Pyrazole Carboxamide Derivatives Research Articles

Design, synthesis, and antifungal activity of novel pyrazole carboxamide derivatives containing benzimidazole moiety as potential SDH inhibitors.

To address the urgent need for new antifungal agents, a collection of novel pyrazole carboxamide derivatives incorporating a benzimidazole group were innovatively designed, synthesized, and evaluated for their efficacy against fungal pathogens. The bioassay results revealed that the EC50 values for the compounds A7 (3-(difluoromethyl)-1-methyl-N-(1-propyl-1H-benzo[d]imidazol-2-yl)-1H-pyrazole-4-carboxamide) and B11 (N-(1-(4-chlorobenzyl)-1H-benzo[d]imidazol-2-yl)-3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxamide) against B. cinerea were notably low to 0.79µg/mL and 0.56µg/mL, respectively, demonstrating the potency comparable to that of the control fungicide boscalid, which has an EC50 value of 0.60µg/mL. Noteworthy is the fact that in vivo tests demonstrated that A7 and B11 showed superior protective effects on tomatoes and strawberries against B. cinerea infection when juxtaposed with the commercial fungicide carbendazim. The examination through scanning electron microscopy revealed that B11 notably alters the morphology of the fungal mycelium, inducing shrinkage and roughening of the hyphal surfaces. To elucidate the mechanism of action, the study on molecular docking and molecular dynamics simulations was conducted, which suggested that B11 effectively interacts with crucial amino acid residues within the active site of succinate dehydrogenase (SDH). This investigation contributes a novel perspective for the structural design and diversification of potential SDH inhibitors, offering a promising avenue for the development of antifungal therapeutics.

QSAR, ADMET, and Molecular Docking of Pyrazole Carboxamide Derivatives as Potential Antifungals Against the Fungus Rhizoctonia solani

QSAR, ADMET, and Molecular Docking of Pyrazole Carboxamide Derivatives as Potential Antifungals Against the Fungus Rhizoctonia solani

Design and Synthesis of Pyrazole Carboxamide Derivatives as Selective Cholinesterase and Carbonic Anhydrase Inhibitors: Molecular Docking and Biological Evaluation.

The present study focused on the synthesis and characterization of novel pyrazole carboxamide derivatives (SA1-12). The inhibitory effect of the compounds on cholinesterases (ChEs; AChE and BChE) and carbonic anhydrases (hCAs; hCA I and hCA II) isoenzymes were screened as in vitro. These series compounds have been identified as potential inhibitors with a KI values in the range of 10.69±1.27-70.87±8.11 nM for hCA I, 20.01±3.48-56.63±6.41 nM for hCA II, 6.60±0.62-14.15±1.09 nM for acetylcholinesterase (AChE) and 54.87±7.76-137.20 ±9.61 nM for butyrylcholinesterase (BChE). These compounds have a more effective inhibition effect when compared to the reference compounds. In addition, the potential binding positions of the compounds with high affinity for ChE and hCAs were demonstrated by in silico methods. The results of in silico and in vitro studies support each other. As a result of the present study, the compounds with high inhibitory activity for metabolic enzymes, such as ChE and hCA were designed. The compounds may be potential alternative agents used as selective ChE and hCA inhibitors in the treatment of Alzheimer's disease and glaucoma.

Synthesis Characterization and In silico Anticancer Activity of D-ring Substituted Steroidal Pyrazolecarboxamides

In the present study, a few D ring substituted pyrazolecarboxamide derivatives were synthesized from the key intermediate 2,3-dihydrothiopyrano[3,2-c]thiochromen-4(5H)-one(2). In order to determine the structure-activity relationships, the pyrazolecarboxamide derivatives (7 a-m) were analyzed for anticancer activity and molecular docking studies were carried out against two cancer cell lines (HeLa and HCT116). The structures of all these compounds have treating been elucidated on the basis of their spectral data. We performed docking studies with the selective inhibitor proteins 4J96 (HeLa) and 5FGK (HCT 116). The binding energy of compound 7k (-9.6 Kcal/mol-HeLa and -10.1 Kcal/mol-HCT116) was found to be lower than that of all other pyrazole derivatives as well as standard doxorubicin. Furthermore, compound 7k was also found to be a promising anticancer agent against 4J96 and 5FGK cells, given its significant inhibitory effect [IC50=20.56μM (HeLa) and 18.19μM (HCT116)] compared to doxorubicin [IC50=21.32 μM (HeLa) and 19.58 μM (HCT116)]. Hence it is understood that, the pyrazole carboxamide derivatives (7k) has selectivity for inhibitor proteins having anticancer activity against HeLa and HCT116 compared with doxorubicin.

Design, synthesis, and molecular docking of pyrazole carboxamide derivatives bearing benzene sulfonamide tail as potential anticancer agents

Design, synthesis, and molecular docking of pyrazole carboxamide derivatives bearing benzene sulfonamide tail as potential anticancer agents

Discovery of N-Methoxy-(biphenyl-ethyl)-pyrazole-carboxamides as Novel Succinate Dehydrogenase Inhibitors.

Succinate dehydrogenase (SDH) inhibitor is one of the research hotspots for the development of fungicides. Herein, we describe the design and synthesis of N-methoxy-(biphenyl-ethyl)-pyrazole-carboxamide derivatives with enhanced fungicidal activity by employing fragment combination strategy. The SDH enzymatic activity was evaluated for 24 title compounds, and compound 7s was identified as the highest activity against porcine SDH with an IC50 value of 0.014 μM, 205-fold greater than that of fluxapyroxad. Furthermore, the greenhouse experiments showed that compound 7u exhibited potent fungicidal activity against wheat powdery mildew with an EC50 value of 0.633 mg/L, higher activity than fluxapyroxad and benzovindiflupyr. The computational results showed that the fluorine atom substituted on the pyrazole ring formed an extra dipolar-dipolar interaction with C_S42 and then increased the van der Waals interaction between the compound and SDH. The structural and mechanistic insights obtained from the present work will provide a valuable clue to developing novel SDH inhibitors.

Synthesis, antifungal activity and in vitro mechanism of novel 1-substituted-5-trifluoromethyl-1H-pyrazole-4-carboxamide derivatives

Inspired by the wide application of amides in plant pathogens, a series of novel 1-substituted-5-trifluoromethyl‑1H‑pyrazole-4-carboxamide derivatives were designed and synthesized. Bioassay results indicated that some target compounds exhibited excellent and broad-spectrum in vitro and certain in vivo antifungal activities. Among them, the in vitro EC50 values of Y13 against G. zeae, B. dothidea, F. prolifeatum and F. oxysporum were 13.1, 14.4, 13.3 and 21.4 mg/L, respectively. The in vivo protective activity of Y13 against G. zeae at 100 mg/L was 50.65%. SAR analysis revealed that the phenyl on the 1-position of the pyrazole ring was important for this activity. An antifungal mechanism study of Y13 against G. zeae demonstrated that this compound may disrupt the cell membrane of mycelium, thus inhibiting the growth of fungi. These mechanistic study results were inconsistent with those for traditional amides and may provide a novel view for deep study of this series of pyrazole carboxamide derivatives.

Design, synthesis, characterization, crystal structure, Hirshfeld surface analysis, DFT calculations, anticancer, angiogenic properties of new pyrazole carboxamide derivatives

The present study demonstrate the utility of a reverse ligand similarity based approach to identify potential targets for a new series of synthesized pyrazole carboxamides that shows potent anticancer activities against MCF-7 cells compared to other structurally related molecules and controls. Molecular docking studies revealed that the compound 5b interacted very strongly with human estrogen receptor with docking score of -8.82kcal/mol. In case of hERα-LBD, it interacted very well via hydrogen bond with Thr347 with docking score of -8.19 kcal/mol and very good binding with Asp351 via both hydrogen bonding and salt bridge. These results indicate that compound 5b act as better inhibitor for estrogen receptors comparable with the standard inhibitor tamoxifen. Further, ADMET studies reveal that the synthesized compounds have good ADME properties as compared with the data from 95% of drugs readily available in the market. The compound possesses three dimensional supramolecular self-assembly, in which N—H•••O bonds connects the molecules and build up two dimensional arrays, which are extended to 3D network through C—H•••Cg and C—Cl•••Cg interactions. The structure also exhibits π•••π stacking interactions, which contributes to the crystal packing. The Hirshfeld surface analysis was carried out to quantify the intermolecular interactions involved in the crystalline environment. We further optimized the molecular geometry of the compound 5d by DFT method with B3LYP hybrid functional and 6-311+G(d,p) basis set. The optimized structure is in good agreement with the experimental findings. The electrostatic potential map was plotted to understand the energy distribution and chemical reactive regions of the molecule.

Corrosion Inhibition of Mild Steel by newly Synthesized Pyrazole Carboxamide Derivatives in HCl Acid Medium: Experimental and Theoretical Studies

Corrosion inhibition of mild steel in hydrochloride acid solution was performed by a two pyrazole carboxamides named 5-(4-(dimethylamino)phenyl)-3-phenyl-4,5-dihydro-1H-pyrazole-1-carboxamide DPC-1 and (E)-5-(4-(dimethylamino)phenyl)-3-(4-(dimethylamino)styryl)-4,5-dihydro-1H-pyrazole-1-carboxamide DPC-2 using weight loss measurements, Tafel polarization curves and electrochemical impedance spectroscopies (EIS). The obtained results show that DPC-1 and DPC-2 are effective corrosion inhibitors in 1 mol l−1 HCl solution. The inhibition efficiency η (%) increases with the increase of inhibitors concentration to reach 84.56% at 4 × 10−4 mol l−1 and 80% at 1.6 × 10−4 mol l−1 for DPC-1 and DPC-2 at 303 K, respectively. The adsorption of synthesized pyrazoles on MS surface obeys the Langmuir adsorption isotherm. Tafel polarization curves reveal that DPC-1 and DPC-2 acts as a mixed-type inhibitor and EIS spectra show the increase of the transfer resistance with the inhibitors concentration. The SEM surface analysis shows the formation of protective organic film on steel surface. The relationship between the inhibition performance of pyrazoles and their structural parameters was investigated using DFT calculations.

Synthesis, characterization, and biological studies of some novel pyrazole carboxamide, pyridazine and thienopyridazine derivatives

The arylhydrazones 3a, b were prepared and reacted with various reagents to yield the target compounds pyrazoles 6a–f, 1,6-dihydropyridazine-3-carboxamide derivatives 9a,b and thieno[3,4-d]pyridazine-1-carboxamide derivatives 10a,b. The structures of the synthesized compounds were confirmed by various spectral data and elemental analyses. Furthermore, all target derivatives were tested for their antibacterial bioactivity against different types of Gram+‏ve and Gram-ve strains and for antifungal activity against two fungi micro-organisms by well diffusion method. Thus, the observed results showed that the 5-cyano-6-imino-N-(4-methoxyphenyl)-4-methyl-1-phenyl-1,6-dihydropyridazine-3-carboxamide (9b) displayed the best antimicrobial activity (with MIC values ranged from 0.49 ± 0.2 to 3.9 ± 0.6 μg/mL).

Novel Trifluoromethylpyrazole Acyl Thiourea Derivatives: Synthesis, Antifungal Activity and Docking Study

Background: In recent years, pyrazole carboxamide derivatives possessed excellent fungicidal activity. In the process of designing new fungicides, the carboxamide group was modified in order to find novel structure pyrazole carboxamide derivatives. Methods: Ten novel trifluoromethyl pyrazole acyl thiourea derivatives were designed and synthesized. In vivo fungicidal activities of these compounds were tested against Fusarium oxysporum, Corynespora mazei and Botrytis cinerea, respectively Results: Particularly compounds exhibited significant control effective at 100 mg/L. More importantly, some compounds showed the good control effective at 10 mg/L. Furthermore, docking was established to study the structure-activity relationship of the title compounds. Conclusion: It is possible that trifluoromethylpyrazole acyl thiurea derivatives, which possess good control effective against Botrytis cinerea, may become novel lead compounds for the development of fungicides with further structure modification.

Novel 4-pyrazole carboxamide derivatives containing flexible chain motif: design, synthesis and antifungal activity.

In recent years, carboxamide fungicides, targeting succinate dehydrogenase (SDH), have shown highly efficient and broad spectrum fungicidal activity. Structure-activity relationship (SAR) results for these commercial fungicides show that the carboxamide group was a key active group. This is useful information for the discovery of new pyrazole carboxamide derivatives with fungicidal activity. Twenty-seven novel pyrazole carboxamides were designed and synthesized. Their fungicidal activities against Gibberella zeae, Phytophthora infestans, Phytophthora capsici, Rhizoctonia solani, Alternaria solani, Botrytis cinerea, Fusarium oxysporum, Cercospora arachidicola, Sclerotinia sclerotiorum and Physalospora piricola were tested; derivatives possessed excellent inhibitory at 50 mg L-1 in particular. Furthermore, some pyrazole carboxamides exhibited remarkably high activities against Sclerotinia sclerotiorum in vitro with EC50 values of 2.04 to 15.2 μgmL-1 . In addition, some compounds also exhibited high activities against Physalospora piricola, Cercospora arachidicola and Phytophthora capsici. Inhibition activities against SDH proved that the designed analogues were effective at the enzyme level. The SAR of these pyrazole carboxamides was studied by using the docking method. It is possible that pyrazole carboxamides, which exhibit good activity against Sclerotinia sclerotiorum, can be further optimized as a lead compounds of carboxamide fungicides. © 2019 Society of Chemical Industry.

Design, synthesis, antifungal activity and 3D-QSAR study of novel pyrazole carboxamide and niacinamide derivatives containing benzimidazole moiety

The synthesized pyrazole carboxamide and niacinamide derivatives containing a benzimidazole moiety showed effective inhibition of the fungus B. cinereal growth. The 3D-QSAR model was built and revealed fine predictive ability.

Design, Synthesis, Antifungal and Antibacterial Activities of N‐phenyl and N‐pyridinyl‐5‐(trifluoromethyl)‐pyrazole‐4‐carboxamide Derivatives

A series of N‐phenyl and N‐pyridinyl‐5‐(trifluoromethyl)‐pyrazole carboxamide derivatives (T1–T25) were designed and synthesized. Bioassay results indicated that antifungal and antibacterial activities of title compounds could be obviously improved by placing trifluoromethyl on the 5‐position of the pyrazole ring and substituted 4‐pyridinyl at the amine side of the amide bond. The EC50 values of T3 against Gibberella zeae, Cytospora mandshurica, and Fusarium oxysporum were 14.7, 21.1, and 32.7 μg/mL, respectively, better than hymexazol (30.2, 47.3, and 42.5 μg/mL) and carboxin (34.2, >200, and >200 μg/mL). And the EC50 values of T6, T11, T12, T15, T18, T19, T23, and T25 against rice bacterial leaf blight were 17.0, 21.8, 21.9, 18.6, 16.8, 25.9, 9.4, and 24.4 μg/mL, respectively, much better than bismerthiazol (70.5 μg/mL).

Design, synthesis, DFT study and antifungal activity of the derivatives of pyrazolecarboxamide containing thiazole or oxazole ring

Pyrazolecarboxamide fungicides are one of the most important classes of agricultural fungicides, which belong to succinodehydrogenase inhibitors (SDHIS). To discover new pyrazolecarboxamide analogues with broad spectrum and high activity, a class of new compounds of pyrazole carboxamide derivatives containing thiazole or oxazole ring were designed by scaffold hopping and bioisosterism, and 36 pyrazole carboxamide derivatives with antifungal activity were synthesized. Those compounds were evaluated against five phytopathogenic fungi, Gibberella zeae, Phytophythora capsici, Sclerotonia sclerotiorum, Erysiphe graminis and Puccinia sorghi. The results indicated that most of the compounds displayed good fungicidal activities, especially against E. graminis. Theoretical calculations were carried out at the B3LYP/6-31G (d, p) level and the full geometry optimization was carried out using the 6-31G (d, p) basis set, and the frontier orbital energy, atomic net charges, molecular docking were discussed, and the structure-activity relationships were also studied.

Synthesis, Docking and Evaluation of Novel Pyrazole Carboxamide Derivatives as Multifunctional Anti-Alzheimer's Agents

Synthesis, Docking and Evaluation of Novel Pyrazole Carboxamide Derivatives as Multifunctional Anti-Alzheimer's Agents

Structure-Based Discovery of Potential Fungicides as Succinate Ubiquinone Oxidoreductase Inhibitors.

A series of diphenyl ether-containing pyrazole-carboxamide derivatives was designed and synthesized as new succinate ubiquinone oxidoreductase (SQR) inhibitors. This highly potent molecular scaffold was developed from a moderately activie hit 3, obtained from our previous pharmacophore-linked fragment virtual screening (PFVS) method. The results of greenhouse tests indicated that some analogues showed good SQR inhibitory activity, with promising fungicidal activity against Rhizoctonia solani and Sphaerotheca fuliginea at a dosage of 200 mg/L. Most surprisingly, compound 62 showed the highest SQR inhibitory activity with a Ki value of 0.081 μM, about 4-fold more potent than penthiopyrad (Ki = 0.307 μM). In addition, compounds 43 and 62 displayed excellent fungicidal activity even at a dosage as low as 6.25 mg/L, which was superior to thifluzamide. Moreover, compound 62 exhibited excellent protection effect against R.solani and provided about 81.2% protective control efficancy after 21 days with two sprayings. The present work indicated that these two compounds could be used as potential agricultural fungicides targeting SQR.

Synthesis and in vivo nematocidal evaluation of novel 3-(trifluoromethyl)-1H-pyrazole-4-carboxamide derivatives

Pyrazole carboxamide derivatives represent an important class of fungicides in agrochemicals. To find more novel structural pyrazole carboxamides, a novel series of 3-(trifluoromethyl)-1H-pyrazole-4-carboxamide compounds were prepared from ethyl 4,4,4-trifluoroacetoacetate and triethyl orthoformate as starting materials. All the products were characterized by Fourier transform infrared spectroscopy, 1H nuclear magnetic resonance (NMR), 13C NMR, 19F NMR and mass spectrography. The bioassay results showed these fluorine-containing pyrazole carboxamides have a weak fungicidal activity but some of them exhibit a good nematocidal activity against M. incognita.

Synthesis, Nematocidal Activity and Docking Study of Novel Chiral 1‐(3‐Chloropyridin‐2‐yl)‐3‐(difluoromethyl)‐1H‐pyrazole‐4‐carboxamide Derivatives

A novel series of pyrazole carboxamide derivatives had been designed, synthesized and some of them exhibited good nematocidal activity.

Design, Synthesis, DFT Study and Antifungal Activity of Pyrazolecarboxamide Derivatives.

A series of novel pyrazole amide derivatives were designed and synthesized by multi-step reactions from phenylhydrazine and ethyl 3-oxobutanoate as starting materials, and their structures were characterized by NMR, MS and elemental analysis. The antifungal activity of the title compounds was determined. The results indicated that some of title compounds exhibited moderate antifungal activity. Furthermore, DFT calculations were used to study the structure-activity relationships (SAR).