Synthesis and Biological Evaluation of Novel Piperidine-3-Carboxamide Derivatives as Anti-Osteoporosis Agents Targeting Cathepsin K.

A series of novel piperidamide-3-carboxamide derivatives were synthesized and evaluated for their inhibitory activities against cathepsin K. Among these derivatives, compound H-9 exhibited the most potent inhibition, with an IC50 value of 0.08 µM. Molecular docking studies revealed that H-9 formed several hydrogen bonds and hydrophobic interactions with key active-site residues of cathepsin K. In vitro, H-9 demonstrated anti-bone resorption effects that were comparable to those of MIV-711, a cathepsin K inhibitor currently in phase 2a clinical trials for the treatment of bone metabolic disease. Western blot analysis confirmed that H-9 effectively downregulated cathepsin K expression in RANKL-reduced RAW264.7 cells. Moreover, in vivo experiments showed that H-9 increased the bone mineral density of OVX-induced osteoporosis mice. These results suggest that H-9 is a potent anti-bone resorption agent targeting cathepsin K and warrants further investigation for its potential anti-osteoporosis values.

Structure-activity relationships study of N-ethylene glycol-comprising alkyl heterocyclic carboxamides against A549 lung cancer cells.

Aim: Certain cancer cells depend on oxidative phosphorylation for survival; thus, inhibiting this process may be a promising treatment strategy. This study explored the structure-activity relationships of the mitochondrial inhibitor N-ethylene glycol-comprising alkyl thiophene-3-carboxamide 3.Methods & results: We synthesized and evaluated 13 analogs (5a-m) with different ethylene glycol units, heterocycles and connecting groups for their growth-inhibitory effects on A549 non-small cell lung cancer cells. We found that increasing the number of ethylene glycol units significantly enhanced inhibitory activity. Some analogs activated adenosine monophosphate-activated protein kinase, similar to 3. Notably, analog 5e, which contains tetraethylene glycol units, significantly inhibited tumor growth in vivo.Conclusion: Analog 5 may be a potential therapeutic agent for non-small cell lung cancer treatment.

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Discovery of novel substituted pyridine carboxamide derivatives as potent allosteric SHP2 inhibitors.

Src homology-2-containing protein tyrosine phosphatase 2 (SHP2), a critical regulator of proliferation pathways and immune checkpoint signaling in various cancers, is an attractive target for cancer therapy. Here, we report the discovery of a novel series of substituted pyridine carboxamide derivatives as potent allosteric SHP2 inhibitors. Among them, compound C6 showed excellent inhibitory activity against SHP2 and antiproliferative effect on MV-4-11 cell line with IC50 values of 0.13 and 3.5 nM, respectively. Importantly, orally administered C6 displayed robust in vivo antitumor efficacy in the MV-4-11 xenograft mouse model (TGI = 69.5 %, 30 mg/kg). Subsequent H&E and Ki67 staining showed that C6 significantly suppressed the proliferation of tumor cells. Notably, flow cytometry, ELISA and immunofluorescence experiments showed that C6 remarkably decreased the population of CD206+/Ly6C+ M2-like tumor-associated macrophages (TAMs), the expression level of interleukin-10 (IL-10), and the number of F4/80+/CD206+ M2-like TAMs, suggesting that C6 could effectively alleviate the activation and infiltration of M2-like TAMs. Taken together, these results illustrate that C6 is a promising SHP2 inhibitor worthy of further development.

Design and discovery of carboxamide-based pyrazole conjugates with multifaceted potential against Triple-Negative Breast cancer MDA-MB-231 cells.

We report the design, synthesis, and validation of carboxamide-based pyrazole and isoxazole conjugates with a multifaceted activity against Breast Cancer Cell Line MDA-MB-231. The study established that amongst the series, N-(3,5-bis(trifluoromethyl)benzyl)-3-(3,4,5-trimethoxyphenyl)-1H-pyrazole-5-carboxamide (5g) exhibits the highest potency in inhibiting Breast Cancer Cell Line MDA-MB-231 with an IC50 value of 15.08 ± 0.04 µM. The MDA-MB-231 cells, upon treatment with compound 5g, exhibited characteristic apoptotic specific activities such as nuclear fragmentation, phosphatidylserine translocation to the outer plasma membrane, release of lactate dehydrogenase (LDH), and upregulation of caspase 3 and caspase 9 activities. Also, the modulation of pro and antiapoptotic proteins in 5g treated MDA-MB-231 cells was revealed by membrane array analysis. More importantly, the combination of paclitaxel and compound 5g has exhibited improved activity by several folds via their synergistic effects.

Evaluation of the antifungal activity of novel bis-pyrazole carboxamide derivatives and preliminary investigation of the mechanism.

To facilitate the development of novel agricultural succinate dehydrogenase inhibitor (SDHI) fungicides, we synthesized three series of derivatives by introducing phenyl pyrazole fragments into the structure of pyrazol-4-yl amides. The results of the bioactivity assay showed that most of the target compounds possessed varying degrees of inhibitory activity against the tested fungi. At a concentration of 100 mg/L, the compound B8 exhibited effective protective activity against S. sclerotiorum in vivo. Molecular docking analysis and succinate dehydrogenase (SDH) inhibition assay indicated that B8 was not a potential SDHI. The preliminary antifungal mechanism of studies showed that B8 induced a large amount of reactive oxygen species (ROS) and severe lipid peroxidation damage in S. sclerotiorum mycelium, resulting in mycelial rupture and disruption of the integrity of the cell membrane and leakage of soluble proteins, soluble sugars and nucleic acids. Further transcriptome analysis showed that compound B8 blocked various metabolic pathways by downregulating the differentially expressed genes (DEGs) catalase, disrupting hydrogen peroxide hydrolysis, accelerating membrane oxidative damage, and upregulating neutral ceramidase, accelerating sphingolipid metabolism to disrupt cell membrane structure and cell proliferation and differentiation, potentially accelerating cell death. The above results indicated that the potential target of these dis-pyrazole carboxamide derivatives may be the cell membrane of pathogenic fungi.

Design, synthesis and structure-activity relationship of novel pyrazole-4-carboxamide derivatives.

BACKGROUND: Plant diseases seriously decrease the yield and quality of agricultural crops. Fungicide treatments remain the main means of field fungi control. However, the residual activity of fungicides is rapidly reduced due to various factors in the natural environment, therefore the development of agents with novel modes of action is desirable. It is highly required to design and develop new fungicides to address the resistance issue. Designing low impact chemicals to safely and sustainably address needs of agriculture. RESULTS: In this work, we used the highly active fluxapyroxad and flutolanil as parent structures, to design and synthesize a series of pyrazole-4-carboxamide derivatives. Some of the pyrazole-4-carboxamide derivatives exhibit fungicidal activities that are comparable to or higher than those of the commercialized fungicides fluxapyroxad and bixafen. In particular, compounds TM-1, TM-2, TM-3, TM-4, TM-5, TM-7 and TM-8 showed excellent fungicidal activities against corn rust that were 2-4 times higher than those of fluxapyroxad and bixafen. Field trial results demonstrated that at the same dosage levels, compound TM-2 exhibited comparable field control efficacy against wheat rust as compared to triadimefon and pyrazophenamide. Molecular docking simulations reveal that compound TM-2 interacts with TRP 173 of succinate dehydrogenase (SDH) through hydrogen bonding, which could explain the probable mechanism of action between compound TM-2 and the target protein. CONCLUSION: These results indicate that compound TM-2 may be a promising fungicide candidate and provide valuable reference for further investigation. © 2024 Society of Chemical Industry.

New substituted benzenesulphonamoyl 'Cys-Gly' dipeptide carboxamide derivatives: Design, synthesis, characterization and pharmacological studies.

Twelve new sulphonamide (Cys-Gly) dipeptide carboxamide derivatives 17a-17l were designed, prepared and characterized through spectroscopic techniques and their pharmacological properties investigated. The molecular docking analyses revealed good interactions of the derivatives with the desired amino residues active pockets. In vitro antimicrobial, in vivo antimalarial, haematological and other related tests (liver and kidney) were also conducted. Compounds 17b exhibited good minimum inhibitory concentration (MIC) results (0.9-11) mg/mL for the studied organisms when compared with ciprofloxacin and fluconazole. Derivatives 17a -17l showed parasitaemia inhibition in the range (31.11-67.78) % on the fourth day after treating the animals with 40 mg/kg of the compounds. Derivative 17b also displayed the highest parasitaemia inhibition (67.78 %) comparable with the standard (Lumenfantrine) 75.27 %. The prepared derivatives showed promising pharmacological properties with regards to hematological, liver and kidney function tests.

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.

Adiponectin receptor 1 regulates endometrial receptivity via the adenosine monophosphate­activated protein kinase/E­cadherin pathway.

Endometrial receptivity is essential for successful embryo implantation and pregnancy initiation and is regulated via various signaling pathways. Adiponectin, an important adipokine, may be a potential regulator of reproductive system functions. The aim of the present study was to elucidate the regulatory role of adiponectin receptor 1 (ADIPOR1) in endometrial receptivity. The endometrial receptivity between RL95­2 and AN3CA cell lines was confirmed using an in vitro JAr spheroid attachment model. 293T cells were transfected with control or short hairpin (sh)ADIPOR1 vectors and RL95­2 cells were transduced with lentiviral particles targeting ADIPOR1. Reverse transcription­quantitative PCR and immunoblot assays were also performed. ADIPOR1 was consistently upregulated in the endometrium during the mid­secretory phase compared with that in the proliferative phase and in receptive RL95­2 cells compared with that in non­receptive AN3CA cells. Stable cell lines with diminished ADIPOR1 expression caused by shRNA showed reduced E­cadherin expression and attenuated in vitro endometrial receptivity. ADIPOR1 regulated AMP­activated protein kinase (AMPK) activity in endometrial epithelial cells. Regulation of AMPK activity via dorsomorphin and 5­aminoimidazole­4­carboxamide ribonucleotide affected E­cadherin expression and in vitro endometrial receptivity. The ADIPOR1/AMPK/E­cadherin axis is vital to endometrial receptivity. These findings can help improve fertility treatments and outcomes.

Assessing the Effects of Thiazole-Carboxamide Derivatives on the Biophysical Properties of AMPA Receptor Complexes as a Potential Neuroprotective Agent.

An optimal balance between excitatory and inhibitory transmission in the central nervous system provides essential neurotransmission for good functioning of the neurons. In the neurology field, a disturbed balance can lead to neurological diseases like epilepsy, Alzheimer's, and Autism. One of the critical agents mediating excitatory neurotransmission is α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid receptors, which are concerned with synaptic plasticity, memory, and learning. An imbalance in neurotransmission finally results in excitotoxicity and neurological pathologies that should be corrected through specific compounds. Hence, the current study will prove to be an evaluation of new thiazole-carboxamide derivatives concerning AMPAR-modulating activity and extended medicinal potential. In the current project, five previously synthesized thiazole-carboxamide derivatives, i.e., TC-1 to TC-5, were used to interact with the AMPARs expressed in HEK293T cells, which overexpress different subunits of the AMPAR. Patch-clamp analysis was carried out while the effect of the drugs on AMPAR-mediated currents was followed with a particular emphasis on the kinetics of inhibition, desensitization, and deactivation. All tested TC compounds, at all subunits, showed potent inhibition of AMPAR-mediated currents, with TC-2 being the most powerful for all subunits. These compounds shifted the receptor kinetics efficiently, mainly enhancing the deactivation rates, and hence acted as a surrogate for their neuroprotective potentials. Additionally, recently published structure-activity relationship studies identified particular substituent groups as necessary for improving the pharmacologic profiles of these compounds. In this regard, thiazole-carboxamide derivatives, particularly those classified as TC-2, have become essential negative allosteric modulators of AMPAR function and potential therapeutics in neurological disturbances underlain by the dysregulation of excitatory neurotransmission. Given their therapeutic effectiveness and safety profiles, these in vivo studies need to be further validated, although computational modeling can be further developed for drug design and selectivity. This will open possibilities for new drug-like AMPAR negative allosteric modulators with applications at the clinical level toward neurology.

Synthesis, docking and characterization of some novel 5-(S-alkyl)-1.3.4-thiadiazole-2-carboxamide derivatives as anti-inflammatory and antibacterial agents.

Because of the great pharmacological and industrial significance of 1,3,4-thiadiazole and its related compounds, researchers are still very interested in them. For this reason, in this study, we looked at ways to create new hybrid compounds containing carboxamide and 1,3,4-thiadiazole moieties. The thioxoacetamide derivatives used to make these compounds were reacted with various alkylated reagents to produce multiple S-alkyl groups. Additionally, these compounds were reacted with aldehydes to form novel derivatives known as 5-(substituent)-N-phenyl-1,3,4-thiadiazole-2-carboxamide. Here, we used the agar well diffusion method to examine the antibacterial activity of all the produced compounds against a few pathogenic bacteria that were resistant to multiple drugs. Additionally, look into their capacity to lower inflammation through the use of bovine serum albumin in the protein denaturation procedure. The substances were characterized by spectral analysis (IR, 1HNMR, 13CNMR and Elemental Analysis), and efficient as antibacterial agents against all the tested bacterial strains, except for Escherichia coli. Compounds 4a and 8c showed the highest level of inhibition zone against Gram-positive bacteria (Staph. aureus, Bacillus subtilis) at concentration 0.3, 0.4 and 0.5 mg/ml compared with ciprofloxacin at the same concentrations. The results demonstrated that every compound has significant anti-inflammatory activity. At a concentration of 250 µg/ml, compounds 3a, 4c and 8c had the highest percentage inhibition of protein denaturation when (83.24%, 86.44% and 85.14%, respectively) compared to other compounds and diclofenac sodium as reference drug. Comparing compounds 4c and 8c to ciprofloxacin and diclofenac sodium, they showed powerful antibacterial and anti-inflammatory action. Furthermore, an investigation using molecular docking against DHPS from S. aureus (PDB ID: 6CLV) showed a strong connection with the intended protein and an elevated docking score, making it a prime candidate for antibiotics.

New prospective insecticidal agents based on N-(arylcarbamothioyl)arylmide derivatives against Spodoptera frugiperda: Design, Synthesis, Toxicological, Biological, Biomedical Studies and Antibacterial Activity.

In this work, a novel series of N-(arylcarbamothioyl)arylmide) 2-11 were synthesized by treating One-Pot three-multicomponent of Aroyl chloride ammonium isothiocyanate and amine compounds under refluxing conditions. Using spectroscopic methods, the chemical structure of the novelty developed compounds were investigated. After five days, the proposed derivatives' insecticidal bioassay was assessed using the median lethal concentration (LC50) against the second & fourth larvae of Spodoptera frugiperda as toxicity agents. The findings showed that, to varying degrees, every tested substance exerted insecticidal effects on S. frugiperda larvae in both of their instars. Compound 9 was the most poisonous of them all, having an LC50 against larvae in their second and fourth instars of 60.45 and 123.21 mg/L, respectively. Additionally, a few biological and biochemical characteristics of the substances that were generated in a lab setting were also looked at. Furthermore, this work discusses how to discover novel compounds that may one day be employed as insecticidal agents. Finally, all the designed components were monitored for their antibacterial effectiveness toward both Gram-positive & Gram-negative bacteria.

Design, Synthesis, and Biological Activity of Silicon-Containing Carboxamide Fungicides.

Bioisosteric silicon replacement has proven to be a valuable strategy in the design of bioactive molecules for crop protection and drug development. Twenty-one novel carboxamides possessing a silicon-containing biphenyl moiety were synthesized and tested for their antifungal activity and succinate dehydrogenase (SDH) enzymatic inhibitory activity. Among these novel succinate dehydrogenase inhibitors (SDHIs), compounds 3a, 3e, 4l, and 4o possessing appropriate clog P and topological polar surface area values showed excellent inhibitory effects against Rhizoctonia solani, Sclerotinia sclerotiorum, Botrytis cinerea, and Fusarium graminearum at 10 mg/L in vitro, and the EC50 values of 4l and 4o were 0.52 and 0.16 mg/L against R. solani and 0.066 and 0.054 mg/L against S. sclerotiorum, respectively, which were superior to those of Boscalid. Moreover, compound 3a demonstrated superior SDH enzymatic inhibitory activity (IC50 = 8.70 mg/L), exhibiting 2.54-fold the potency of Boscalid (IC50 = 22.09 mg/L). Docking results and scanning electron microscope experiments revealed similar mode of action between compound 3a and Boscalid. The new silicon-containing carboxamide 3a is a promising SDHI candidate that deserves further investigation.

Design, synthesis, in vitro, and in silico anti-α-glucosidase assays of N-phenylacetamide-1,2,3-triazole-indole-2-carboxamide derivatives as new anti-diabetic agents.

In this work, a novel series of N-phenylacetamide-1,2,3-triazole-indole-2-carboxamide derivatives 5a-n were designed by consideration of the potent α-glucosidase inhibitors containing indole and carboxamide-1,2,3-triazole-N-phenylacetamide moieties. These compounds were synthesized by click reaction and evaluated against yeast α-glucosidase. All the newly title compounds demonstrated superior potency when compared with acarbose as a standard inhibitor. Particularly, compound 5k possessed the best inhibitory activity against α-glucosidase with around a 28-fold improvement in the inhibition effect in comparison standard inhibitor. This compound showed a competitive type of inhibition in the kinetics. The molecular docking and dynamics demonstrated that compound 5k with a favorable binding energy well occupied the active site of α-glucosidase.

Synthesis, molecular docking and molecular dynamics simulations, drug-likeness studies, ADMET prediction and biological evaluation of novel pyrazole-carboxamides bearing sulfonamide moiety as potent carbonic anhydrase inhibitors.

Pyrazoles are unique bioactive molecules with a versatile biological profile and they have gained an important place on pharmaceutical chemistry. Pyrazole compounds containing sulfonamide nuclei also attract attention as carbonic anhydrase (CA) inhibitors. In this study, a library of pyrazole-carboxamides were synthesized and the structures of the synthesized molecules were characterized using FT-IR, 1H-NMR, 13C-NMR and HRMS. Then the inhibition effects of newly synthesized molecules on human erythrocyte hCA I and hCA II isoenzymes were investigated. Ki values of the compounds were in the range of 0.063-3.368 µM for hCA I and 0.007-4.235 µM for hCA II. Molecular docking studies were performed between the most active compounds 6a, 6b and the reference inhibitor, acetazolamide (AAZ) and the hCA I and hCA II receptors to investigate the binding mechanisms between the compounds and the receptors. These compounds showed better interactions than the AAZ. ADMET analyzes were performed for the compounds and it was seen that the compounds did not show AMES toxicity. The stability of the molecular docking results over time was analysed by 50 ns molecular dynamics simulations. Molecular dynamics simulations revealed that 6a and 6b exhibited good stability after docking to the binding sites of hCA I and hCA II receptors, with minor conformational changes and fluctuations.

Molecular Mechanism of Fusarium Fungus Inhibition by Phenazine-1-carboxamide.

Fusarium head blight caused by Fusarium graminearum is a devastating disease in wheat that seriously endangers food security and human health. Previous studies have found that the secondary metabolite phenazine-1-carboxamide produced by biocontrol bacteria inhibited F. graminearum by binding to and inhibiting the activity of histone acetyltransferase Gcn5 (FgGcn5). However, the detailed mechanism of this inhibition remains unknown. Our structural and biochemical studies revealed that phenazine-1-carboxamide (PCN) binds to the histone acetyltransferase (HAT) domain of FgGcn5 at its cosubstrate acetyl-CoA binding site, thus competitively inhibiting the histone acetylation function of the enzyme. Alanine substitution of the residues in the binding site shared by PCN and acetyl-CoA not only decreased the histone acetylation level of the enzyme but also dramatically impacted the development, mycotoxin synthesis, and virulence of the strain. Taken together, our study elucidated a competitive inhibition mechanism of Fusarium fungus by PCN and provided a structural template for designing more potent phenazine-based fungicides.

Design, synthesis and biological evaluation of 5-amino-1H-pyrazole-4-carboxamide derivatives as pan-FGFR covalent inhibitors.

The aberrant activation of FGFRs plays a critical role in various cancers, leading to the development of several FGFR inhibitors in clinic. However, the emergence of drug resistance, primarily due to gatekeeper mutations in FGFRs, has limited their clinical efficacy. To address the unmet medical need, a series of 5-amino-1H-pyrazole-4-carboxamide derivatives were designed and synthesized as novel pan-FGFR covalent inhibitors targeting both wild-type and the gatekeeper mutants. The representative compound 10h demonstrated nanomolar activities against FGFR1, FGFR2, FGFR3 and FGFR2 V564F gatekeeper mutant in biochemical assays (IC50 = 46, 41, 99, and 62 nM). Moreover, 10h also strongly suppressed the proliferation of NCI-H520 lung cancer cells, SNU-16 and KATO III gastric cancer cells with IC50 values of 19, 59, and 73 nM, respectively. Further X-ray co-crystal structure revealed that 10h irreversibly binds to FGFR1. The study provides a new promising point for anticancer drug development medicated by FGFRs.

The discovery of indazapyroxamet: a novel 3-pyridinyl insecticide targeting piercing/sucking insectsa.

In recent years, the registrations for a number of commercial insecticides utilized for piercing/sucking insects have been cancelled or restricted. To meet this growing need for new hemipteran controlling agrochemicals, we discovered a 2-(pyridin-3-yl)-thiazole compound, with limited insecticidal activity against cotton/melon aphid (Aphis gossypii). The 2-(pyridin-3-yl)-thiazole moiety offered us a basis to pursue the bicyclic 2-(pyridin-3-yl)-2H-indazole carboxamides. Evaluation of such 2-(pyridin-3-yl)-2H-indazole carboxamides revealed that even analogs containing only simple alkyl amides attached at the 4 or 5 positions possess promising insecticidal activity. Extensive optimization of this novel class of 2-(pyridin-3-yl)-2H-indazole carboxamides led to identifying indazapyroxamet for commercial development. © 2024 Society of Chemical Industry.

Synthesis, fungicidal activity and molecular docking of novel pyrazole-carboxamides bearing a branched alkyl ether moiety.

Succinate dehydrogenase inhibitors are essential fungicides used in agriculture. To explore new pyrazole-carboxamides with high fungicidal activity, a series of N-substitutedphenyl-3-di/trifluoromethyl-1-methyl-1H-pyrazole-4-carboxamides bearing a branched alkyl ether moiety were designed and synthesized. The in vitro bioassay indicated that some target compounds displayed appreciable fungicidal activity. For example, compounds 5d and 5e showed high efficacy against S. sclerotiorum with EC50 values of 3.26 and 1.52 µg/mL respectively, and also exhibited excellent efficacy against R. solani with EC50 values of 0.27 and 0.06 µg/mL respectively, which were comparable or superior to penflufen. The further in vivo bioassay on cucumber leaves demonstrated that 5e provided strong protective activity of 94.3 % against S. sclerotiorum at 100 µg/mL, comparable to penflufen (99.1 %). Cytotoxicity assessment against human renal cell lines (239A cell) revealed that 5e had low cytotoxicity within the median effective concentrations. Docking study of 5e with succinate dehydrogenase illustrated that R-5e formed one hydrogen bond and two π-π stacking interactions with amino acid residues of target enzyme, while S-5e formed only one π-π stacking interaction with amino acid residue. This study provides a valuable reference for the design of new succinate dehydrogenase inhibitor.

Synthesis and evaluation of pyridine-3-carboxamide analogs as effective agents against bacterial wilt in tomatoes.

This study focused on developing novel pyridine-3-carboxamide analogs to treat bacterial wilt in tomatoes caused by Ralstonia solanacearum. The analogs were synthesized through a multistep process and their structures confirmed using spectroscopy. Molecular docking studies identified the most potent analog from the series. A specific analog, compound 4a, was found to significantly enhance disease resistance in tomato plants infected with R. solanacearum. The structure-activity relationship analysis showed the positions and types of substituents on the aromatic rings of compounds 4a-i strongly influenced their biological activity. Compound 4a, with a chloro group at the para position on ring C and hydroxyl group at the ortho position on ring A, was exceptionally effective against R. solanacearum. When used to treat seeds, the analogs displayed remarkable efficacy, especially compound 4a which had specific activity against bacterial wilt pathogens. Compound 4a also promoted vegetative and reproductive growth of tomato plants, increasing seed germination and seedling vigor. In plants mechanically infected with bacteria, compound 4a substantially reduced the percentage of infection, pathogen quantity in young tissue, and disease progression. The analogs were highly potent due to their amide linkage. Molecular docking identified the best compounds with strong binding affinities. Overall, the strategic design and synthesis of these pyridine-3-carboxamide analogs offers an effective approach to targeting and controlling R. solanacearum and bacterial wilt in tomatoes.