeting membrane active potentiator against clinical drug-resistant E. coli.
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http://dx.doi.org/10.1021/acs.molpharmaceut.8b01021DOI Listing
March 2019

Design and Synthesis of Novel Sulfonamide-Derived Triazoles and Bioactivity Exploration.

Med Chem 2020 ;16(1):104-118

School of Chemistry and Chemical Engineering, Southwest University, Chongqing 400715, China.

Objective: Due to the incidence of resistance, a series of sulfonamide-derived 1,2,4- triazoles were synthesized and evaluated.

Method: The novel sulfonamide-derived 1,2,4-triazoles were prepared starting from commercial acetaniline and chlorosulfonic acid by sulfonylation, aminolysis, N-alkylation and so on. The antimicrobial activity of the synthesized compounds were evaluated in vitro by two-fold serial dilution technique.

Results: In vitro antimicrobial evaluation found that 2-chlorobenzyl sulfonamide 1,2,4-triazole 7c exhibited excellent antibacterial activities against MRSA, B. subtilis, B. typhi and E. coli with MIC values of 0.02-0.16 μmol/mL, which were comparable or even better than Chloromycin. The preliminary mechanism suggested that compound 7c could effectively bind with DNA, and also it could bind with human microsomal heme through hydrogen bonds in molecular docking. Computational chemical studies were performed on compound 7c to understand the structural features that are essential for activity. Additionally, compound 7c could generate a small amount of reactive oxygen species (ROS).

Conclusion: Compound 7c could serve as a potential clinical antimicrobial candidate.
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http://dx.doi.org/10.2174/1573406414666181106124852DOI Listing
February 2020

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

Medchemcomm 2018 Sep 1;9(9):1529-1537. Epub 2018 Aug 1.

Institute of Bioorganic & Medicinal Chemistry , Key Laboratory of Applied Chemistry of Chongqing Municipality , School of Chemistry and Chemical Engineering , Southwest University , Chongqing 400715 , PR China . Email: ; ; Tel: +86 23 68254967.

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 exhibited more potent inhibitory activity against MRSA with an MIC value of 4 μg mL in comparison with the clinical drugs chloromycin and norfloxacin. Experiments revealed that the active molecule 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 could bind with DNA gyrase hydrogen bonds and other weak interactions. Further exploration disclosed that the active molecule could also effectively intercalate into MRSA DNA and form a steady -DNA supramolecular complex, which might further block DNA replication to exert powerful antibacterial effects.
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http://dx.doi.org/10.1039/c8md00301gDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6149443PMC
September 2018

Design, synthesis of novel azolyl flavonoids and their protein tyrosine Phosphatase-1B inhibitory activities.

Bioorg Chem 2018 10 5;80:195-203. Epub 2018 Jun 5.

Laboratory of Bioorganic & Medicinal Chemistry, School of Chemistry and Chemical Engineering, Southwest University, Chongqing 400715, People's Republic of China.

A series of azolyl flavonoids were synthesized and characterized by NMR, IR, MS and HRMS spectra. All the newly prepared compounds were screened for their potential protein tyrosine phosphatase inhibitory activities. Bioactive assay manifested that most of the azolyl flavonoids exhibited good protein phosphatase 1B (PTP1B) inhibitory activities. Especially, triazolyl flavonoid 6a displayed the best inhibitory activity (IC = 1.6 μM) with 9.9-fold selectivity for PTP1B over the closely related T-cell protein tyrosine phosphatase (TCPTP). Cell viability assays indicated 6a has lower cytotoxicity. Molecular modeling and dynamics studies revealed the reason of selectivity for PTP1B over TCPTP. Quantum chemical studies were carried out on these compounds to understand the structural features essential for activity.
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http://dx.doi.org/10.1016/j.bioorg.2018.06.008DOI Listing
October 2018

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

Bioorg Med Chem Lett 2018 08 12;28(14):2426-2431. Epub 2018 Jun 12.

Institute of Bioorganic & Medicinal Chemistry, Key Laboratory of Applied Chemistry of Chongqing Municipality, School of Chemistry and Chemical Engineering, Southwest University, Chongqing 400715, PR China. Electronic address:

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.
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http://dx.doi.org/10.1016/j.bmcl.2018.06.016DOI Listing
August 2018

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

Eur J Med Chem 2018 Jul 15;155:579-589. Epub 2018 Jun 15.

Institute of Bioorganic & Medicinal Chemistry, Key Laboratory of Applied Chemistry of Chongqing Municipality, School of Chemistry and Chemical Engineering, Southwest University, Chongqing, 400715, China. Electronic address:

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.
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http://dx.doi.org/10.1016/j.ejmech.2018.06.022DOI Listing
July 2018

Novel naphthalimide nitroimidazoles as multitargeting antibacterial agents against resistant Acinetobacter baumannii.

Future Med Chem 2018 04 19;10(7):711-724. Epub 2018 Apr 19.

Institute of Bioorganic & Medicinal Chemistry, Key Laboratory of Applied Chemistry of Chongqing Municipality, School of Chemistry & Chemical Engineering, Southwest University, Chongqing 400715, PR China.

Aim: The increasing emergence of resistant bacteria imposed an urgent request to discover novel antibacterial agents. This work was to develop naphthalimide nitroimidazoles as potentially antibacterial agents. Results/methodology: Compound 9e showed the strong antibacterial activity (minimal inhibitory concentration = 0.013 μmol/ml) against resistant Acinetobacter baumannii (A. baumannii) with rapid killing effect and no obvious triggering of the development of resistance. Its combination use with chloromycin, norfloxacin or clinafloxacin improved the antibacterial potency. It could not only effectively permeate membrane of resistant A. baumannii bacteria, but also intercalate into resistant A. baumannii DNA to form 9e-DNA complex. The interaction with bacterial DNA gyrase B was driven by hydrogen bonds.

Conclusion: Compound 9e should be a potentially multitargeting antibacterial agent against resistant A. baumannii.
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http://dx.doi.org/10.4155/fmc-2017-0160DOI Listing
April 2018

Palladium-catalyzed aerobic regio- and stereo-selective olefination reactions of phenols and acrylates via direct dehydrogenative C(sp)-O cross-coupling.

Chem Commun (Camb) 2018 Apr;54(35):4437-4440

Key Laboratory of Applied Chemistry of Chongqing Municipality, Institute of Bioorganic & Medicinal Chemistry, School of Chemistry and Chemical Engineering, Southwest University, Chongqing 400715, China.

An efficient olefination protocol for the oxidative dehydrogenation of phenols and acrylates has been achieved using a palladium catalyst and O2 as the sole oxidant. This reaction exhibits high regio- and stereo-selectivity (E-isomers) with moderate to excellent isolated yields and a wide substrate scope (32 examples) including ethyl vinyl ketone and endofolliculina.
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http://dx.doi.org/10.1039/c8cc01226aDOI Listing
April 2018

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

Bioorg Med Chem Lett 2018 05 19;28(9):1621-1628. Epub 2018 Mar 19.

Institute of Bioorganic & Medicinal Chemistry, Key Laboratory of Applied Chemistry of Chongqing Municipality, School of Chemistry and Chemical Engineering, Southwest University, Chongqing 400715, China. Electronic address:

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.
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http://dx.doi.org/10.1016/j.bmcl.2018.03.046DOI Listing
May 2018

Potential Antimicrobial Isopropanol-Conjugated Carbazole Azoles as Dual Targeting Inhibitors of .

ACS Med Chem Lett 2018 Mar 5;9(3):244-249. Epub 2018 Feb 5.

Institute of Bioorganic & Medicinal Chemistry, Key Laboratory of Applied Chemistry of Chongqing Municipality, School of Chemistry and Chemical Engineering, Southwest University, Chongqing 400715, China.

A series of isopropanol-bridged carbazole azoles as potential antimicrobial agents were designed and synthesized from commercial carbazoles. Bioassay revealed that 3,6-dichlorocarbazolyl triazole could effectively inhibit the growth of with minimal inhibitory concentration of 2 μg/mL. The active molecule showed lower propensity to trigger the development of resistance in bacteria than norfloxacin and exerted rapidly bactericidal ability. Compound also exhibited low cytotoxicity to normal mammalian RAW264.7 cells. Further mechanism exploration indicated that conjugate was membrane active against and could form -DNA complex by intercalating into DNA of resistant , which might be responsible for its antimicrobial action. Molecular docking showed an efficient binding of triazole derivative with DNA gyrase enzyme through noncovalent interactions.
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http://dx.doi.org/10.1021/acsmedchemlett.7b00514DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5846035PMC
March 2018

Molecular interaction of novel benzothiazolyl triazolium analogues with calf thymus DNA and HSA-their biological investigation as potent antimicrobial agents.

Eur J Med Chem 2018 Apr 21;150:228-247. Epub 2018 Feb 21.

Department of Engineering Chemistry, Andhra University, Vishakapatnam 530 003, India. Electronic address:

The binding behaviour between calf thymus DNA and synthesized benzothiazolyl triazolium derivatives as potent antimicrobial agents was explored by means of spectroscopic applications together with molecular docking study at the sub-domain IIA, binding site I of human serum albumin (HSA). Most of the synthesized derivatives presented significant antimicrobial inhibition when compared with the clinical Norfloxacin, Chloromycin, and Fluconazole. In particular, compound 5q presented efficient anti-Bacillus subtilis, anti-Escherichia coli, anti-Salmonella typhi, and anti-Psuedomonas aeruginosa activity with low MIC values of 2-8 μg/mL which were relatively superior to the reference drugs. The preliminarily investigation of interaction studies with calf thymus DNA demonstrated that the most active compound 5q could effectively intercalate into DNA to form 5q-DNA complex. Further investigations revealed that human serum albumin could effectively transport compound 5q while molecular modelling studies with good docking score showed that hydrophobic interactions as well as hydrogen bonds played a significant role in the interaction of compound 5q with HSA. In addition, the cytotoxic investigation carried out on four different cancerous cell lines (3 human cell lines and 1 murine cell lines) by MTT assay presented that compound 5n is active against MDA cell lines with IC values less than 100 μg/mL.
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http://dx.doi.org/10.1016/j.ejmech.2018.02.056DOI Listing
April 2018

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

ChemMedChem 2018 05 16;13(10):1004-1017. Epub 2018 Apr 16.

Institute of Bioorganic & Medicinal Chemistry, Key Laboratory of Applied Chemistry of Chongqing Municipality, School of Chemistry and Chemical Engineering, Southwest University, Chongqing, 400715, P.R. China.

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.
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http://dx.doi.org/10.1002/cmdc.201700739DOI Listing
May 2018

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

Eur J Med Chem 2018 Feb 12;146:15-37. Epub 2018 Jan 12.

Institute of Bioorganic & Medicinal Chemistry, Key Laboratory of Applied Chemistry of Chongqing Municipality, School of Chemistry and Chemical Engineering, Southwest University, Chongqing, 400715, PR China. Electronic address:

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.
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http://dx.doi.org/10.1016/j.ejmech.2018.01.038DOI Listing
February 2018

Recent advance in oxazole-based medicinal chemistry.

Eur J Med Chem 2018 Jan 14;144:444-492. Epub 2017 Dec 14.

School of Chemistry and Chemical Engineering, Southwest University, Chongqing 400715, China.

Oxazole compounds containing nitrogen and oxygen atoms in the five-membered aromatic ring are readily able to bind with a variety of enzymes and receptors in biological systems via diverse non-covalent interactions, and thus display versatile biological activities. The related researches in oxazole-based derivatives including oxazoles, isoxazoles, oxazolines, oxadiazoles, oxazolidones, benzoxazoles and so on, as medicinal drugs have been an extremely active topic, and numerous excellent achievements have been acquired. Noticeably, a large number of oxazole compounds as clinical drugs or candidates have been frequently employed for the treatment of various types of diseases, which have shown their large development value and wide potential as medicinal agents. This work systematically reviewed the recent researches and developments of the whole range of oxazole compounds as medicinal drugs, including antibacterial, antifungal, antiviral, antitubercular, anticancer, anti-inflammatory and analgesic, antidiabetic, antiparasitic, anti-obesitic, anti-neuropathic, antioxidative as well as other biological activities. The perspectives of the foreseeable future in the research and development of oxazole-based compounds as medicinal drugs are also presented. It is hoped that this review will serve as a stimulant for new thoughts in the quest for rational designs of more active and less toxic oxazole medicinal drugs.
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http://dx.doi.org/10.1016/j.ejmech.2017.12.044DOI Listing
January 2018

Novel Naphthalimide Aminothiazoles as Potential Multitargeting Antimicrobial Agents.

ACS Med Chem Lett 2017 Dec 1;8(12):1331-1335. Epub 2017 Dec 1.

Institute of Bioorganic & Medicinal Chemistry, Key Laboratory of Applied Chemistry of Chongqing Municipality, School of Chemistry and Chemical Engineering, Southwest University, Chongqing 400715, China.

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 displayed superior antibacterial activity against MRSA and with MIC values of 4 and 8 μg/mL, respectively, to reference drugs. The most active compound 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 could not only bind with gyrase-DNA complex through hydrogen bonds but could effectively intercalate into MRSA DNA to form -DNA supramolecular complex, which might be responsible for the powerful bioactivity. Further transportation behavior evaluation indicated that molecule could be effectively stored and carried by human serum albumin, and the hydrophobic interactions and hydrogen bonds played important roles in the binding process.
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http://dx.doi.org/10.1021/acsmedchemlett.7b00452DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5733258PMC
December 2017