Carboxamide Derivatives Research Articles

Discovery of Thiazole Carboxamides as Novel Vanin-1 Inhibitors for Inflammatory Bowel Disease Treatment.

Inflammatory bowel disease (IBD) is a clinically heterogeneous disease demanding more therapeutic targets and intervention strategies. Vanin-1, an oxidative stress-regulating protein, has emerged as a promising target for alleviating inflammation and oxidative stress. In this study, a series of thiazole carboxamide derivatives as vanin-1 inhibitors were designed and synthesized. The preferred compound, X17, demonstrated potent inhibition against vanin-1 at the protein, HT-29 cell, and tissue levels, whose binding mode with the target was confirmed via the cocrystal structure. X17 achieved a high bioavailability of 81% in rats, accompanied by concentration-dependent inhibition of serum vanin-1. In a DSS-induced mouse colitis model, X17 exhibited potent anti-inflammatory and antioxidant activities, repressing the inflammatory factor expressions and myeloperoxidase activity, elevating the colonic glutathione reserve, and restoring the intestinal barrier. Collectively, these findings depict the discovery of a potent vanin-1 inhibitor, providing an opportunity for further drug candidate development for treating IBD.

Galectins: a potential pharmacological target

Aim. To consider the use of galectin-1 and galectin-3 inhibitors as potential pharmacological targets in antitumor and antifibrotic therapy.The lecture includes the analysis of experimental research and review articles presented in the PubMed database. A brief description of the structure of galectins is given. Their generally accepted classification and features of the structure of the carbohydrate recognition domain in galectin-1 and galectin-3 are presented. The main part of the lecture describes the results of research on the development of carbohydrate-based (β-galactoside derivatives or analogues) and non-carbohydrate-based (peptide-based, carboxamide derivatives) inhibitors capable of interacting with galectin-1 and galectin-3.The results of experiments performed on animal models and tumor cell cultures demonstrate that the antitumor effect of galectin antagonists is realized through the suppression of proliferation and metastasis, activation of tumor cell apoptosis, and modulation of the antitumor immune response. Antagonists of galectin-1 and galectin-3 potentiate the effect of antitumor drugs and have an antifibrotic effect. Some of the compounds discussed in the lecture are undergoing clinical trials. The data presented in the lecture open up opportunities for the development and synthesis of new molecules of potential galectin-1 and 3 inhibitors.

Discovery of a novel thiophene carboxamide analogue as a highly potent and selective sphingomyelin synthase 2 inhibitor for dry eye disease therapy

Dry eye disease (DED) is a prevalent and intractable ocular disease induced by a variety of causes. Elevated sphingomyelin (SM) levels and pro-inflammatory cytokines were detected on the ocular surface of DED patients, particularly in the meibomian glands. Sphingomyelin synthase 2 (SMS2), one of the proteins involved in SM synthesis, would light a novel way of developing a DED therapy strategy. Herein, we report the design and optimization of a series of novel thiophene carboxamide derivatives to afford 14l with an improved highly potent inhibitory activity on SM synthesis (IC50, SMS2 = 28 nmol/L). Moreover, 14l exhibited a notable protective effect of anti-inflammation and anti-apoptosis on human corneal epithelial cells (HCEC) under TNF-α-hyperosmotic stress conditions in vitro, with an acceptable ocular specific distribution (corneas and meibomian glands) and pharmacokinetics (PK) profiles (t1/2, cornea = 1.11 h; t1/2, meibomian glands = 4.32 h) in rats. Furthermore, 14l alleviated the dry eye symptoms including corneal fluorescein staining scores and tear secretion in a dose-dependent manner in mice. Mechanically, 14l reduced the mRNA expression of Tnf-α, Il-1β and Mmp-9 in corneas, as well as the proportion of very long chain SM in meibomian glands. Our findings provide a new strategy for DED therapy based on selective SMS2 inhibitors.

Synthesis, Characterization, DFT Calculations, Antimicrobial Activity, Molecular Docking, and ADMET Study of New Pyrazole-Carboxamide Derivatives

An efficient one-step synthesis of carboxamides from pyrazole acid was achieved using thionyl chloride as an activating agent. Thirteen new pyrazole carboxamide derivatives were synthesized and characterized through spectroscopic and spectrometric techniques. These compounds were evaluated for antifungal activity against Candida albicans, Aspergillus brasiliensis, and Saccharomyces cerevisiae. Notably, compounds R5, R11, and R13 showed significant antifungal efficacy, while none exhibited antibacterial activity against Escherichia coli. To further our understanding, a computational DFT analysis revealed crucial information about the structure, electronic proprieties, and reactivity of these materials. The experimental results were supported by molecular docking analysis, reinforcing the validity of the results. Extending our exploration, an analysis of the pharmacokinetic properties and toxicity by ADMET profiling confirmed the safe use of these newly synthesized compounds, paving the way for promising applications in the medical field.

Stability Indicating RP-HPLC Method Development and Validation for Quantification of Favipiravir and its Related Substances.

Background: Favipiravir is an influenza antiviral medication. DEM Avigan is the commercial name for a pyrazine carboxamide derivative. Aim: According to the guidelines framed by ICH - International Council for Harmonisation, the present method was developed and validated for the system suitability, specificity, linearity, precision, limit of quantification and limit of detection, accuracy, & robustness. Results: All the results obtained were within the acceptable range. This method was used to better separate the peaks of Favipiravir and its three impurities. The retention times and squared correlation coefficient values of Impurity-1, Impurity-2, Favipiravir & Impurity-3 were obtained at 1.998, 3.223, 4.438 & 7.052 min and 0.9993, 0.9995, 0.9998 & 0.9997 respectively. Conclusion: Thus, the results show that the suggested RP-HPLC method for separating three contaminants with Favipiravir was effective and may be utilised in routine pharmaceutical analysis and quality control. Forced degradation was carried out under different stress conditions thus proving as stability indicating as per ICH guidelines.

Tandem diazotization/cyclization approach for the synthesis of a fused 1,2,3-triazinone-furazan/furoxan heterocyclic system.

A straightforward protocol for the synthesis of a previously unknown [1,2,5]oxadiazolo[3,4-d][1,2,3]triazin-7(6H)-one heterocyclic system was developed. The described approach is based on tandem diazotization/azo coupling reactions of (1,2,5-oxadiazolyl)carboxamide derivatives bearing both aromatic and aliphatic substituents. The NO-donor ability of the synthesized furoxano[3,4-d][1,2,3]triazin-7(6H)-ones was additionally evaluated. The elaborated method provides access to novel nitrogen heterocyclic compounds with potential applications as drug candidates or thermostable components of functional organic materials.

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 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.

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.

Analysis and correlation between electrochemical and theoretical findings for inhibiting carbon steel corrosion in acidic environments with two carboxamide derivatives

Analysis and correlation between electrochemical and theoretical findings for inhibiting carbon steel corrosion in acidic environments with two carboxamide derivatives

Reduction of 2-phenyl-3a,4,7,7a-tetrahydro-1H-isoindole-1,3(2H)-dione with NaBH4: Investigation of exo-selectivity and reaction mechanism via theoretical computations

The reaction of the bicyclic imide with NaBH4 afforded acylaminocarbinol and carboxamide derivatives. The exact configuration of acylaminocarbinol 7 was determined by X-ray crystal analysis. Theoretical studies were carried out to explain the mechanism of the exo-selectivity observed in the first step of the reduction reaction and the formation of the secondary product in the second step. According to the obtained findings, i) in the first step of the reaction, the exo-path is kinetically more favorable, and ii) an alternative mechanism has been proposed instead of the mechanism proposed in the literature. The canonical forms of the amide group in the lactam ring were found to make an important contribution to the mechanism. iii) The amount of products formed in the reduction reaction depends on the reaction conditions.

Palladium‐Catalyzed Isocyanide Insertion into the Remotely Activated N−H bond of 3‐(Phenylhydrazono)oxindoles: Facile Access to Indole‐N‐Carboxamide Derivatives

AbstractA convenient approach for synthesizing indole‐N‐carboxamide derivatives through palladium‐catalyzed isocyanide insertion into the N−H bond of 3‐(phenylhydrazono)oxindoles has been developed. The inclusion of the 3‐phenylhydrazone group proved essential in remotely activating the N−H bond of the oxindole. Also, it has been established that the reaction outcome is highly dependent on the electronic effects of the substituents.

Design and evaluation of piperidine carboxamide derivatives as potent ALK inhibitors through 3D-QSAR modeling, artificial neural network and computational analysis

Tumor stands as one of the principal contributors to global mortality. As research into tumor treatments advances, tumor inhibitors emerge as pivotal milestones in tumor therapy. Among these inhibitors, Anaplastic Lymphoma Kinase (ALK), a receptor tyrosine kinase, is critical owing to its close association with tumor cell proliferation and growth, which renders it a critical therapeutic target. This work systematically explores the relationship between the chemical structures of 36 piperidine carboxamide derivatives and their efficacy in inhibiting Karpas-299 tumor cell activity by employing a rigorous 3D-QSAR modeling approach. A robust Topomer CoMFA model was generated and was meticulously validated through ANN neural network analysis (q2 = 0.597, r2 = 0.939, F = 84.401, N = 4, SEE = 0.268). Based on the model, 60 new compounds with desirable inhibitory activities were successfully designed. Combined with Lipinski’s rule and ADMET criteria alongside molecular docking and dynamics simulations, a lead compound with high inhibitory activity and good drug-likeness was selected. Further computational analyses, encompassing free energy landscape and binding free energy calculations, provided compelling evidence of the stable binding conformation of the lead compound and the superior affinity with the target protein at the active site, underscoring its potential therapeutic utility. In summary, this investigation offers valuable insights and methodological guidance for advancing tumor therapy and underscores the promise of piperidine carboxamide derivatives as prospective ALK inhibitors.

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

Synthesis, Nematicidal Activity, and Molecular Docking of Some New Pyrazole-5- carboxamide Derivatives with Flexible Chain

A series of new pyrazole-5-carboxamide derivatives was synthesized containing flexible chain moiety. The synthetic route involved four-step approach starting from ethyl 3-ethyl-1-methyl-1H-pyrazole-5-carboxylate (1). The primarily nematicidal bioassay results have shown that some of them exhibited moderate activity against Meloidogyne incognita at 10 mg/L. In addition, the molecular docking simulation results indicated that compound 5r interacts with succinate dehydrogenase (SDH) through p-cation, p-p, and hydrogen bond interaction, which may provide useful information to further design novel nematicides.. KEYWORDS :Molecular docking, Nematicidal activity, Pyrazole carboxamide, Synthesis.

Benzodioxane Carboxamide Derivatives As Novel Monoamine Oxidase B Inhibitors with Antineuroinflammatory Activity.

In this study, a series of N-phenyl-2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamide derivatives were designed, synthesized, and evaluated for their inhibitory activities against human MAO-B (hMAO-B). The structure-activity relationship (SAR) was investigated and summarized. Compound 1l (N-(3,4-dichlorophenyl)-2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamide) showed the most potent inhibitory activity with an IC50 value of 0.0083 μM and the selectivity index (IC50 (hMAO-A)/IC50 (hMAO-B)) was >4819. Kinetics and reversibility studies confirmed that compound 1l acted as a competitive and reversible inhibitor of hMAO-B. Molecular docking studies revealed the enzyme-inhibitor interactions, and the rationale was provided. Additionally, compound 1l could effectively inhibit the release of NO, TNF-α, and IL-1β in both LPS- and Aβ1-42-stimulated BV2 cells and attenuate the cytotoxicity induced by Aβ1-42. Since compound 1l exhibited low neurotoxicity, we believe that the hit compound with dual activities of inhibiting MAO-B and antineuroinflammation could be further investigated as a novel potential lead for future studies in vivo.

New Carbothioamide and Carboxamide Derivatives of 3-Phenoxybenzoic Acid as Potent VEGFR-2 Inhibitors: Synthesis, Molecular Docking, and Cytotoxicity Assessment.

Because of the well-established link between angiogenesis and tumor development, the use of antiangiogenic therapeutics, such as those targeting VEGFR-2, presents a promising approach to cancer treatment. In the current study, a set of five hydrazine-1-- carbothioamide (compounds 3a-e) and three hydrazine-1-carboxamide derivatives (compounds 4a-c) were successfully synthesized from 3-phenoxybenzoic acid. These compounds were specially created as antiproliferative agents with the goal of targeting cancer cells by inhibiting VEGFR-2 tyrosine kinase. The new derivatives were synthesized by conventional organic methods, and their structure was versified by IR, 1HNMR, 13CNMR, and mass spectroscopy. In silico investigation was carried out to identify the compounds' target, molecular similarity, ADMET, and toxicity profile. The cytotoxic activity of the prepared compounds was evaluated in vitro against three human cancer cell lines (DLD1 colorectal adenocarcinoma, HeLa cervical cancer, and HepG2 hepatocellular carcinoma). The effects of the leading compound on cell cycle progression and apoptosis induction were investigated by flow cytometry, and the specific apoptotic pathway triggered by the treatment was evaluated by RT-PCR and immunoblotting. Finally, the inhibitory activities of the new compounds against VEGFR-2 was measured. The designed derivatives exhibited comparable binding positions and interactions to the VEGFR-2 binding site to that of sorafenib (a standard VEGFR-2 tyrosine kinase inhibitor), as determined by molecular docking analysis. Compound 4b was the most cytotoxic compound, achieving the lowest IC50 against HeLa cells. Compound 4b, a strong representative of the synthesized series, induced cell cycle arrest at the G2/M phase, increased the proportion of necrotic and apoptotic HeLa cells, and activated caspase 3. The EC50 value of compound 4b against VEGFR-2 kinase activity was comparable to sorafenib's. Overall, the findings suggest that compound 4b has a promising future as a starting point for the development of new anticancer drugs.

Design, synthesis, antifungal evaluation and mechanism study of novel norbornene derivatives as potential laccase inhibitors.

To discover novel fungicide candidates, five series of novel norbornene hydrazide, bishydrazide, oxadiazole, carboxamide and acylthiourea derivatives (2a-2t, 3a-3f, 4a-4f, 5a-5f and 7a-7f) were designed, synthesized and assayed for their antifungal activity toward seven representative plant fungal pathogens. In the in vitro antifungal assay, some title norbornene derivatives presented good antifungal activity against Botryosphaeria dothidea, Sclerotinia sclerotiorum and Fusarium graminearum. Especially, compound 2b exhibited the best inhibitory activity toward B. dothidea with the median effective concentration (EC50) of 0.17 mg L-1, substantially stronger than those of the reference fungicides boscalid and carbendazim. The in vivo antifungal assay on apples revealed that 2b had significant curative and protective effects, both of which were superior to boscalid. In the preliminary antifungal mechanism study, 2b was able to injure the surface morphology of hyphae, destroy the cell membrane integrity and increase the intracellular reactive oxygen species (ROS) level of B. dothidea. In addition, 2b could considerably inhibit the laccase activity with the median inhibitory concentration (IC50) of 1.02 μM, much stronger than that of positive control cysteine (IC50 = 35.50 μM). The binding affinity and interaction mode of 2b with laccase were also confirmed by molecular docking. This study presented a promising lead compound for the study of novel laccase inhibitors as fungicidal agrochemicals, which demonstrate significant anti-B. dothidea activity and laccase inhibitory activity. © 2024 Society of Chemical Industry.

Design and Synthesis of Quinoline‐Pyrazine Based Carboxamides: Leukemic Cancer Active Ugi Adducts

AbstractThe design and synthesis of new chemical entities (NCEs) with suitable physicochemical properties are playing a key role in medicinal research areas. Hence, we have designed and synthesized the 10 diverse scaffolds by rightly selecting the quinoline and pyrazine to articulate carboxamide derivatives in a single‐step process with maximum conversation in a shorter time through diverse studies of Ugi multi‐component reaction. Molecular docking studies against FMS‐like tyrosine kinase‐3 (FLT3) provided well‐clustered solutions for the binding modes of these molecules and shed light on the key structural features governing the binding affinity. Two carboxamides derivatives with 3,4,5‐trimethoxy, and chloro substituents showed comparable potency in Leukemia cell lines and medium efficacy in Breast and Melanoma cancer. These results suggest that pyrazine and quinoline‐based carboxamides may be prominent as new anti‐cancer agents in chemotherapy. Additionally, in silico analysis was employed to predict the comprehensive physicochemical ADME profile (absorption, distribution, metabolism, and excretion) of the carboxamide derivatives which was proven drug‐like properties.

Discovery of an enantiopure N-[2-hydroxy-3-phenyl piperazine propyl]-aromatic carboxamide derivative as highly selective α1D/1A-adrenoceptor antagonist and homology modelling

α1-Adrenergic receptor (AR) blockers can be effective for the treatment of benign prostatic hyperplasia/lower urinary tract symptoms (BPH/LUTS), their usage is limited by cardiovascular-related side effects that are caused by the subtype nonselective nature or low selectivity of many current drugs. We previously reported that phenylpiperazine analogues with amide and propane linker were moderate α1D/1A adrenoceptor antagonists and exhibited better anti-BPH effect than lead compound naftopidil (NAF) in vivo, however, with modest α1D/1A-subtype selectivity. Herein, we replaced propane moiety with 2-hydroxypropanol linker and synthesized twenty-seven racemic derivatives with modified aromatic and hetero aromatic groups. Of these new compounds, quinoline surrogate 17 exhibited extremely weak antagonistic affinity on α1B in both cell-based calcium assay and tissue-based functional assay, so that elicited significant α1A/1B and α1D/1B selectivity. Intriguingly, the R enantiomer of 17 preferentially displayed superior anti-BPH effect in rat model compared with S-17, supporting ligand regulates the receptor in a highly stereospecific manner. Finally, the computer-aided modelling research was also performed in order to deeply understand the unique binding mode of R-17 in complex with α1A and the subtype receptor selectivity for R-17 was also rationalized in this study. Taken together, our work enriched the diversity of phenylpiperazines for the treatment of BPH/LUTS, and provided a basis for discovery of α1D/1A-selective ligands.