Synthesis and biological evaluation of 2,5-disubstituted furan derivatives containing 1,3-thiazole moiety as potential α-glucosidase inhibitors.

α-Glucosidase, which is involved in the hydrolysis of carbohydrates to glucose and directly mediates blood glucose elevation, is a crucial therapeutic target for type 2 diabetes. In this work, 2,5-disubstituted furan derivatives containing 1,3-thiazole-2-amino or 1,3-thiazole-2-thiol moiety (III-01 âˆ¼ III-30) were synthesized and screened for their inhibitory activity against α-glucosidase. α-Glucosidase inhibition assay demonstrated that all compounds had IC50 in the range of 0.645-94.033 µM and more potent than standard inhibitor acarbose (IC50 = 452.243 ± 54.142 µM). The most promising inhibitors of the two series were compound III-10 (IC50 = 4.120 ± 0.764 µM) and III-24 (IC50 = 0.645 ± 0.052 µM), respectively. Kinetic study and molecular docking simulation revealed that compound III-10 (Ki = 2.04 ± 0.72 µM) is a competitive inhibitor and III-24 (Ki = 0.44 ± 0.53 µM) is a noncompetitive inhibitor against α-glucosidase. Significantly, these two compounds showed nontoxicity towards HEK293, RAW264.7 and HepG2 cells, suggesting that compounds may be considered as a class of potential candidates for further developing novel antidiabetic drugs.

2,5-Disubstituted furan derivatives containing imidazole, triazole or tetrazole moiety as potent α-glucosidase inhibitors.

α-Glucosidase inhibitors (AGIs) are oral antidiabetic drugs, preferably used in treating type 2 diabetes mellitus, that delay the absorption of carbohydrates from the gastrointestinal system. In this work, 2,5-disubstituted furan derivatives containing imidazole, triazole or tetrazole moiety (III-01 âˆ¼ III-45) were synthesized and characterized by elemental analysis, HRMS, 1H NMR, 13C NMR and single crystal X-ray. Their inhibitory activity against α-glucosidase was screened. The most promising inhibitors were compound III-11 (IC50 = 6.0 ± 1.1 µM), III-16 (IC50 = 2.2 ± 0.2 µM) and III-39 (IC50 = 4.6 ± 1.9 µM), respectively. Kinetic study revealed that compounds III-11 and III-39 were uncompetitive inhibitors against α-glucosidase. Meanwhile, III-16 (Ki = 5.1 ± 0.7 µM) was a competitive inhibitor. Furthermore, molecular docking studies indicated that the existence of the azole group played a critically important role in hydrogen bond interaction with α-glucosidase. Significantly, in vivo toxicity towards HEK293 cells, RAW264.7 cells and HepG2 cells suggested that compounds III-11 and III-39 possessed non-toxicity, that could be considered as potential candidates for further development of novel antidiabetic drugs.

Derivative of cinnamic acid inhibits T3SS of Xanthomonas oryzae pv. oryzae through the HrpG-HrpX regulatory cascade.

Bacterial leaf blight (BLB) caused by Xanthomonas oryzae pv. oryzae (Xoo) has a significant impact on rice yield and quality worldwide. Traditionally, bactericide application has been commonly used to control this devastating disease. However, the overuse of fungicides has led to a number of problems such as the development of resistance and environmental pollution. Therefore, the development of new methods and approaches for disease control are still urgent. In this paper, a series of cinnamic acid derivatives were designed and synthesized, and three novel T3SS inhibitors A10, A12 and A20 were discovered. Novel T3SS inhibitors A10, A12 and A20 significantly inhibited the hpa1 promoter activity without affecting Xoo growth. Further studies revealed that the title compounds A10, A12 and A20 significantly impaired hypersensitivity in non-host plant tobacco leaves, while applications on rice significantly reduced symptoms of bacterial leaf blight. RT-PCR showed that compound A20 inhibited the expression of T3SS-related genes. In summary, this work exemplifies the potential of the title compound as an inhibitor of T3SS and its efficacy in the control of bacterial leaf blight.

A novel strategy to control Pseudomonas syringae through inhibition of type III secretion system.

Pseudomonas syringae (P. syringae) is a highly prevalent Gram-negative pathogen with over 60 pathogenic variants that cause yield losses of up to 80% in various crops. Traditional control methods mainly involve the application of antibiotics to inactivate pathogenic bacteria, but large-scale application of antibiotics has led to the development of bacterial resistance. Gram-negative pathogens including P. syringae commonly use the type III secretion system (T3SS) as a transport channel to deliver effector proteins into host cells, disrupting host defences and facilitating virulence, providing a novel target for antibacterial drug development. In this study, we constructed a high-throughput screening reporter system based on our previous work to screen for imidazole, oxazole and thiazole compounds. The screening indicated that the three compounds (II-14, II-15 and II-24) significantly inhibited hrpW and hrpL gene promoter activity without influencing the growth of P. syringae, and the inhibitory activity was better than that of the positive control sulforaphane (4-methylsulfinylbutyl isothiocyanate, SFN) at 50 µM. Three compounds suppressed the transcript levels of representative T3SS genes to different degrees, suggesting that the compounds may suppress the expression of T3SS by modulating the HrpR/S-HrpL regulatory pathway. Inoculation experiments indicated that all three compounds suppressed the pathogenicity of Pseudomonas syringae pv. tomato DC3000 in tomato and Pseudomonas syringae pv. phaseolicola 1448A in bean to varying degrees. One representative compound, II-15, significantly inhibited the secretion of the Pst DC3000 AvrPto effector protein. These findings provide a theoretical basis for the development of novel P. syringae T3SS inhibitors for application in disease prevention and control.

Discovery of a series of 5-phenyl-2-furan derivatives containing 1,3-thiazole moiety as potent Escherichia coli ß-glucuronidase inhibitors.

Gut microbial ß-glucuronidases have drawn much attention due to their role as a potential therapeutic target to alleviate some drugs or their metabolites-induced gastrointestinal toxicity. In this study, fifteen 5-phenyl-2-furan derivatives containing 1,3-thiazole moiety (1-15) were synthesized and evaluated for their inhibitory effects against Escherichia coli ß-glucuronidase (EcGUS). Twelve of them showed satisfactory inhibition against EcGUS with IC50 values ranging from 0.25 µM to 2.13 µM with compound 12 exhibited the best inhibition. Inhibition kinetics studies indicated that compound 12 (Ki = 0.14 ± 0.01 µM) was an uncompetitive inhibitor for EcGUS and molecular docking simulation further predicted the binding model and capability of compound 12 with EcGUS. A preliminary structure-inhibitory activity relationship study revealed that the heterocyclic backbone and bromine substitution of benzene may be essential for inhibition against EcGUS. The compounds have the potential to be applied in drug-induced gastrointestinal toxicity and the findings would help researchers to design and develop more effective 5-phenyl-2-furan type EcGUS inhibitors.

Thiazolidin-2-cyanamides derivatives as novel potent Escherichia coli ß-glucuronidase inhibitors and their structure-inhibitory activity relationships.

Gut microbial ß-glucuronidases have the ability to deconjugate glucuronides of some drugs, thus have been considered as an important drug target to alleviate the drug metabolites-induced gastrointestinal toxicity. In this study, thiazolidin-2-cyanamide derivatives containing 5-phenyl-2-furan moiety (1-13) were evaluated for inhibitory activity against Escherichia coli ß-glucuronidase (EcGUS). All of them showed more potent inhibition than a commonly used positive control, d-saccharic acid 1,4-lactone, with the IC50 values ranging from 1.2 µM to 23.1 µM. Inhibition kinetics studies indicated that compound 1-3 were competitive type inhibitors for EcGUS. Molecular docking studies were performed and predicted the potential molecular determinants for their potent inhibitory effects towards EcGUS. Structure-inhibitory activity relationship study revealed that chloro substitution on the phenyl moiety was essential for EcGUS inhibition, which would help researchers to design and develop more effective thiazolidin-2-cyanamide type inhibitors against EcGUS.

Discovery of novel inhibitors of phosphodiesterase 4 with 1-phenyl-3,4-dihydroisoquinoline scaffold: Structure-based drug design and fragment identification.

Currently, it is in urgent need to develop novel selective PDE4 inhibitors with novel structural scaffolds to overcome the adverse effects and improve the efficacy. Novel 1-phenyl-3,4-dihydroisoquinoline amide derivatives were developed as potential PDE4 inhibitors based on the structure-based drug design and fragment identification strategy. A SARs analysis was performed in substituents attached in the C-3 side chain phenyl ring, indicating that the attachment of methoxy group or halogen atom substitution at the ortho-position of the phenyl ring was helpful to enhance both inhibitory activity toward PDE4B and selectivity. Compound 15 with excellent selectivity, exhibited the most potent inhibition in vitro and in vivo, which is a promising lead for development of a new class of selective PDE4 inhibitors.

Direct thiocarbamation of imidazoheterocycles via dual C-H sulfurization.

A copper-catalyzed DTBP oxidative dual C-H sulfurization has been developed for the direct thiocarbamation of imidazopyridines using a combination of elemental sulfur and formamides as carbamothioyl surrogates. NBS (bromo succinimide) was found to promote the thiocarbamation in good yields. This dual C-H sulfurization strategy enables access to a wide range of carbamothioyl imidazoheterocycles without the use of highly toxic phosgene.

Synthesis and fungicidal activity of novel pyrazole derivatives containing 5-Phenyl-2-Furan.

Pyrazole constitutes an important heterocyclic family covering a broad range of synthetic as well as natural products that exhibit numerous chemical, biological, agrochemical and pharmacological properties. In order to explore compounds with good fungicidal activity, a series of new pyrazole derivatives containing 5-phenyl-2-furan were designed and synthesized. In vitro and in vivo fungicidal activities were evaluated and the compound ethyl-1-(5-phenylfuran-2-carbonyl)-5-propyl-1H-pyrazole-3-carboxylate (I8) displayed significant fungicidal activity against various fungi, especially against P. infestans. The structures of the novel pyrazole derivatives were confirmed by 1H NMR, 13C NMR, MS, elemental analysis and X-ray single crystal diffraction. Further study showed that compound I8 might act on the synthesis of cell walls from morphological and ultrastructural studies by SEM and TEM. The results also revealed that compound I8 could block the nutritional transportation leading to cells senescence and death. These results suggested that the novel pyrazole derivatives proved to be promising lead compounds.

Synthesis and bioactivity of 1,3-thiazolidine-2-thione derivatives against type III secretion system of Xanthomonas oryzae.

Targeting virulence factors of bacterial without affecting their growth and survival, has been an initiative strategy for the development of novel anti-microbial agents. The type III secretion system (T3SS), one of essential and highly conserved virulence factors in most Gram-negative pathogenic bacteria, has been regarded as an effective target that developed new anti-microbial drugs. Xanthomonas oryzae pv. oryzae (Xoo) is one of the most important bacterial pathogens on rice, which causes leaf blight disease. To discover potential anti-virulence agents against the pathogens, a new series of 1,3-thiazolidine-2-thione derivatives containing 5-phenyl-2-furan were designed and synthesized. Their structures were characterized by 1H NMR, 13C NMR, MS, and elemental analysis. All the title compounds inhibited the promoter activity of a harpin gene hpa1, significantly, that were further checked for the impact on bacterial growth. The results indicated that treatment of Xoo with the title compound III-7 did not affect bacterial growth or survival. Moreover, quantitative reverse transcription-polymerase chain reaction (qRT-PCR) analysis showed that the expression of the Xoo T3SS was suppressed by treatment with the inhibitor. The mRNA levels of representative genes in the hrp (hypersensitive response and pathogenicity) cluster, as well as the regulatory genes hrpG and hrpX, were reduced. Finally, the in vivo test demonstrated that the compounds could reduce the disease symptoms of Xoo on the rice cultivar (Oryza sativa) IR24.

Structure-aided optimization of 3-O-ß-chacotriosyl ursolic acid as novel H5N1 entry inhibitors with high selective index.

Currently, entry inhibitors contribute immensely in developing a new generation of anti-influenza virus drugs. Our earlier studies have identified that 3-O-ß-chacotriosyl ursolic acid (1) could inhibit H5N1 pseudovirus by targeting hemagglutinin (HA). In the present study, a series of C-28 modified pentacyclic triterpene saponins via conjugation with a series of amide derivatives were synthesized and their antiviral activities against influenza A/Duck/Guangdong/99 virus (H5N1) in MDCK cells were evaluated. The SARs analysis of these compounds revealed that introduction of certain amide structures at the 17-COOH of ursolic acid could significantly enhance both their antiviral activity and selective index. This study indicated that the attachment of the methoxy group or Cl atom to the phenyl ring at the ortho- or para-position was crucial to improve inhibitory activity. Mechanism studies demonstrated that these title triterpenoids could bind tightly to the viral envelope HA to block the attachment of viruses to host cells, which was consistent with docking studies.

Synthesis and biological evaluation of 1,3,4-thiadiazole derivatives as type III secretion system inhibitors against Xanthomonas oryzae.

Xanthomonas oryzae pv. oryzae (Xoo) infection directly leads to a severe disease known as leaf blight, which is a major cause of yield loss of rice. Use of traditional bactericides has resulted in severe resistance in pathogenic bacteria. A new approach screening compounds that target the virulence factors rather than killing bacterial pathogens is imperative. In gram-negative bacteria, the type III secretion system (T3SS) is a conserved and significant virulence factor considered as a target for drug development. Therefore, we designed and synthesized a new series of 5-phenyl-2-furan carboxylic acid derivatives stitched with 2-mercapto-1,3,4-thiadiazole. Bioassays revealed that the title candidates attenuated the hypersensitive response through suppressing the promoter activity of a harpin gene hpa1 without affecting bacterial growth. Quantitative real time polymerase chain reaction (qRT-PCR) analysis demonstrated reduced the expression of several genes associated with T3SS, when title compounds were applied. Additionally, hrp gene cluster members, including hrpG and hrpX, had reduced mRNA levels. In vivo greenhouse tests showed that candidate compounds could alleviate the effects of Xoo infection in rice (Oryza sativa) and possess better protective activity against rice bacterial leaf blight than bismerthiazol and thiodiazole copper. All tested compounds were safe to rice. This work suggests there are new safe options for Xoo control in rice from these 1,3,4-thiadiazole derivatives.

Small Molecule Inhibitors Specifically Targeting the Type III Secretion System of Xanthomonas oryzae on Rice.

The initiative strategy for the development of novel anti-microbial agents usually uses the virulence factors of bacteria as a target, without affecting their growth and survival. The type III secretion system (T3SS), one of the essential virulence factors in most Gram-negative pathogenic bacteria because of its highly conserved construct, has been regarded as an effective target that developed new anti-microbial drugs. Xanthomonas oryzae pv. oryzae (Xoo) causes leaf blight diseases and is one of the most important pathogens on rice. To find potential anti-virulence agents against this pathogen, a number of natural compounds were screened for their effects on the T3SS of Xoo. Three of 34 compounds significantly inhibited the promoter activity of the harpin gene, hpa1, and were further checked for their impact on bacterial growth and on the hypersensitive response (HR) caused by Xoo on non-host tobacco plants. The results indicated that treatment of Xoo with CZ-1, CZ-4 and CZ-9 resulted in an obviously attenuated HR without affecting bacterial growth and survival. Moreover, quantitative reverse transcription-polymerase chain reaction (qRT-PCR) analysis showed that the expression of the Xoo T3SS was suppressed by treatment with the three inhibitors. The mRNA levels of representative genes in the hypersensitive response and pathogenicity (hrp) cluster, as well as the regulatory genes hrpG and hrpX, were reduced. Finally, the in vivo test demonstrated that the compounds could reduce the disease symptoms of Xoo on the rice cultivar (Oryza sativa) IR24.

Synthesis and bioactivity of 3,5-dimethylpyrazole derivatives as potential PDE4 inhibitors.

A series of 3,5-dimethylpyrazole derivatives containing 5-phenyl-2-furan moiety were designed and synthesized as phosphodiesterase type 4 (PDE4) inhibitors. Bioassay results showed that the title compounds exhibited considerable inhibitory activity against PDE4B and blockade of LPS-induced TNFα release. Among the designed compounds, compound If showed the best inhibitory activity against PDE4B with the IC50 value of 1.7 µM, which also showed good in vivo activity in animal models of asthma/COPD and sepsis induced by LPS. The primary structure-activity relationship (SAR) study and docking results suggested that introduction of the substituent groups to the phenyl ring at the para-position, especially methoxy group, was helpful to enhance inhibitory activity against PDE4B.

Tetrahydroquinoline and tetrahydroisoquinoline derivatives as potential selective PDE4B inhibitors.

Tetrahydroquinoline and tetrahydroisoquinoline derivatives containing 2-phenyl-5-furan moiety were designed and synthesized as phosphodiesterase type 4 (PDE4) inhibitors. The bioassay results showed that title compounds showed good inhibitory activity against PDE4B and blockade of LPS (lipopolysaccharide) induced TNF-α release, which also exhibited considerable in vivo activity in animal models of asthma/COPD (chronic obstructive pulmonary disease) and sepsis induced by LPS. The bioactivity of compounds containing tetrahydroquinoline (series 4) was higher than that of tetrahydroisoquinoline derivatives (series 3). Compound 4 m with 4-methoxybenzene moiety exhibited the best potential selective activity against PDE4B. The primary structure-activity relationship study and docking results showed that the tetrahydroquinoline moiety of compound 4 m played a key role to form hydrogen bonds and π-π stacking interaction with PDE4B protein while the rest part of the molecule extended into the catalytic domain to block the access of cAMP and formed the foundation for inhibition of PDE4B. Based on LPS induced sepsis model for the measurement of TNF-α inhibition in Swiss Albino mice and neutrophilia inhibition for asthma and COPD in Sprague Dawley rats with the potential molecules, compound 4 m would be great promise as a hit inhibitor in the future study.

Synthesis and bioactivity of thiazolidin-2-cyanamide derivatives against type III secretion system of Xanthomonas oryzae on rice.

Targeting virulence factors of bacterial without affecting their growth and survival, has been an initiative strategy for the development of novel anti-microbial agents. The type III secretion system (T3SS), one of essential and highly conserved virulence factors in most Gram-negative pathogenic bacteria, has been regarded as an effective target that developed new anti-microbial drugs. Xanthomonas oryzae pv. oryzae (Xoo) is one of the most Important bacterial pathogens on rice, which causes leaf blight disease. To discover potential anti-virulence agents against the pathogens, a new series of thiazolidin-2-cyanamide derivatives containing 5-phenyl-2-furan were designed and synthesized. Their structures were characterized by 1H NMR, 13C NMR, MS, and elemental analysis. All the title compounds inhibited the promoter activity of a harpin gene hpa1, significantly, that were further checked for the impact on bacterial growth and on the hypersensitive response (HR) caused by Xoo on non-host tobacco plants. The results indicated that treatment of Xoo with the title compounds II-2, II-3 and II-4 resulted in significantly attenuated HR without affecting bacterial growth or survival. Moreover, quantitative reverse transcription-polymerase chain reaction (qRT-PCR) analysis showed that the expression of the Xoo T3SS was suppressed by treatment with the three inhibitors. The mRNA levels of representative genes in the hrp (hypersensitive response and pathogenicity) cluster, as well as the regulatory genes hrpG and hrpX, were reduced. Finally, the in vivo test demonstrated that the compounds could reduce the disease symptoms of Xoo on the rice cultivar (Oryza sativa) IR24.

Design, synthesis and fungicidal activity of novel 2-substituted aminocycloalkylsulfonamides.

A series of novel 2-substituted aminocycloalkylsulfonamides were designed and synthesized by highly selective N-alkylation reaction, whose structures were characterized by 1H NMR, 13C NMR and HRMS. Among them, the configuration of compounds III12 and III20 were confirmed by X-ray single crystal diffraction. Bioassays demonstrated that the title compounds had considerable effects on different strains of Botrytis cinerea and Pyricularia grisea. Comparing with positive control procymidone (EC50=10.31mg/L), compounds III28, III29, III30 and III31 showed excellent fungicidal activity against a strain of B. cinerea (CY-09), with EC50 values of 3.17, 3.04, 2.54 and 1.99mg/L respectively. Their in vivo fungicidal activities were also better than the positive controls cyprodinil, procymidone, boscalid and carbendazim in pot experiments. Moreover, the fungicidal activity of III28 (EC50=4.62mg/L) against P. grisea was also better than that of the positive control isoprothiolane (EC50=6.11mg/L). Compound III28 would be great promise as a hit compound for further study based on the structure-activity relationship.

Design, synthesis and biological evaluation of 2,4-disubstituted oxazole derivatives as potential PDE4 inhibitors.

In this study, a series of pyrazole derivatives containing 4-phenyl-2-oxazole moiety were designed and synthesized in a concise way, some of which exhibited considerable inhibitory activity against PDE4B and blockade of LPS-induced TNF-α release. Compound 4c displayed the strongest inhibition activity (IC50=1.6±0.4µM) and good selectivity against PDE4B. Meanwhile, compound 4c showed good in vivo activity in animal models of asthma/COPD and sepsis induced by LPS. The primary structure-activity relationship study showed the 3,5-dimethylpyrazole residue was essential for the bioactivity, and the substituted group R1 at the benzene ring also affected the activity. Docking results showed that compound 4c played a key role to form integral hydrogen bonds and a π-π stacking interaction, using hydrazide scaffold (CONN) and pyrazole ring respectively, with PDE4B protein. While the rest part of the molecule extended into the catalytic domain to block the access of cAMP and formed the foundation for inhibition of PDE4B. Compound 4c would be great promise as a lead compound for further study based on the preliminary structure-activity relationship and molecular modeling studies.

Rational design of conformationally constrained oxazolidinone-fused 1,2,3,4-tetrahydroisoquinoline derivatives as potential PDE4 inhibitors.

Improvement of subtype selectivity of an inhibitor's binding activity using the conformational restriction approach has become an effective strategy in drug discovery. In this study, we applied this approach to PDE4 inhibitors and designed a series of novel oxazolidinone-fused 1,2,3,4-tetrahydroisoquinoline derivatives as conformationally restricted analogues of rolipram. The bioassay results demonstrated the oxazolidinone-fused tetrahydroisoquinoline derivatives exhibited moderate to good inhibitory activity against PDE4B and high selectivity for PDE4B/PDE4D. Among these derivatives, compound 12 showed both the strongest inhibition activity (IC50=0.60µM) as well as good selectivity against PDE4B and good in vivo activity in animal models of asthma/COPD and sepsis induced by LPS. The primary SAR study showed that restricting the conformation of the catechol moiety in rolipram with the scaffold of oxazolidinone-fused tetrahydroisoquinoline could lead to an increase in selectivity for PDE4B over PDE4D, which was consistent with the observed docking simulation.

Synthesis and bioactivity of pyrazole and triazole derivatives as potential PDE4 inhibitors.

A series of pyrazole and triazole derivatives containing 5-phenyl-2-furan functionality were designed and synthesized as phosphodiesterase type 4 (PDE4) inhibitors. The bioassay results showed that title compounds exhibited considerable inhibitory activity against PDE4B and blockade of LPS-induced TNFα release. Meanwhile, the activity of compounds containing 1,2,4-triazole (series II) was higher than that of pyrazole-attached derivatives (series I). The primary structure-activity relationship study and docking results showed that the 1,2,4-triazole moiety of compound IIk played a key role to form integral hydrogen bonds and π-π stacking interaction with PDE4B protein while the rest part of the molecule extended into the catalytic domain to block the access of cAMP and formed the foundation for inhibition of PDE4. Compound IIk would be great promise as a hit compound for further study based on the preliminary structure-activity relationship and molecular modeling studies.