Synthesis and Anti-Trypanosoma cruzi Activity of New Pyrazole-Thiadiazole Scaffolds.

Chagas disease, a silent but widespread disease that mainly affects a socioeconomically vulnerable population, lacks innovative safe drug therapy. The available drugs, benznidazole and nifurtimox, are more than fifty years old, have limited efficacy, and carry harmful side effects, highlighting the need for new therapeutics. This study presents two new series of pyrazole-thiadiazole compounds evaluated for trypanocidal activity using cellular models predictive of efficacy. Derivatives 1c (2,4-diCl) and 2k (4-NO2) were the most active against intracellular amastigotes. Derivative 1c also showed activity against trypomastigotes, with the detachment of the flagellum from the parasite body being a predominant effect at the ultrastructural level. Analogs have favorable physicochemical parameters and are predicted to be orally available. Drug efficacy was also evaluated in 3D cardiac microtissue, an important target tissue of Trypanosoma cruzi, with derivative 2k showing potent antiparasitic activity and a significant reduction in parasite load. Although 2k potentially reduced parasite load in the washout assay, it did not prevent parasite recrudescence. Drug combination analysis revealed an additive profile, which may lead to favorable clinical outcomes. Our data demonstrate the antiparasitic activity of pyrazole-thiadiazole derivatives and support the development of these compounds using new optimization strategies.

Development of novel pyrazole-1,2,4-triazole derivatives as tyrosinase inhibitors: Design, preparation, mechanism of action and anti-browning application.

Tyrosinase (Polyphenol oxidase), a key enzyme in enzymatic browning, is an attractive target for developing new anti-browning agents in the food industry. In this work, twenty pyrazole-1,2,4-triazole derivatives (3a-3n, 4a-4f) were synthesized and tested in vitro, most of compounds showed potent anti-tyrosinase activity. Of these, 3c (IC50 = 1.02 ± 0.08 µM) was found to be 14 folds stronger than kojic acid (IC50 = 14.74 ± 1.23 µM) and behaved as a mixed type inhibitor. Besides, the disappeared peak of dopaquinone in the HPLC assay intuitively validated the inhibitory effect of 3c. Copper ions chelating, fluorescence quenching and molecular docking assays showed that coordination with copper is the key to play a role. Furthermore, 3c exhibited excellent anti-browning ability for the Rosa roxburghii Tratt, the non-enzymatic browning experiment showed that 3c could prevent browning in non-enzymatic ways. It is suggested that these derivatives could serve as the leading compounds to find more efficient anti-browning agents in the future.

Synthesis, DFT, and in silico biological evaluation of chalcone bearing pyrazoline ring against Helicobacter pylori receptors.

Peptic ulcer disease (PUD), often caused by Helicobacter pylori infection, is a prevalent gastrointestinal condition characterized by the erosion of the gastric or duodenal mucosal lining. H. pylori adheres to gastric epithelial cells, secreting toxins and disrupting the stomach's defenses. H. pylori relies on various receptors to establish infection, making these molecules attractive therapeutic targets. This study aimed to develop novel anti-ulcer compounds by combining benzothiazole, pyrazoline, and chalcone pharmacophores. A series of chalcone derivatives 4a-c were synthesized via Claisen-Schmidt condensation and characterized using spectroscopic techniques such as FT-IR, NMR and elemental analysis. The DFT calculations, using B3LYP method with 6-311G basis set, revealed the p-tolyl derivative 4b exhibited the highest thermal stability while the p-bromophenyl derivative 4c showed the lowest stability but highest chemical reactivity. The HOMO-LUMO energy gaps as well as the dipole moments decreased in the order: 4b > 4a > 4c, reflecting a similar reactivity trend. Molecular docking showed ligands 4a-c bound effectively to the H. pylori urease enzyme, with docking scores from -5.3862 to -5.7367 kcal/mol with superior affinity over lansoprazole. Key interactions involved hydrogen bonds and hydrophobic pi-hydrogen bonds with distances ranging 3.46-4.34 Å with active site residues ASN666, SER714 and ASN810. The combined anti-inflammatory, antimicrobial, and H. pylori anti-adhesion properties make these novel chalcones promising PUD therapeutic candidates.

Design, synthesis and biological evaluation of novel pyrazole-based compounds as potential chemotherapeutic agents.

Aim: Design and synthesis of pyrazole-based chemotherapeutic agents. Materials & methods: A series of novel diphenyl pyrazole-chalcone derivatives were synthesized and assessed for their cytotoxic activities against 14 cancer cell lines and their antimicrobial activities against MRSA and Escherichia coli along with their safety using HSF normal cell line. Results & conclusion: Majority of the compounds showed moderate-to-significant anticancer activity with selective high percentage inhibition (>80%) against HNO-97 while being nontoxic toward normal cells. Compounds 6b and 6d were the most potent congeners with IC50 of 10 and 10.56 µM respectively. The synthesized compounds exhibited moderate to potent antimicrobial activities. Interestingly, compound 6d exhibited a minimum inhibitory concentration of 15.7 µg/ml against MRSA; and a minimum inhibitory concentration of 7.8 µg/ml versus E. coli.

[Box: see text].

Multicomponent syntheses of pyrazoles via (3 + 2)-cyclocondensation and (3 + 2)-cycloaddition key steps.

Pyrazoles are rarely found in nature but are traditionally used in the agrochemical and pharmaceutical industries, while other areas of use are also actively developing. However, they have also found numerous other applications. The search for new and efficient syntheses of these heterocycles is therefore highly relevant. The modular concept of multicomponent reactions (MCR) has paved a broad alley to heteroaromatics. The advantages over traditional methods are the broader scope and increased efficiency of these reactions. In particular, traditional multistep syntheses of pyrazoles have considerably been extended by MCR. Progress has been made in the cyclocondensation of 1,3-dielectrophiles that are generated in situ. Limitations in the regioselectivity of cyclocondensation with 1,3-dicarbonyls were overcome by the addition-cyclocondensation of α,ß-unsaturated ketones. Embedding 1,3-dipolar cycloadditions into a one-pot process has additionally been developed for concise syntheses of pyrazoles. The MCR strategy also allows for concatenating classical condensation-based methodology with modern cross-coupling and radical chemistry, as well as providing versatile synthetic approaches to pyrazoles. This overview summarizes the most important MCR syntheses of pyrazoles based on ring-forming sequences in a flashlight fashion.

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 0.79 µg/mL and 0.56 µg/mL, respectively, demonstrating the potency comparable to that of the control fungicide boscalid, which has an EC50 value of 0.60 µg/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.

Ferrocenyl Azoles: Versatile N-Containing Heterocycles and their Anticancer Activities.

The medicinal chemistry of ferrocene has gained its momentum after the discovery of biological activities of ferrocifen and ferroquine. These ferrocenyl drugs have been designed by replacing the aromatic moiety of the organic drugs, tamoxifen and chloroquine respectively, with a ferrocenyl unit. The promising biological activities of these ferrocenyl drugs have paved a path to explore the medicinal applications of several ferrocenyl conjugates. In these conjugates, the ferrocenyl moiety has played a vital role in enhancing or imparting the anticancer activity to the molecule. The ferrocenyl conjugates induce the cytotoxicity by generating reactive oxygen species and thereby damaging the DNA. In medicinal chemistry, the five membered nitrogen heterocycles (azoles) play a significant role due to their rigid ring structure and hydrogen bonding ability with the biomolecules. Several potent drug candidates with azole groups have been in use as chemotherapeutics. Considering the importance of ferrocenyl moiety and azole groups, several ferrocenyl azole conjugates have been synthesized and screened for their biological activities. Hence, in the view of a wide scope in the development of potent drugs based on ferrocenyl azole conjugates, herein we present the details of synthesis and the anticancer activities of ferrocenyl compounds bearing azole groups such as imidazole, triazoles, thiazole and isoxazoles.

New 1,3-diphenyl-1H-pyrazol-5-ols as anti-methicillin resistant Staphylococcus aureus agents: Synthesis, antimicrobial evaluation and in silico studies.

In the present work, two hybrid series of pyrazole-clubbed pyrimidine and pyrazole-clubbed thiazole compounds 3-21 from 4-acetyl-1,3-diphenyl-1H-pyrazole-5(4H)-ole 1 were synthesized as novel antimicrobial agents. Their chemical structures were thoroughly elucidated in terms of spectral analyses such as IR, 1H NMR, 13C NMR and mass spectra. The compounds were in vitro evaluated for their antimicrobial efficiency against various standard pathogen strains, gram -ive bacteria (Pseudomonas aeruginosa, Klebsiella pneumonia), gram + ive bacteria (MRSA, Bacillus subtilis), and Unicellular fungi (Candida albicans) microorganisms. The ZOI results exhibited that most of the tested molecules exhibited inhibition potency from moderate to high. Where compounds 7, 8, 12, 13 and 19 represented the highest inhibition potency against most of the tested pathogenic microbes comparing with the standard drugs. In addition, the MIC results showed that the most potent molecules 7, 8, 12, 13 and 19 showed inhibition effect against most of the tested microbes at low concentration. Moreover, the docking approach of the newly synthesized compounds against DNA gyrase enzyme was performed to go deeper into their molecular mechanism of antimicrobial efficacy. Further, computational investigations to calculate the pharmacokinetics parameters of the compounds were performed. Among them 7, 8, 12, 13 and 19 are the most potent compounds revealed the highest inhibition efficacy against most of the tested pathogenic microbes comparing with the standard drugs.

DMF-DMA catalyzed Synthesis, molecular docking, in-vitro, in-silico design, and binding free energy studies of novel thiohydantoin derivatives as antioxidant and antiproliferative agents targeting EGFR tyrosine kinase and aromatase cytochrome P450 enzyme.

A set of novels 2-thiohydantoin derivatives were synthesized and enaminone function was discussed at position 5 using DMFDMA catalyst which result in formation of pyrazole, isoxazole, benzoxazepine by using reagents such as hydrazine, hydroxylamine and 2-aminothiophenol. These newly synthesized compounds were evaluated for their antioxidant and antiproliferative activity. In vitro studies on the effect of 2-thiohydantoin on scavenging 2,2-diphenyl-1-picrylhydrazyl radical (DPPH•) confirmed the free radical scavenging and antioxidant activity of 2-thiohydantoin. The synthesized compounds show significant antioxidant activity. The in vitro antitumor activity of 2-thiohydantoin on MCF7 (breast) and PC3 cells (prostate) was evaluated using MTT assay. Some of the synthesized compounds show significant to moderate antiproliferative properties compared to reference drug erlotinib. Among all, compound 4a exhibit potent antitumor properties against MCF7 and PC3 cancer cell lines with IC50 = 2.53 ± 0.09 /ml & with IC50 = 3.25 ± 0.12 µg/ml respectively and has potent antioxidant activity with IC50 = 10.04 ± 0.49 µg/ml.

Regioselective Synthesis of Cycloalkane-fused Pyrazolo[4,3-e]pyridines through Tandem Reaction of 5-aminopyrazoles, Cyclic Ketones and Electron-rich Olefins.

BACKGROUND: Pyrazolopyridines are interesting fused heterocyclic pharmacophores that combine pyrazole and pyridine; two privileged nuclei extensively studied and with a wide range of applications. They can be obtained by a broad variety of synthetic methods among which multicomponent reactions have gained importance, especially from 5-aminopyrazoles and dielectrophilic reagents. However, the search for new approaches more in tune with sustainable chemistry and the use of unconventional heating in three-component synthesis are open and highly relevant study fields. METHODS: A novel, practical and efficient three-component synthesis of cycloalkane-fused pyrazolo[ 4,3-e]pyridines was developed through a tandem reaction of 5-aminopyrazoles, cyclic ketones and electron-rich olefins, using microwave induction in perfluorinated solvent and iodine as catalyst. RESULTS: The microwave-induced three-component approach applied in this work promoted the construction of 10 new pyrazolopyridines with high speed and excellent control of regioselectivity, favoring the linear product with good yields; where the versatility of electron-rich olefins in iodine-catalyzed cascade heterocyclizations, granted the additional benefit of easy isolation and the possibility to reuse the fluorous phase. CONCLUSION: Although pyrazolopyridines have been synthetically explored because of their structural and biological properties, most of the reported synthetic methods use common or even toxic organic solvents and conventional heating or multi-step processes. In contrast, this study applied a multicomponent methodology in a single step by microwave induction and with the versatility provided in this case by the use of perfluorinated solvent, which allowed easy isolation of the final product and recovery of the fluorous phase.

Pyrazole derivatives ameliorate synovial inflammation in collagen-induced arthritis mice model via targeting p38 MAPK and COX-2.

The type II collagen-induced arthritis (CIA) model and human rheumatoid arthritis exhibit similar characteristics. Both diseases involve the production of inflammatory cytokines and other mediators, triggering an inflammatory cascade linked to bone and cartilage damage. Recently, new pyrazole compounds with various pharmacological activities, including antimicrobial, anticancer, anti-inflammatory, and analgesic agents, have been reported. Our aim is to evaluate the therapeutic effectiveness of two newly synthesized pyrazole derivatives, M1E and M1G, in reducing inflammation and oxidative stress in a mouse model of collagen-induced arthritis. Arthritis was induced in DBA/1J mice, and the therapeutic effect of the M1E and M1G is assessed by measuring the arthritic index, quantifying the expression of inflammatory genes such as p38 MAPK, COX-2, IL1ß, MMP3, and TNF-α using real-time PCR and analyzing protein expression using western blotting for phosphorylated p38 MAPK and COX-2. Oxidative stress markers and hind paws joint histopathology were also evaluated. Treatment with the two pyrazole derivatives significantly (p < 0.001) improved the arthritic score; downregulated the expression of inflammatory genes p38 MAPK, COX-2, IL1ß, MMP3, and TNF-α; and reduced the protein expression of phosphorylated p3  MAPK and COX-2. In addition, both compounds ameliorated oxidative stress by increasing the activities of SOD and reducing the formation of MDA in the paw tissue homogenates. Both M1E and M1G significantly (p < 0.001) improved the pathological features of synovitis. The pyrazole derivatives, M1E and M1G, significantly reduced the arthritic score and the inflammatory cytokine expression, improved synovitis histopathology, and ameliorated oxidative stress in the CIA mice model.

Chiral versus achiral crystal structures of 4-benzyl-1H-pyrazole and its 3,5-di-amino derivative.

The crystal structures of 4-benzyl-1H-pyrazole (C10H10N2, 1) and 3,5-di-amino-4-benzyl-1H-pyrazole (C10H12N4, 2) were measured at 150 K. Although its different conformers and atropenanti-omers easily inter-convert in solution by annular tautomerism and/or rotation of the benzyl substituent around the C(pyrazole)-C(CH2) single bond (as revealed by 1H NMR spectroscopy), 1 crystallizes in the non-centrosymmetric space group P21. Within its crystal structure, the pyrazole and phenyl aromatic moieties are organized into alternating bilayers. Both pyrazole and phenyl layers consist of aromatic rings stacked into columns in two orthogonal directions. Within the pyrazole layer, the pyrazole rings form parallel catemers by N-H⋯N hydrogen bonding. Compound 2 adopts a similar bilayer structure, albeit in the centrosymmetric space group P21/c, with pyrazole N-H protons as donors in N-H⋯π hydrogen bonds with neighboring pyrazole rings, and NH2 protons as donors in N-H⋯N hydrogen bonds with adjacent pyrazoles and other NH2 moieties. The crystal structures and supra-molecular features of 1 and 2 are contrasted with the two known structures of their analogs, 3,5-dimethyl-4-benzyl-1H-pyrazole and 3,5-diphenyl-4-benzyl-1H-pyrazole.

Review of the recent advances of pyrazole derivatives as selective COX-2 inhibitors for treating inflammation.

Pyrazole heterocycle is regarded as an extremely significant agent for the therapy of inflammation. Celecoxib, lonazolac, deracoxib, and phenylbutazone are examples of commercially approved pyrazole drugs with COX-2 inhibitory potential for curing inflammation. There have been recently many reviews for the biological significance of pyrazole derivatives. This review talks about pyrazole derivatives with anti-inflammatory activity and also sheds the light on the recent updates on pyrazole research with an emphasis on some synthetic pathways utilized to construct this privileged scaffold and structure activity relationship that accounts for the anti-inflammatory activity in an attempt to pave the opportunity for medicinal chemists to develop novel anti-inflammatory agents with better COX-2 selectivity.

Nano silicated-FeAl2O4 functionalized by DL-alaninium nitrate ionic liquid (FeAl2O4-SiO2@[DL-Ala][NO3]) as versatile promotor for aqua-mediated synthesis of spiro[chromenopyrazole-indene-triones and spiro[chromenopyrazole-indoline-diones.

In this work, the spinel FeAl2O4 was prepared and functionalized step-by-step with silica and alaninium nitrate ionic liquid ([DL-Ala][NO3]) to produce a bio-based multi-layered nanostructure (nano FeAl2O4-SiO2@[DL-Ala][NO3]). The obtained magnetized inorganic-bioorganic nanohybrid characterized by Fourier transform infrared spectroscopy (FT-IR), vibrating-sample magnetometry (VSM), field emission scanning electron microscopy (FESEM), energy-dispersive X-ray spectroscopy (EDAX), transmission electron microscopy (TEM), thermogravimetric analysis/differential scanning calorimetry (TGA/DSC), X-ray fluorescence (XRF), and X-Ray diffraction (XRD) analysis. A facile synthesis of some tricyclic dihydro-spiro[chromeno[2,3-c]pyrazole-4,2'-indene]triones and dihydro-spiro[chromeno[2,3-c]pyrazole-4,3'-indoline]diones via domino four-component one-pot reaction of various hydrazine derivatives, ethyl acetoacetate, heterocyclic 1,2-ketones (ninhydrin, isatin, 5-bromoisatin) and cyclic 1,3-diketones (dimedone and 1,3-cyclohexanedine), examined in the presence of nano FeAl2O4-SiO2@[DL-Ala][NO3] nanohybrid in refluxing aqueous media, successfully. The multi-aspect characteristics of the nanohybrid which consist of magnetized inorganic and bioorganic parts, could be the reason of its special catalytic efficacy. The recovery and reusability of the FeAl2O4-SiO2@[DL-Ala][NO3] magnetized nanoparticles (MNPs) were performed in two runs without significant activity loss.

Synthesis and photodynamic activity of new 5-[(E)-2-(3-alkoxy-1-phenyl-1H-pyrazol-4-yl)ethenyl]-2-phenyl-3H-indoles.

A series of new indole-pyrazole hybrids 8a-m were synthesized through the palladium-catalyzed ligandless Heck coupling reaction from easily accessible unsubstituted, methoxy- or fluoro-substituted 4-ethenyl-1H-pyrazoles and 5-bromo-3H-indoles. These compounds exerted cytotoxicity to melanoma G361 cells when irradiated with blue light (414 nm) and no cytotoxicity in the dark at concentrations up to 10 µM, prompting us to explore their photodynamic effects. The photodynamic properties of the example compound 8d were further investigated in breast cancer MCF-7 cells. Evaluation revealed comparable anticancer activities of 8d in both breast and melanoma cancer cell lines within the submicromolar range. The treatment induced a massive generation of reactive oxygen species, leading to different types of cell death depending on the compound concentration and the irradiation intensity.

Pyrazole, Pyrazoline, and Fused Pyrazole Derivatives: New Horizons in EGFR-Targeted Anticancer Agents.

Pyrazole and its derivatives remain popular heterocycles in drug design, and development. Pyrazole derivatives been extensively studied by the scientific community and as they possess a wide range of biological activity, especially anti-EGFR properies. Overexpression of EGFR signaling promotes tumor growth by inhibiting apoptosis. EGFR dysfunction has been described in several cancer. Therefore, EGFR represents a prospective target for cancer treatment. Several anti-EGFR drugs are thriving the market, notably dacomitinib, afatinib, erlotinib etc. However, almost all drugs have limited therapeutic effectiveness due to a lack of selectivity as well as substantial side effects.  To address this, innovative therapeutic anti-EGFR drugs with high effectiveness and low toxicity are needed. To combat therapeutic resistance to EGFR inhibitors, pyrazole, and pyrazole-based derivatives have been explored as a promising pharmacophore for developing novel compounds with higher potency, lower toxicity, and desirable pharmacokinetic profiles. The current review outlines the investigation of advancements towards anti- EGFR via pyrazole, pyrazoline, and fused pyrazole-based compounds and represents inclusive data on pyrazole-based marketed drugs as well as therapeutic candidates undergoing preclinical and clinical development. We have also summarised structure-activity relationship (SAR), mechanistic studies to afford ideas for the design and development of new anti-EGFR derivatives.

Functionalized pyrazole: Synthesis, Insecticide Evaluation & Molecular Docking Studies of Some New Pyrazole Derivatives against the Cotton leafworm, Spodoptera littoralis.

5-(Cyanomethyl)-3-((5,5-dimethyl-3-oxocyclohex-1-en-1-yl)amino)-1H-pyrazole-4-carbonitrile (3) is used as a key for the synthesis of arylidenes 5a-fvia its reaction with some aldehydes 4a-f. 5-[(5,5-Dimethyl-3-oxocyclohex-1-en-1-yl)amino]-3-(2-imino-2H-chromen-3-yl)-1H-pyrazole-4-carbonitrile (7) was synthesized via the reaction of compound (3) with 2-hydroxybenzaldehyde in EtOH/piperidine. The target compounds were tested against cotton leafworm larvae in their second and fourth instar. The available data demonstrated that the LC50 values for commercial phenylpyrazole were 3.37 mg/L and 4.55 mg/L for the most affected synthesized compound, 5b. The chemical structure of compound 5b has two cyano moieties, a pyrazole ring and a chlorophenyl, which may be increasing it efficiency. Evaluation of the latent effects of the examined synthesized compounds on various biological parameters, including adult longevity, pupal weight, proportion of normal, deformed pupae, adult emergency, fecundity, and egg hatchability, was done in an additional effort to slightly improve insecticidal compounds. Twelve synthesized compounds were subjected to a molecular docking analysis against glutamate-activated chloride channels. Twelve artificial compounds with the PDB ID of 4COF were subjected to a molecular docking study against the gamma-aminobutyric acid receptor (GABA).

Discovery, Optimization, and Biological Evaluation of Novel Pyrazol-5-yl-phenoxybenzamide Derivatives as Potent Succinate Dehydrogenase Inhibitors.

The diphenyl ether molecular pharmacophore has played a significant role in the development of fungicidal compounds. In this study, a variety of pyrazol-5-yl-phenoxybenzamide derivatives were synthesized and evaluated for their potential to act as succinate dehydrogenase inhibitors (SDHIs). The bioassay results indicate certain compounds to display a remarkable and broad-spectrum in their antifungal activities. Notably, compound 12x exhibited significant in vitro activities against Valsa mali, Gaeumannomyces graminis, and Botrytis cinerea, with EC50 values of 0.52, 1.46, and 3.42 mg/L, respectively. These values were lower or comparable to those of Fluxapyroxad (EC50 = 12.5, 1.93, and 8.33 mg/L, respectively). Additionally, compound 12x showed promising antifungal activities against Sclerotinia sclerotiorum (EC50 = 0.82 mg/L) and Rhizoctonia solani (EC50 = 1.86 mg/L), albeit lower than Fluxapyroxad (EC50 = 0.23 and 0.62 mg/L). Further in vivo experiments demonstrated compound 12x to possess effective protective antifungal activities against V. mali and S. sclerotiorum at a concentration of 100 mg/L, with inhibition rates of 66.7 and 89.3%, respectively. In comparison, Fluxapyroxad showed inhibition rates of 29.2 and 96.4% against V. mali and S. sclerotiorum, respectively. Molecular docking analysis revealed that compound 12x interacts with SDH through hydrogen bonding, π-cation, and π-π interactions, providing insights into the probable mechanism of action. Furthermore, compound 12x exhibited greater binding energy and SDH enzyme inhibitory activity than Fluxapyroxad (ΔGcal = -46.8 kcal/mol, IC50 = 1.22 mg/L, compared to ΔGcal = -41.1 kcal/mol, IC50 = 8.32 mg/L). Collectively, our results suggest that compound 12x could serve as a promising fungicidal lead compound for the development of more potent SDHIs for crop protection.

Design, Synthesis, Characterization, and Cytotoxicity of New Pyrazolylmethylene-2-thioxoimidazolidin-4-one Derivatives towards Androgen-Sensitive LNCaP Prostate Cancer Cells.

A new class of pyrazolylmethylene-2-thioxoimidazolidin-4-one derivatives 3a-p were rationally designed and synthesized with the aim of exploring their potential as treatments for prostate cancer. The synthesized compounds 3a-p were biologically analyzed for their anticancer effects against AR+LNCaP, AR-PC-3, and Wi38 cell lines. The observed IC50 values against AR+LNCaP ranged between 10.27 ± 0.14 and 109.72 ± 2.06 µM after 24 h of incubation. Compounds 3i-k, 3m, and 3o-p recorded IC50 values of 05.22 ± 0.12 to 11.75 ± 0.07 µM after 48 h incubation in the presence of 1 nM DHT, with higher selectivity towards AR+LNCaP. Moreover, compounds 3i and 3k significantly induced Caspase 3 accumulation, reduced DNA content at the various stages of the cell cycle, and ultimately caused AR+LNCaP cell growth arrest, as confirmed by cell apoptosis assays. These findings suggest that these analogues of androgen receptor blockers have promising potential for further investigation as effective treatments for prostate cancer.