Discovery of novel multi-substituted benzo-indole pyrazole schiff base derivatives with antibacterial activity targeting DNA gyrase.

The design and synthesis of novel multi-substituted benzo-indole pyrazole Schiff base derivatives of potent DNA gyrase inhibitory activity were the main aims of this study. All the novel synthesized compounds were examined for their antibacterial activities against Staphylococcus aureus, Listeria monocytogenes, Escherichia coli, and Salmonella. In addition, we selected 20 compounds for the in vitro antibacterial activities assay of 6 drug-resistant bacteria strains. The result revealed compound 8I-w exhibited excellent antibacterial activity against 4 drug-resistant E. coli bacteria strains with IC50 values of 7.0, 17.0, 13.5, and 1.0 µM, respectively. In vitro enzyme inhibitory assay showed that compound 8I-w displayed potent inhibition against DNA gyrase with IC50 values of 0.10 µM. The molecular docking model indicated that compounds 8I-w can bind well to the DNA gyrase by interacting with various amino acid residues. This study demonstrated that the compound 8I-w can act as the most potent DNA gyrase inhibitor in the reported series of compounds and provide valuable information for the commercial DNA gyrase inhibiting bactericides.

Novel coumarin-thiazolyl ester derivatives as potential DNA gyrase Inhibitors: Design, synthesis, and antibacterial activity.

The design and synthesis of novel coumarin-thiazolyl ester derivatives of potent DNA gyrase inhibitory activity were the main aims of this study. All the novel synthesized compounds were examined for their antibacterial activity against Staphylococcus aureus, Listeria monocytogenes, Escherichia coli and Salmonella. Compound 8p exhibited excellent antibacterial activity against four bacteria strains with MIC values of 0.05, 0.05, 8, and 0.05 µg/mL, respectively. In vitro drug-resistant bacterial inhibition experiments indicated that compound 8p exhibited the best bacteriostatic effect in the selected compounds and four positive control drugs with MIC values of 4 µg/mL. In vitro enzyme inhibitory assay showed that compound 8p exhibited potent inhibition against DNA gyrase with IC50 values of 0.13 µM. The molecular docking model indicated that compounds 8p can bind well to the DNA gyrase by interacting with amino acid residues. This study demonstrated that the compound 8p can act as the most potent DNA gyrase inhibitor in the reported series of compounds and provide valuable information for the commercial DNA gyrase inhibiting bactericides.

A bioactivity-oriented modification strategy for SDH inhibitors with superior activity against fungal strains.

In this work, a total of 36 novel 5-(nicotinamido)-1-phenyl-1H-pyrazole-4-carboxylic acid derivatives were designed and synthesized successfully by introducing a carboxyl group based on the N-(1-(4-chlorophenyl)-4-cyano-1H-pyrazol-5-yl)-6-methoxynicotinamide. Among them, the growth inhibition assays on agar plates showed that compound 5IV-d(5-(2-chloronicotinamido)-1-(p-tolyl)-1H-pyrazole-4-carboxylic acid) exhibited the significant antifungal activity against four important fruit and main crop disease fungi (i.e., Valsa mali Miyabe et Yamada, Botryosphaeria dothidea, Helminthosporium maydis and Rhizoctonia cerealis) with EC50 values of 22.6, 14.5, 17.6 and 18.2 µM, respectively. In addition, 5IV-d showed the excellent inhibitory effect against SDH enzymes with IC50 values ranging from 9.4 to 15.6 µM. In vivo bioassay and molecular docking were applied to explore the potential in practical application and combination of modified structure and SDH. The results of structure-activity relationships indicates that the methoxy substitution at the benzene ring attached to the pyrazole ring and a wide variety of substituents could be responsible for the promising antifungal efficacy of the designed compounds. This study demonstrated that the compound 5IV-d can act as the most potent SDH inhibitor in the reported series of compounds.

Design, synthesis and biological evaluation of novel flavone Mannich base derivatives as potential antibacterial agents.

A series of novel Mannich base derivatives of flavone containing benzylamine moiety was synthesized using the Mannich reaction. The results of antifungal activity are not ideal, but its antifungal effect has a certain increase compared to flavonoids. After that, four bacteria were used to test antibacterial experiments of these compounds; compound 5g (MIC = 0.5, 0.125 mg/L) showed significant inhibitory activity against Staphylococcus aureus and Salmonella gallinarum compared with novobiocin (MIC = 2, 0.25 mg/L). Compound 5s exhibited broad spectrum antibacterial activity (MIC = 1, 0.5, 2, 0.05 mg/L) against four bacteria. The selected compounds 5g and 5s exhibit potent inhibition against Topo II and Topo IV with IC50 values (0.25-16 mg/L). Molecular docking model showed that the compounds 5g and 5s can bind well to the target by interacting with amino acid residues. It will provide some valuable information for the commercial antibacterial agents.

Discovery of Novel Triazole-Containing Pyrazole Ester Derivatives as Potential Antibacterial Agents.

To develop new antibacterial agents, a series of novel triazole-containing pyrazole ester derivatives were designed and synthesized and their biological activities were evaluated as potential topoisomerase II inhibitors. Compound 4d exhibited the most potent antibacterial activity with Minimum inhibitory concentration (MIC) alues of 4 µg/mL, 2 µg/mL, 4 µg/mL, and 0.5 µg/mL against Staphylococcus aureus, Listeria monocytogenes, Escherichia coli, and Salmonella gallinarum, respectively. The in vivo enzyme inhibition assay 4d displayed the most potent topoisomerase II (IC50 = 13.5 µg/mL) and topoisomerase IV (IC50 = 24.2 µg/mL) inhibitory activity. Molecular docking was performed to position compound 4d into the topoisomerase II active site to determine the probable binding conformation. In summary, compound 4d may serve as potential topoisomerase II inhibitor.

Design, Synthesis and Biological Evaluation of Novel Pyrazole Sulfonamide Derivatives as Potential AHAS Inhibitors.

Acetohydroxy acid synthase (AHAS; EC 2.2.1.6, also referred to as acetolactate synthase, ALS) has been considered as an attractive target for the design of herbicides. In this work, an optimized pyrazole sulfonamide base scaffold was designed and introduced to derive novel potential AHAS inhibitors by introducing a pyrazole ring in flucarbazone. The results of in vivo herbicidal activity evaluation indicates compound 3b has the most potent activity with rape root length inhibition values of 81% at 100 mg/L, and exhibited the best inhibitory ability against Arabidopsis thaliana AHAS. With molecular docking, compound 3b insert into Arabidopsis thaliana AHAS stably by an H-bond with Arg377 and cation-π interactions with Arg377, Trp574, Tyr579. This study suggests that compound 3b may serve as a potential AHAS inhibitor which can be used as a novel herbicides and provides valuable clues for the further design and optimization of AHAS inhibitors.

Design, synthesis, and antifungal activity of novel cinnamon-pyrazole carboxamide derivatives.

Hit, Lead & Candidate Discovery To discover succinate dehydrogenase inhibitors with a novel structure, we introduced cinnamic acid structure to optimize the lead structure 1 and synthesized four series of cinnamon-pyrazole carboxamide derivatives. The bioassay data showed that compounds (E)-N-(1-[4-chlorophenyl]-4-cyano-1H-pyrazol-5-yl)-3-(2-fluorophenyl) acrylamide (5III-d) and (E)-3-(2-chlorophenyl)-N-(1-[4-chlorophenyl]-4-cyano-1H-pyrazol-5-yl) acrylamide (5III-f) showed the significant antifungal activity against three fungi. In addition, 5III-d and 5III-f exhibited the excellent inhibitory effect against succinate dehydrogenase (SDH) enzymes with IC50 values ranging from 19.4 to 28.7 µM. The study demonstrates that the chlorine substituent group is present on both the phenyl and pyrazole rings that have a very good effect on the antifungal effect, and the compounds 5III-d and 5III-f can act as potential SDH inhibitors (SDHI) and throw a sprat for a new generation of SDHI.

Discovery of N-(benzyloxy)-1,3-diphenyl-1H-pyrazole-4-carboxamide derivatives as potential antiproliferative agents by inhibiting MEK.

Mitogen activated protein kinase (MAPK) signal transduction pathway has been proved to play an important role in tumorigenesis and cancer development. MEK inhibitor has been demonstrated significant clinical benefit for blocking MAPK pathway activation and possibly could block reactivation of the MAPK pathway at the time of BRAF inhibitor resistance. Twenty N-(benzyloxy)-1,3-diphenyl-1H-pyrazole-4-carboxamide derivatives have been designed and synthesized as MEK inhibitors, and their biological activities were evaluated. Among these compounds, compound 7b showed the most potent inhibitory activity with IC50 of 91nM for MEK1 and GI50 value of 0.26µM for A549 cells. The SAR analysis and docking simulation were performed to provide crucial pharmacophore clues that could be used in further structure optimization.

Design, Synthesis and Biological Evaluation of α-Aminophosphonate Derivatives Containing a Pyrazole Moiety.

Acetylcholinesterase (AChE) is a key enzyme which present in the central nervous system of living organisms. Organophosphorus pesticides (OPs) that serve as insecticides are AChE inhibitors which have been used widely in agriculture. A series of novel OPs containing pyrazole moiety have been designed and synthesized. The biological evaluation indicated compound 4e appeared 81% larvicidal activity against Plutella xylostella at the concentration of 0.1 mg/L and the inhibition of AChE by compound 4e was distinctly enhanced with the increasing doses. Molecular docking of compound 4e into the three dimensional X-ray structure of the Drosophila melanogaster AChE (DmAChE, PDB code: 1QO9) was carried out utilizating the Discovery Studio (DS), the binding model revealed that the title structure was tightly embedded in the binding sites of DmAChE. Therefore, we suggest that compound 4e may serve as a novel AChE inhibitor that can be utilized as a new insecticidal drug.

Design, synthesis and anti-tobacco mosaic virus (TMV) activity of 5-chloro-N-(4-cyano-1-aryl-1H-pyrazol-5-yl)-1-aryl-3-methyl-1H-pyrazole-4-carboxamide derivatives.

A series of novel pyrazole amide derivatives 3a-3p which take TMV PC protein as the target has been designed and synthesized by the reactions of 5-chloro-1-aryl-3-methyl-1H-pyrazole-4-carboxylic acids with 5-amino-1-aryl-1H-pyrazole-4-carbonitriles. All the compounds were characterized by 1H-NMR, mass spectroscopy and elemental analysis. Preliminary bioassays indicated that all the compounds acted against the tobacco mosaic virus (TMV) with different in vivo and in vitro modes at 500 µg/mL and were found to possess promising activity. Especially, compound 3p showed the most potent biological activity against tobacco mosaic virus (TMV) compared to ningnanmycin, and a molecular docking study was performed and the binding model revealed that the pyrazole amide moiety was tightly embedded in the binding sites of TMV PC (PDB code: 2OM3).

Identification of novel 3,5-diarylpyrazoline derivatives containing salicylamide moiety as potential anti-melanoma agents.

There is an accumulating body of experimental evidences validating oncogenic BRAF(V600E) as a therapeutic target and offering opportunities for anti-melanoma drug development. Encouraged by the positive results of pyrazole derivatives as BRAF(V600E) inhibitors, we sought to design diverse novel potential BRAF(V600E) inhibitors as antitumor agents based on pyrazole skeleton. In silico and in vitro screening of our designed pyrazole derivatives has identified Hit 1 as BRAF(V600E) inhibitor. Based on its structure and through further structure modification, compound 25, which exhibited the most potent inhibitory activity with an IC(50) value of 0.16 µM for BRAF(V600E) and GI(50) value of 0.24 µM for mutant BRAF-dependent melanoma cells, was obtained. The 3D-QSAR models and the molecular docking simulation were introduced to analyze the structure-activity relationship.

Design, synthesis, biological evaluation and molecular modeling of novel 1,3,4-oxadiazole derivatives based on Vanillic acid as potential immunosuppressive agents.

In present study, a series of novel 1,3,4-oxadiazole derivatives have been designed, synthesized and purified. All of these compounds are reported for the first time, the chemical structures of these compounds were confirmed by means of (1)H NMR, ESI-MS and elemental analyses. Besides, we evaluated their immunosuppressive activity. Most of these synthesized compounds were proved to have potent immunosuppressive activity and low toxicity. Among them, the bioassay results demonstrated that compounds 5c, 5n, 5p, 5o, 6f and 6g exhibited immunosuppressive activities with IC(50) concentration range from 1.25µM to 7.60 µM against the T cells, and the IC(50) of positive control (csa) is 2.12 µM. Moreover, all the title compounds were assayed for PI3K/AKT signaling pathway inhibition using the ELISA assay. We examined the compounds with potent inhibitory activities against IL-1, IL-6 and IL-10 released in ConA-simulated mouse lymph node cells. The results showed compounds 5o and 6f displayed the most potential biological activity against T cells (IC(50)=1.25 µM and 4.75 µM for T cells). The preliminary mechanism of compound 5o inhibition effects was also detected by flow cytometry (FCM). The results of apoptosis and ELISA assay demonstrated that the immunosuppressive activity of compounds 5o and 6f against T cells may be mediated by the inhibition of PI3Kγ/AKT signaling pathway. Molecular docking was performed to position compounds 5o and 6f into PI3Kγ binding site in order to indicate the potential target.

Novel coumarin-pyrazole carboxamide derivatives as potential topoisomerase II inhibitors: Design, synthesis and antibacterial activity.

The identification of novel Topoisomerase II (Topo II) inhibitors is one of the most attractive directions in the field of bactericide research and development. In our ongoing efforts to pursue the class of inhibitors, six series of 70 novel coumarin-pyrazole carboxamide derivatives were designed and synthesized. As a result of the evaluation against four destructive bacteria, including Staphylococcus aureus, Listeria monocytogenes, Escherichia coli and Salmonella. Compound 8III-k (MIC = 0.25 mg/L) showed considerable inhibitory activity than ciprofloxacin (MIC = 0.5 mg/L) against Escherichia coli and 8V-c (MIC = 0.05 mg/L) exhibited excellent antibacterial activity than ciprofloxacin (MIC = 0.25 mg/L) against Salmonella. The selected compounds (8III-k, 8V-c and 8V-k) exhibit potent inhibition against Topo II and Topo IV with IC50 values (9.4-25 mg/L). Molecular docking model showed that the compounds 8V-c and 8V-k can bind well to the target by interacting with amino acid residues. It will provide some valuable information for the commercial Topo II inhibiting bactericides.

Design, synthesis and biological evaluation of novel nicotinamide derivatives bearing a substituted pyrazole moiety as potential SDH inhibitors.

BACKGROUND: Succinate dehydrogenase (SDH) plays an important role in the Krebs cycle, which is considered as an attractive target for development of succinate dehydrogenase inhibitors (SDHIs) based on antifungal agents. Thus, in order to discover novel molecules with high antifungal activities, SDH as the target for a series of novel nicotinamide derivatives bearing substituted pyrazole moieties were designed and synthesised via a one-pot reaction. RESULTS: The biological assay data showed that compound 3 l displayed the most potent antifungal activity with EC50 values of 33.5 and 21.4 µm against Helminthosporium maydis and Rhizoctonia cerealis, respectively. Moreover, 3 l exhibited the best inhibitory ability against SDH enzymes. The results of docking simulation showed that 3 l was deeply embedded into the SDH binding pocket, and the binding model was stabilised by a cation-π interaction with Arg 43, Tyr 58 and an H-bond with Trp 173. CONCLUSION: The study suggests that the pyrazole nicotinamide derivative 3 l may serve as a potential SDHI that can be used as a novel antifungal agent, and provides valuable clues for the further design and optimisation of SDH inhibitors. © 2016 Society of Chemical Industry.

(E)-1,3-diphenyl-1H-pyrazole derivatives containing O-benzyl oxime moiety as potential immunosuppressive agents: Design, synthesis, molecular docking and biological evaluation.

A series of novel (E)-1,3-diphenyl-1H-pyrazole derivatives containing O-benzyl oxime moiety were firstly synthesized and their immunosuppressive activities were evaluated. Among all the compounds, 4n exhibited the most potent inhibitory activity (IC50 = 1.18 µM for lymph node cells and IC50 = 0.28 µM for PI3Kγ), which was comparable to that of positive control. Moreover, selected compounds were tested for their inhibitory activities against IL-6 released in ConA-simulated mouse lymph node cells, 4n exhibited the most potent inhibitory ability. Furthermore, in order to study the preliminary mechanism of the compounds with potent inhibitory activity, the RT-PCR experiment was performed to assay the effect of selected compounds on mRNA expression of IL-6. Among them, compound 4n strongly inhibited the expression of IL-6 mRNA.

Discovery of novel dinitrobenzotrifluoride containing o-hydroxybenzylamine derivatives as potential antibacterial agents.

The continual emergence of bacterial resistance problems to current clinical drugs has brought a severe threat against human being's health; and the development of novel antimicrobial agents for selectively inhibiting the constantly evolved bacterial targets has also been continually promoted, with challenging processes like marathon race. FabH, which initiated the fatty acid biosynthesis cycle, provided considerable new opportunities in novel antibacterial drug discovery. Based on our previous findings that o-hydroxybenzylamine derivatives demonstrated potent FabH inhibitory and antimicrobial activities, computer-assistant drug design was introduced and then a series of novel nitrobenzotrifluoride-containing ohydroxybenzylamine derivatives (3a-3x) was designed and synthesized. Most of them were more potent than the corresponding urea analogues, with compound 3d being the most potent member. Furthermore, the structure-activity relationship of all synthesized o-hydroxybenzylamine derivatives as FabH inhibitors was studied, and inhibitory potency of top antimicrobial compounds against the aminoacylation of S. aureus tyrosyl-tRNA synthetase was also evaluated.

Synthesis, biological evaluation and molecular docking studies of pyrazole derivatives coupling with a thiourea moiety as novel CDKs inhibitors.

It was discovered that a number of cyclin dependent kinase inhibitors containing the pyrazole core structure exhibited high inhibitory potency against broad-range CDKs and corresponding anti-proliferative activities. This information guided us to design and synthesize a series of 1,3-diphenyl-N-(phenylcarbamothioyl)-1H-pyrazole-4-carboxamide derivatives (5a-10d), and evaluate their biological activities as CDKs inhibitors. Among all the synthesized compounds, compound 10b inhibited CDK2 with an IC50 value of 25 nM, counteracting tumor cell proliferation of three cancer cell lines (H460, MCF-7, A549) in the micromolar range (from 0.75 µM to 4.21 µM), In addition, flow cytometry indicated that compound 10b could induce cycle G0/G1 phase arrest in A549 cells with a dose dependent. Taken together, compound 10b could be selected for further preclinical evaluation.