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The carboxamide functional group has a privileged role in organic and biological chemistry due to its prevalence and utility across synthetic and natural products. Due to nN → π*CO delocalisation, amides and related functional groups are typically kinetically resistant to degradation. Nonetheless, over the past decade, transition metal catalysis has transformed our ability to utilise molecules featuring C(acyl)–N units as reactants. Alongside the burgeoning catalytic applications ranging from COx utilisation to small molecule synthesis, elucidation of the underlying mechanisms remains a critical ongoing effort. Herein, we aggregate and analyse current understanding of the mechanisms for C(acyl)–N functionalisation of amides and related functional groups with a focus on recent developments involving mechanisms unique to the late transition metals. Discussion is organized around three general mechanistic manifolds: redox-neutral mechanisms, 2e− redox-cycling mechanisms, and mechanisms involving 1e− redox steps. For each class, we focus on reactions that directly involve a transition metal mediator/catalyst in the C(acyl)–N cleavage step. We conclude with an outlook on the outstanding ambiguities and opportunities for innovation. [ABSTRACT FROM AUTHOR]

In this study, β-diketone derivative new carboxamide Eu(III) and Tb(III) lanthanide complexes were synthesized and characterized by FT-IR, elemental analysis, UV–Vis, and molar conductivity techniques. There is no electrolytic conductivity in the compounds. Moreover, the photoluminescence properties and thermal behavior of the synthesized lanthanide complexes were investigated. Photoluminescence data revealed that the Tb(III) complex showed metal-based f-f transitions. The β-diketone derivative carboxamide ligand exhibited as antenna that transmitted the excited energy to the emission energy levels of the Tb(III) ion. These metal complexes were screened in two different common cancer cell lines and a human normal embryonic kidney cell line for 48 h. The results showed that these complexes have more antiproliferative activities in the colon cancer cell line compared to the lung cancer cell line. [ABSTRACT FROM AUTHOR]

Reduction of carboxamides is an efficient approach to obtain the corresponding amines, albeit it is one of the most problematic. In this work, by use of pinacolborane (HBpin) as a reductant, the rare‐earth metal tris (arylamido) complex supported by a ferrocenyl‐modified arylamido ligand La[NH‐2,6‐iPr2‐4‐FcC6H2]3 was employed as a precatalyst for primary and secondary amide reductions. This catalyst system exhibited high activity toward hydroborative reduction of amides to amines under mild conditions, as well good tolerance for heteroatoms and functional groups in the reduction. A lanthanide hydride was experimentally verified as the active species and the reduction mechanism was proposed. [ABSTRACT FROM AUTHOR]

In this paper, we reported the development of an efficient and highly productive synthetic protocol for preparing new 2,5-diamino-1,3,4-thiadiazole derivatives functionalized with N-(2,2,2-trichloroethyl)carboxamide group. The method of their preparation was based on the reaction of oxidative dehydrosulfurization of N-(2,2,2-trichloro-1-(2-(phenylcarbamothioyl)hydrazine-1-carbothioamido)ethyl)-carboxamides and N-(1-(2-carbamothioylhydrazine-1-carbothioamido)-2,2,2-trichloroethyl)benzamide under the action of a mixture of iodine and triethylamine in DMF. This reaction took place at room temperature for two hours and allowed obtaining the target products with a 69-75% yield. Using the developed protocol, we obtained ten new derivatives of 1,3,4-thiadiazole. Their structure was proven by IR,1H NMR,13C NMR, 1H-1H COSY, 1H-13C HSQC, 1H-13C HMBC spectroscopy, and LC/HRMS spectrometry. [ABSTRACT FROM AUTHOR]

Succinate dehydrogenase inhibitor (SDHI) is an important fungicide to control grain diseases. For this reason, a series of novel pyrazole‐4‐carboxamide derivatives with an N‐methoxy group were designed and synthesized. All the target compounds were characterized by 1H NMR, 13C NMR, and HRMS. The compound 3c was further confirmed by X‐ray diffraction, which crystallized in the triclinic system, space group P‐1, Z = 2. The fungicidal activity results indicated that most of these compounds possessed good activity against Sclerotinia sclerotiorum at 50 ppm. Especially, compound 3h exhibited the best activity with the EC50 is 7.80 μg/mL, which is comparable with the positive control bixafen (EC50 = 6.70 μg/mL). Furthermore, the physicochemical properties, molecular docking simulation, ADMET analyses, DFT of compounds 3h, 3k and two commercial SDHIs, isoflucypram and pydiflumetofen, were investigated in this study. [ABSTRACT FROM AUTHOR]

Pd(II)‐catalyzed 2‐aminoacetophenone oxime‐assisted sp2 and sp3 C─H arylation of aryl carboxamides is disclosed. The 2‐aminoacetophenone oxime is an N,N‐bidentate auxiliary that proceeds C─H activation through a six‐membered palladacycle intermediate, and the activation/functionalization on C(sp3)─H bond by the six‐membered ligand palladacycle is novel and achieved. This auxiliary facilitates the subsequent sp3 and sp2 C─H bond activation/functionalization in one step. The optimized protocol enables access to various aryl groups at the β‐sp2‐ and γ‐sp3‐centers of aryl carboxamides. The bidentate auxiliary is easy to synthesize on a gram scale, and we also described deoximination procedure after C─H functionalization. [ABSTRACT FROM AUTHOR]

A new series of phenylalanine‐derived carboxamides with sulfonamide functionality is designed, synthesized, and assessed for their in silico studies, in vitro antimalarial, and antioxidant activities. The interaction of 4‐nitrobenzene sulfonyl chloride with phenylalanine in a basic aqueous solution yielded an intermediate ((4‐nitrophenyl)sulfonyl)phenylalanine. The reaction of various cyclic amines with the intermediate, utilizing phenylboronic acid as the coupling agent, yielded the carboxamides derivatives. The derived‐carboxamides passed in silico test and fulfilled all the allowed ranges for molecular descriptors. Optimization was achieved before compounds were deployed as ligands in molecular docking studies using density functional theory utilizing the functional B3LYP and the basis set 6–31G**. The docking experiments were done on the active site of FKBP35 binding domain of Plasmodium falciparum for antimalarial impact whereas that of antioxidants was performed on the active site of PDB ID:IXAN. The computational antimalarial and antioxidant study demonstrated that the compounds displayed a high binding affinity with the target protein residues via hydrogen bonding, π‐π, π‐alkyl, π‐sigma, and π‐cation bonding interactions. Additionally, the new compounds were evaluated for in vitro antimalarial and antioxidant properties. The screening findings suggest that the new compounds exhibit effective antimalarial and antioxidant action compared to traditional medicines. [ABSTRACT FROM AUTHOR]

Nitrile‐stabilized quaternary ammonium ylide as an effective aryl‐cyanomethylene transfer agent has been explored for the first time, which enables a spirocyclopropanation process with conjugated carboxamide of indole heterocycle. The developed In(OTf)3‐catalyzed method provides a straightforward, diastereoselective access to pharmaceutically relevant spiro‐cyclopropane‐2‐oxindole skeleton assembled with an α‐cyano and two (hetero)aromatic substitutions. The common difficulties of a cyclopropanation process, e. g. a conjugated carboxamide as valid substrate, cleavage‐susceptibility of amide bond, substrates scope limited to preferentially electron‐withdrawing group containing molecules, and the competing dehydrocyanation reaction of product generated from nitrile‐stabilized ylide have been overcome in the present spirocyclopropanation process. [ABSTRACT FROM AUTHOR]

Borylation of haloarenes is one of the most important methodologies to synthesize borylated arenes. Generally, borylation of haloarenes occurs smoothly at the sterically less hindered para or meta position by the use of a transition metal catalyst or a photoredox catalyst or under basic conditions. This study reports on the ortho -specific and chemoselective borylation of ortho -iodoarene possessing carboxamide under visible-light irradiation. When a haloarene containing both C–I and C–X bonds is employed as a substrate, another C–X bond (not ortho) remains intact during the reaction. Mechanistic studies revealed that the key to the success of this reaction is the generation of a diboron-bridged five-membered ring as a transition state, in which the diboron-bridged five-membered ring and the benzene ring in the transition state are perpendicular to each other, owing to steric repulsion by the iodine atom at the ortho position. This chemoselectivity is suitable for the synthesis of borylated building blocks. [ABSTRACT FROM AUTHOR]

A series of new 5-(trifluoromethyl)-benzo[d]imidazole linked N-phenylamide compounds was designed and synthesized using 1-chloro-2-nitro-4-(trifluoromethyl)benzene as raw material via five steps. Their structures were confirmed by 1H NMR, 13C NMR and HRMS. The bioassay results indicated that some of them exhibited moderate insecticidal activity (>50% inhibition) against Mythimna separata and Nilaparvata lugens at 500 μg/mL. [ABSTRACT FROM AUTHOR]

A facile synthetic routes to access some new heterocyclic systems containing potent pharmacophoric groups such as pyrazole, pyrazolo[5,1-c]-1,2,4-triazine, 1,2,4-triazino[4,3-a]benzimidazole, and pyridine moieties linked to pyridine-carboxamide moiety are reported. Construction of the target compounds was achieved via reaction of 3-oxo-butanamides 1a,b with hydrazonoyl halides, heterocyclic diazonium salts, and malononitrile derivatives, respectively. The structures of the new products were confirmed by all possible spectral and elemental analyses. The antibacterial assessment showed that one product was moderately active against both K. pneumonia and S. aureus. [ABSTRACT FROM AUTHOR]

Rationale: The phenylalkylamine hallucinogen (-)-2,5-dimethoxy-4-methylamphetamine (DOM) exhibits an inverted U-shaped dose-response curve for both head twitch response (HTR) and locomotor activity in mice. Accumulated studies suggest that HTR and locomotor hyperactivity induced by DOM are mainly caused by the activation of serotonin 5-hydroxytryptamine 2 A receptor (5-HT2A receptor). However, the mechanisms underlying the biphasic dose response of HTR and locomotor activity induced by DOM, particularly at high doses, remain unclear. Objectives: The primary objective of this study is to investigate the modulation of 5-HT2A/2C/1A receptors in HTR and locomotor activity, while also exploring the potential receptor mechanisms underlying the biphasic dose response of DOM. Methods: In this study, we employed pharmacological methods to identify the specific 5-HT receptor subtypes responsible for mediating the biphasic dose-response effects of DOM on HTR and locomotor activity in C57BL/6J mice. Results: The 5-HT2A receptor selective antagonist (R)-[2,3-di(methoxy)phenyl]-[1-[2-(4-fluorophenyl)ethyl]piperidin-4-yl]methanol (M100907) (500 µg/kg, i.p.) fully blocked the HTR at every dose of DOM (0.615–10 mg/kg, i.p.) in C57BL/6J mice. M100907 (50 µg/kg, i.p.) decreased the locomotor hyperactivity induced by a low dose of DOM (0.625, 1.25 mg/kg, i.p.), but had no effect on the locomotor hypoactivity induced by a high dose of DOM (10 mg/kg) in C57BL/6J mice. The 5-HT2C antagonist 6-chloro-5-methyl-1-[(2-[2-methylpyrid-3yloxy]pyrid-5yl)carbamoyl]indoline (SB242084) (0.3, 1 mg/kg, i.p.) reduced the HTR induced by a dose of 2.5 mg/kg DOM, but did not affect the response to other doses. SB242084 (1 mg/kg, i.p.) significantly increased the locomotor activity induced by DOM (0.615–10 mg/kg, i.p.) in mice. The 5-HT1A antagonist N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]N-(2-pyridinyl) cyclohexane carboxamide maleate (WAY100635) (1 mg/kg, i.p.) increased both HTR and locomotor activity induced by DOM in mice. The 5-HT1A agonist 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) (1 mg/kg, i.p.) significantly reduced both the HTR and locomotor activity induced by DOM in mice. Additionally, pretreatment with the Gαi/o inhibitor PTX (0.25 µg/mouse, i.c.v.) enhanced the HTR induced by DOM and attenuated the effect of DOM on locomotor activity in mice. Conclusions: Receptor subtypes 5-HT2C and 5-HT1A are implicated in the inverted U-shaped dose-response curves of HTR and locomotor activity induced by DOM in mice. The biphasic dose-response function of HTR and locomotor activity induced by DOM has different mechanisms in mice. [ABSTRACT FROM AUTHOR]

Highlighting the potential of Iqbal multicomponent reaction (MCR), a streamlined two‐step MCR synthetic strategy is proposed for the rapid assembly of structurally complex tripeptidyl ketones, which are valuable building blocks for developing novel peptidomimetics. The approach utilizes consecutive Iqbal MCR and Ugi MCR under mild room temperature conditions, eliminating the need for laborious column chromatography purification. This work demonstrates Iqbal MCR's propensity to generate a diverse library of N‐(3‐oxopropyl) carboxamides containing carboxyl functionality, which can be readily elaborated further to tripeptidyl ketones through subsequent Ugi MCR. [ABSTRACT FROM AUTHOR]

The synthesis of carbon–heteroatom bonds, a crucial element in organic chemistry, often requires obstacles in direct amine integration with olefins. This study introduces a sustainable approach for producing nitrogen-bearing molecules through the Markovnikov hydroamination of vinylarenes with carboxamides, employing Hβ zeolite as an effective heterogeneous catalyst in a solvent-free environment. We explored the method's adaptability over various substrates, achieving consistently high yields and regioselectivity in the resultant products. The procedure's scalability to gram-level production and the catalyst's sustainable reuse for multiple cycles (up to five) underscores its viability for industrial application, indicating a significant increase in organic synthesis activity. [ABSTRACT FROM AUTHOR]

In this work, we report the synthesis of a series of new 4H‐1,3,5‐oxadiazine derivatives. The method of their production is based on the dehydrosulfurization reaction of N‐(2,2,2‐trichloro‐1‐(3‐R‐thioureido)ethyl)carboxamides under the action of a mixture of iodine and triethylamine in DMF. A possible reaction mechanism has been proposed. The target products have been obtained in 58%–75% yield. The structure of the obtained compounds has been confirmed by 1H, 13C NMR, IR spectroscopy data, and x‐ray diffraction analysis carried out for 6‐(tert‐butyl)‐N‐phenyl‐4‐(trichloromethyl)‐4H‐1,3,5‐oxadiazin‐2‐amine. [ABSTRACT FROM AUTHOR]

Triphenylene derivatives are highly investigated for their electronic, supramolecular and photophysical properties, but the direct modification of the central aromatic core is particularly challenging especially in the internal positions 1, 4, 5, 8, 9, and 12. Herein we present an efficient alkylation method of 2,3,6,7,10,11‐hexasubstituted triphenylene derivatives leading to tris‐alkylated C3‐symmetric derivatives in good yields using N‐(hydroxymethyl)carboxamide or N‐(alkoxylmethyl)carboxamide alkylating agents. [ABSTRACT FROM AUTHOR]

The facile generation of the α‐acyloxy carboxamide radical is hereby reported for the first time, utilizing a photoredox catalyzed reaction of Passerini adducts synthesized using a 4‐formyl‐1,4‐dihydropyridine as the carbonyl component. This radical effectively engages in a Giese reaction with a range of olefins, ultimately leading to the synthesis of novel Passerini‐derived products not previously amenable to direct aldehyde‐based transformations. Consequently, the resulting strategy, developed both in batch and in flow, offers a promising opportunity to expand the chemical space accessible through the Passerini reaction, virtually incorporating "impossible" aldehydes. [ABSTRACT FROM AUTHOR]

Here we report the development of a concise and efficient synthetic protocol for the preparation of 1H-perimidin-2-amine derivatives that contain an N-(2,2,2-trichloroethyl)carboxamide substituent near the amino group. These compounds' synthesis method is based on the interaction of naphthalene-1,8-diamine with N-(2,2,2-trichloro-1-isothiocyanatoethyl)carboxamides under reflux in acetonitrile medium for 15 minutes. This transformation is likely to pass through the stage of formation of the intermediate thiourea, which further eliminates hydrogen sulfide, which is accompanied by the closure of the perimidine cycle. Using the developed protocol, we synthesized nine new 1H-perimidin-2-amine derivatives. The yield of synthesized compounds was 67-82%. IR,1H NMR,13C NMR, 1H-1H COSY, 1H-13C HSQC, and 1H-13C HMBC spectroscopy data proved their structures. [ABSTRACT FROM AUTHOR]

The unusual reactivity of key enamine intermediates led to the formation of 3-methylamino-2-(2-nitrobenzoyl)-4H-naphthalen-1-one as an unexpected product in an attempted synthesis of the P. aeruginosa metabolite 2-benzyl-4(1H)-quinolone. Although the synthesis of the natural product has not been successful, this methodology allows for the easy preparation of novel derivatives carrying a carboxamide moiety at the C3 position. [ABSTRACT FROM AUTHOR]

This research examines how heteroatoms in a six- or five-membered pyridine, thiophene or furan ring spacer between two carboxamide groups influence the hydrogen bonding for advancements in supramolecular chemistry and drug development. The solvent-free crystal structures of 3,5-pyridinedicarboxamide (PDC), 2,5-thiophenedicarboxamide (TDC) and 2,5-furandicarboxamide (FDC-subl, crystallized by sublimation), and the monohydrate structure of FDC-solv (crystallized from methanol) are described with the hydrogen-bonding analyzed by the Etter graph-set notation. The carbon atoms of the amide groups form an angle of 121° in PDC, 151° in TDC, 137° in FDC-solv and 135° in FDC-subl with the ring centroid. Only in the structure of PDC does the heteroatom act as an H-bond acceptor as part of a C 1 1 (6) chain. In TDC and FDC, the heteroatoms do not interact with the amide -NH2 groups. [ABSTRACT FROM AUTHOR]

In continuation of our previous efforts for the development of potent small molecules against brain cancer, herein we synthesized seventeen new compounds and tested their anti-gliomapotential against established glioblastoma cell lines, namely, D54MG, U251, and LN-229 as well as patient derived cell lines (DB70 and DB93). Among them, the carboxamide derivatives, BT-851 and BT-892 were found to be the most active leads in comparison to our established hit compound BT#9.The SAR studies of our hit BT#9 compound resulted in the development of two new lead compounds by hit to lead strategy. The detailed biological studies are currently underway. The active compounds could possibly act as template for the future development of newer anti-glioma agents.

We report herein a blue‐light‐promoted iron‐catalyzed reduction of carboxamides and carboxylic esters. Conducting the reaction under hydrosilylation conditions and blue light (2×24 W, 450–460 nm) in the presence of an iron(0) based pre‐catalyst, Fe(CO)4(IMes), amines and alcohols were obtained, respectively, notably at ambient conditions, whereas using white light, higher reaction temperatures up to 100 °C were required. Preliminary mechanism studies highlighted the crucial role of blue light not only to generate the catalytic active species, but also in some steps of the catalytic cycle. [ABSTRACT FROM AUTHOR]

A novel and highly efficient technique has been demonstrated for the transamidation of N-tert-butoxycarbonyl (N-Boc) activated secondary amides, as well as the direct amidation of esters with amines, resulting in the formation of amide bonds. This technique exhibits exceptional selectivity in cleaving N–C/O–C bonds and utilizes Co@NC as a highly efficient magnetic nano-catalyst. The method stands out for its solvent-free conditions, environmentally friendly catalyst, straightforward work-up, and the ability to easily reclaim (aided by an external magnet) and reuse the catalyst for up to five cycles without significant loss of catalytic activity, showcasing both novelty and efficiency. [ABSTRACT FROM AUTHOR]

Many 1,2,4-triazole derivatives have high biological activity. They are of interest for scientific and practical human activity as potential drugs and pesticides. In this work, we report a synthesis of a series of new 3-amino-1,2,4-triazole derivatives containing an alkylamide moiety. It was found that the amidoalkylation of 3-amino-1,2,4-triazole N-(1,2,2,2-tetrachloroethyl)carboxamides in the presence of triethylamine occurred selectively at the endocyclic nitrogen atom N-1 with the formation of the corresponding N-(1-(5-amino-1H-1,2,4-triazol-1-yl)-2,2,2-trichloroethyl)carboxamides. The reaction products were isolated in 79–85% yields and characterized by 1H NMR and 13C NMR spectroscopy. To unambiguously establish the structure of the obtained compounds, we carried out X-ray diffraction analysis for N-(1-(5-amino-1H-1,2,4-triazol-1-yl)-2,2,2-trichloroethyl)-3-methylbutanamide. [ABSTRACT FROM AUTHOR]

A four-step synthesis of the natural product pseudane IX, starting from 3-oxododecanoic acid phenylamide and including only one chromatographic purification, was accomplished with an overall yield of 52%. The same synthetic sequence, but with a controlled partial reduction of a nitro group in the penultimate intermediate, led to the N-oxide of pseudane IX (NQNO). A shortened three-step variation of the synthesis allowed for the preparation of novel carboxamide analogs of the natural product. An agar diffusion assay against six different bacterial strains revealed significant antibacterial activity of the novel analogs against S. aureus at a concentration of 100 µg/mL. One of the novel compounds showed a remarkably broad spectrum of antibacterial activity, comparable to that of the positive control NQNO. [ABSTRACT FROM AUTHOR]

Herein, we report the design, synthesis, and supramolecular behavior of 30 structurally diverse photoresponsive azobenzene molecular systems. To establish structure–property relationships, azobenzenes appended with N‐picolinyl and/or N‐benzyl groups tethered directly through carboxamides or via triazolylmethyl carboxamide linkages were explored. We have evaluated the photoswitching characteristics and thermal stability of the Z isomers through systematic studies. All the targets were also screened for their aggregation behavior and supramolecular aspects. Among all the derivatives, a few carboxamide‐based systems formed microcrystals upon aggregation, showing light responsiveness. In contrast, the derivatives tethered via triazolylmethyl carboxamide linkage exhibited hydrogel formation with excellent water‐absorbing capacity. All supramolecular aspects of the morphology of the microcrystal and hydrogel states and their stimuli‐responsiveness have been studied using spectroscopy and various microscopic techniques. [ABSTRACT FROM AUTHOR]

Background: Quinoline is a significant heterocyclic moiety involved in several biological activities including inhibition of transient receptor potential vanilloid 1. Materials and Methods: A series of 5-amino(N-substituted carboxamide)quinoline derivatives (2o-2t) were synthesized through two steps. FT-IR, 1H NMR and mass spectrum techniques were used to confirm these obtained derivatives. Using acetic acid-induced writhing in rats, all the compounds were tested for TRPV1 inhibition by antinociceptive action. The stomach tissue was investigated by histopathology for checking the ability of synthesized derivatives to damage the stomach mucosa. Also, the biochemical analysis of blood serum was carried out to check the nephrotoxicity and hepatotoxicity. Results: All the derivatives (2o-2t) having the dose of 200 mg/kg gave good TRPV1 inhibition by antinociceptive activity. Among all, the derivatives 2q, 2r and 2s had a percentage inhibition of 43.90%, 34.15% and 39.04% respectively when compared with a dose of 100 mg/kg of Ibuprofen (48.78%). Conclusion: A novel 5-amino (N-substituted carboxamide) quinoline compounds are shown to be an intriguing place to start for further investigation into potent and reliable TRPV1 inhibitors. [ABSTRACT FROM AUTHOR]

An organocatalyzed three‐component protocol using diazoacetonitrile to access a wide range of cyanopyrazole derivatives is reported here. This strategy, which proceeds through a piperidine‐catalyzed Knoevenagel condensation/formal [3+2] cycloaddition/dehydrocyanation sequence, provides an efficient route to construct dicyanopyrazoles from aldehydes, malononitrile, and diazoacetonitrile regioselectively. Interestingly, by engaging cyanoacetate and cyanoacetamide in this protocol, we could achieve cyanopyrazole esters and carboxamides. [ABSTRACT FROM AUTHOR]

The nature of protecting group chemistry necessitates a deprotection step to restore the initially blocked functionality prior to further transformation. As this aspect of protecting group manipulation inevitably adds to the step count of any synthetic sequence, the development of methods enabling simultaneous deprotection and functionalization ("deprotective functionalization"—distinct from "deprotection followed by functionalization") is appealing, as it has the potential to improve efficiency and streamline synthetic routes. Herein, we report a deprotective functionalization of the newly introduced Nms‐amides guided by density functional theory (DFT) analysis, which exploits the inherent Nms reactivity. Mechanistic studies further substantiate and help rationalize the exquisite reactivity of Nms‐amides, as other commonly used protecting groups are shown not to exhibit the same reactivity patterns. The practicality of this approach was ultimately demonstrated in selected case studies. [ABSTRACT FROM AUTHOR]

This work presents the design, synthesis and biological activity of novel N-substituted benzimidazole carboxamides bearing either a variable number of methoxy and/or hydroxy groups. The targeted carboxamides were designed to investigate the influence of the number of methoxy and/or hydroxy groups, the type of substituent placed on the N atom of the benzimidazole core and the type of substituent placed on the benzimidazole core on biological activity. The most promising derivatives with pronounced antiproliferative activity proved to be N-methyl-substituted derivatives with hydroxyl and methoxy groups at the phenyl ring and cyano groups on the benzimidazole nuclei with selective activity against the MCF-7 cell line (IC50 = 3.1 μM). In addition, the cyano-substituted derivatives 10 and 11 showed strong antiproliferative activity against the tested cells (IC50 = 1.2–5.3 μM). Several tested compounds showed significantly improved antioxidative activity in all three methods compared to standard BHT. In addition, the antioxidative activity of 9, 10, 32 and 36 in the cells generally confirmed their antioxidant ability demonstrated in vitro. However, their antiproliferative activity was not related to their ability to inhibit oxidative stress nor to their ability to induce it. Compound 8 with two hydroxy and one methoxy group on the phenyl ring showed the strongest antibacterial activity against the Gram-positive strain E. faecalis (MIC = 8 μM). [ABSTRACT FROM AUTHOR]

The advancement of sustainable chemistry and changes in the economy are strongly intertwined. Reaction time, cost savings, moderate temperatures, and generation of the fewest byproducts are frequently achieved by using catalytic processes. Herein, we report the C−H olefination of imidazo[1,2a] pyridine carboxamides with various acrylates in the presence of Pd (OAc)2 with O2 as the oxidant in aqueous ethanol rather than using non‐ecofriendly solvents. The C−H activation features most user‐friendly reaction conditions, excellent yield as well as plenty substrate scope and applicable for C−H deuteriation of the corresponding heteroarenes with D2O. Experimental mechanistic studies indicate that C−H activation step succeeded after formation of tetra coordinated square planer Pd‐substrate adduct. [ABSTRACT FROM AUTHOR]

A series of novel carboxamide compounds containing benzoxazole motif was synthesized through multiple steps, including electrophilic substitution, cyclization, reduction and amide formation. These processes utilized ortho-aminophenol and heptafluoro-2-iodopropane as starting materials. The structures of these compounds (4a–4r) were characterized by 1H NMR, 13C NMR, and HRMS. Bioassay results revealed that most of these compounds exhibited significant insecticidal activity against Mythimna separata at 500 mg/L. Among them, compound 6-chloro-N-(4-methoxy-3-(6-(perfluoropropan-2-yl)benzo[d]oxazol-2-yl)phenyl)-N-methylnicotinamide (4r) possessed the highest activity, even at 4 mg/L. Molecular docking predicted the binding modes of 4r. These novel carboxamide compounds containing benzoxazole motifs offer valuable insights for designing insecticidal compounds targeting GABA receptors, aiming to control lepidopteran pests effectively. [ABSTRACT FROM AUTHOR]

Novel 1-(3-arylbenzo[c]isoxazol-5-yl)-1H-1,2,3-triazole-4-carboxamides were designed, synthesizing and evaluated for antimicrobial activity toward five key ESKAPE pathogenic bacteria, one Gram-positive bacteria methicillin-resistant Staphylococcus aureus (ATCC 43300), four Gram-negative bacteria, Escherichia coli (ATCC 25922), Klebsiella pneumonia (ATCC 700603), Acinetobacter baumannii (ATCC 19606), and Pseudomonas aeruginosa (ATCC 27853) and antifungal activity towards two pathogenic fungal strains Candida albicans (ATCC 90028) and Cryptococcus neoformans var. Grubii (H99; ATCC 208821). The target compounds were obtained in a convenient synthetic path including consequent Dimroth cyclocondensation of 4-nitrophenyl azide with β-ketoesters, vicarious nucleophilic substitution in nitroaryl fragments and amidation of 1,2,3-triazole-4-carboxylic acid motif. In this way, a mini combinatorial library of 24 compounds was obtained with good overall yields. Five compounds, 7a, 7b, 7i, 7t and 7u, reduced the growth of microorganisms by approximately 20 %. Compounds 7b, 7i, and 7u demonstrated the inhibitory activity towards Staphylococcus aureus. In contrary 7a and 7t towards Cryptococcus neoformans. The data obtained will be used for further design and scaffold optimization. [ABSTRACT FROM AUTHOR]

Introduction: 3-(2-butyl-5-chloro-1H-imidazole-4-yl)-N-[4-methoxy-3-(trifluoromethyl)phenyl]-4,5- dihydro-1,2-oxazole-5-carboxamide is new antirheumatic drug. It is necessary to identify and synthesize the biotransformation products for its complete pharmacokinetic study. Material and Methods: A biotransformation study was carried out by intraperitoneal administration of the drug to Wistar rats and Soviet Chinchilla breed rabbits. Animal blood sampling was performed before the injection and 0.5 h, 1 h, 2 h, 4 h, 24 h after the injection of the investigated compound. The samples were immediately centrifuged for plasma separation. Urine was simultaneously collected from rats before the administration and at intervals of 0-2 h, 2-4 h, 4-6 h, 6-24 h after administration, faeces -- before administration and at intervals of 0-12 h and 12-24 h after administration. The samples were analyzed by HPLC-MS/MS after immediate preparation by adding acetonitrile. Results and Discussion: 3-(2-butyl-5-chloro-1H-imidazole-4-yl)-4,5-dihydro-1,2-oxazole-5-carboxylic acid and 4-methoxy-3-(trifluoromethyl)aniline -- hydrolysis products of the active substance were found during the analysis of plasma, urine and fecal samples. The 4,5-dihydro-1,2-oxazole-5-carboxylic acid derivative has been synthesized. The second metabolite is a raw material for production of active pharmaceutical substance. During comparative tests, no significant difference between the retention times, ratio areas of chromatographic peaks at the main MRM-transitions and mass spectra of these metabolites on chromatograms of standard and animal samples was found, which indicates the correct identification of biotransformation products. Conclusion: The studied drug undergoes biotransformation by hydrolysis to form two main metabolites: 3- (2-butyl-5-chloro-1H-imidazole-4-yl)-4,5-dihydro-1,2-oxazole-5-carboxylic acid and 4-methoxy-3- (trifluoromethyl)aniline. The structure of the metabolites was confirmed by comparison with the synthesized standard samples using HPLC-MS/MS. [ABSTRACT FROM AUTHOR]

Bicyclo[1.1.1]pentane (BCP) carboxamides are prepared from the direct addition of [1.1.1]propellane with semicarbazides in the presence of iron(II) phthalocyanine {Fe(Pc)} and tert‐butyl hydroperoxide (TBHP) in moderate to good yields. BCP ketones are also obtained under similar conditions in moderate yields. This protocol provides a straightforward one‐step access to BCP carboxamides, synthesis of which requires multiple chemical steps in previous reports. [ABSTRACT FROM AUTHOR]

Tridentate bis(carboxamide) pincers are key ligands used in catalysis, investigational medicinal inorganic compounds, and materials science. This study examined the atropisomerism of a group of bis(carboxamide) pincers with C2 symmetry to elucidate their physical, chemical, and structural behaviour, paving the way for the application of their metal complexes in different fields. One of the five compounds structurally elucidated by X-ray crystallography, 1c, has a pair of intramolecularly constrained isoquinoline ring substituents and crystallized enantiomerically pure in a chiral Sohncke space group. PM6 calculations of the 3-D potential energy surface for the main atropisomerisation reaction coordinate of 1c indicated that the lowest-energy conformer (atropisomer) has the isoquinoline rings canted out-of-plane by almost +30° and −30° relative to the central pyridine ring. The X-ray structure of 1c is located close to this energy minimum. Circular dichroism (CD) spectroscopy on bulk solid samples confirmed the presence of an excess population of one enantiomer (C2-symmetric atropisomer), most notably for compounds 1c, 1e, and 1f. CD spectra could be recorded for all compounds in solution, similarly reflecting an excess population of one atropisomer. The experimental spectra were confirmed by TD-DFT simulations at the CAM-B3LYP/def2-tzvp level of theory. We conclude that the present group of ligands are worthy of further investigation as chelating agents for metal ions with applications in chiral catalysis or biology. [ABSTRACT FROM AUTHOR]

[Display omitted] Iodocyclization of N -(2-alkenylphenyl)carboxamides with acetoxybenziodoxolone/NaI system gives 4-iodomethyl- 4 H -3,1-benzoxazines with high efficiency. The process is triggered by the oxidation of NaI with acetoxybenziodo- xolone to afford iodine cation which is added to alkene moiety to form iodonium species, and the ultimate intra- molecular nucleophilic addition generates the final products. [ABSTRACT FROM AUTHOR]

The 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. [ABSTRACT FROM AUTHOR]

Plant diseases caused by pathogenic fungi or oomycetes seriously affect crop growth and the quality and yield of products. A series of novel 1,2,4-triazole derivatives containing carboxamide fragments based on amide fragments widely used in fungicides and the commercialized mefentrifluconazole were designed and synthesized. Their antifungal activities were evaluated against seven kinds of phytopathogenic fungi/oomycete. Results showed that most compounds had similar or better antifungal activities compared to mefentrifluconazole's inhibitory activity against Physalospora piricola, especially compound 6h (92%), which possessed outstanding activity. Compound 6h (EC50 = 13.095 μg/mL) showed a better effect than that of mefentrifluconazole (EC50 = 39.516 μg/mL). Compound 5j (90%) displayed outstanding anti-oomycete activity against Phytophthora capsici, with an EC50 value of 17.362 μg/mL, far superior to that of mefentrifluconazole (EC50 = 75.433 μg/mL). The result of molecular docking showed that compounds 5j and 6h possessed a stronger affinity for 14α-demethylase (CYP51). This study provides a new approach to expanding the fungicidal spectrum of 1,2,4-triazole derivatives. [ABSTRACT FROM AUTHOR]

Cyanide represents a persistent threat for accidental or malicious misuse due to easy conversion into a toxic gas and access to large quantities through several industries. The high safety index of hydroxocobalamin is a cornerstone quality as a cyanide scavenger. Unfortunately, intravenous infusion of hydroxocobalamin limits the utility in a mass casualty setting. We previously reported platinum(II) [Pt(II)] complexes with trans-directing sulfur ligands as an efficacious alternative to hydroxocobalamin when delivered by a bolus intramuscular (IM) injection in mice and rabbits. Thus, to enable Pt(II) as an alternative to hydroxocobalamin, a high safety factor is needed. The objective is to maintain efficacy and mitigate the risk of nephrotoxicity. Platinum amino acid complexes with the ability to form 5- or 6-membered rings and possessing either carboxylates or carboxamides are evaluated in vitro for cyanide scavenging. In vivo efficacy wa s evaluated in the zebrafish and mice cyanide exposure models. In addition, Pt(II) complex toxicity and pharmacokinetics were evaluated in a cyanide naive Sprague Dawley model. Doses for toxicity are escalated to 5× from the efficacious dose in mice using a body surface area adjustment. The results show the carboxamide ligands display a time and pH dependence on cyanide scavenging in vitro and efficacy in vivo. Additionally, exchanging the carboxylate for carboxamide showed reduced indications of renal injury. A pharmacokinetic analysis of the larger bidentate complexes displayed rapid absorption by IM administration and having similar plasma exposure. These findings point to the importance of pH and ligand structures for methionine carboxamide complexes with Pt(II). [ABSTRACT FROM AUTHOR]

The organocatalytic enolization of 2‐arylacetamides, followed by an enantioselective intramolecular conjugate addition to tethered 2,5‐cyclohexadienones, yielding 3D fused N‐heterocycles, is described. The transformation represents the first strong activating group‐free activation of carboxamides via α‐C−H deprotonation in a metal‐free, catalytic, and enantioselective reaction, and is achieved by employing a bifunctional iminophosphorane (BIMP) superbase. [ABSTRACT FROM AUTHOR]

A single-site Fe(III) carboxamide complex, [Fe(HbpH) (Cl) 2 ] (1), (HbpH‾ = N,N′-Bis(picolinoyl)hydrazine) anion), was synthesized and used as the electrocatalyst of water oxidation reaction. Complex 1 catalyzes the oxidation of water to O 2 at the pH of 8 in phosphate buffer solution with the onset of a catalytic wave at about 0.45 V versus RHE with the turnover frequency (TOF) of 5.8 s−1 at room temperature. The stability of the catalyst in water oxidation processes by electrochemical and UV–vis measurements, demonstrated the realistic molecular electrocatalysis of 1. Differential pulse voltammetry (DPV) of 1 in different pH values showed the dependency of oxidation potential to the pH of the environment, establishing the fact that the catalytic cycle involves the proton-coupled electron transfer (PCET) process. Density functional theory (DFT) calculations on the mechanism of water oxidation process of 1 shows that the oxygen evolution reaction is carried out through the water nucleophilic attack (WNA) to the metal center ion, resulted to the formation of FeIV(O) species. Also, DFT calculations showed that the formation of an O–O bond proceeds through the interaction two molecular mechanism (I2M), which compete with the WNA mechanism following from experimental analysis. The electroactivity of the metal centre and carboxamide ligand and the ability of the ligand to stabilize the high oxidation numbers of the metal-ion centre during the oxidation process, provide different oxidation pathways for an OER process. • Synthesis of carboxamide Fe(III) complex using ionic liquid as an environmentally benign reaction medium. • Electrocatalytic studies of the [Fe(HbpH) (Cl) 2 ] (1) in the OER process. • TOF values of 5.8 mol of hydrogen in each mole of catalyst per second for the catalyst 1. • The I2M mechanism competes with the WNA mechanism investigation using DFT calculations in OER process. [ABSTRACT FROM AUTHOR]

A nickel-catalyzed hydrogen isotope exchange has been developed with acetone-d6 as the deuterium source. The reaction showed an improved kinetic feature of H/D exchange under the assistance of 2-pyridones, efficiently affording regioselective labeled aryl and alkyl carboxamides. [ABSTRACT FROM AUTHOR]

Borane-pyridine acts as an efficient (5 mol%) liquid catalyst, providing improved solubility for the direct amidation of a wide range of aromatic and aliphatic carboxylic acids and amines to form secondary and tertiary carboxamides. Tolerance of potentially incompatible halo, nitro, and alkene functionalities has been demonstrated. [ABSTRACT FROM AUTHOR]

In this work, the privileged scaffold of 4-hydroxy-2quinolinone is investigated through the synthesis of carboxamides and hybrid derivatives, as well as through their bioactivity evaluation, focusing on the ability of the molecules to inhibit the soybean LOX, as an indication of their anti-inflammatory activity. Twenty-one quinolinone carboxamides, seven novel hybrid compounds consisting of the quinolinone moiety and selected cinnamic or benzoic acid derivatives, as well as three reverse amides are synthesized and classified as multi-target agents according to their LOX inhibitory and antioxidant activity. Among all the synthesized analogues, quinolinone–carboxamide compounds 3h and 3s, which are introduced for the first time in the literature, exhibited the best LOX inhibitory activity (IC50 = 10 μM). Furthermore, carboxamide 3g and quinolinone hybrid with acetylated ferulic acid 11e emerged as multi-target agents, revealing combined antioxidant and LOX inhibitory activity (3g: IC50 = 27.5 μM for LOX inhibition, 100% inhibition of lipid peroxidation, 67.7% ability to scavenge hydroxyl radicals and 72.4% in the ABTS radical cation decolorization assay; 11e: IC50 = 52 μM for LOX inhibition and 97% inhibition of lipid peroxidation). The in silico docking results revealed that the synthetic carboxamide analogues 3h and 3s and NDGA (the reference compound) bind at the same alternative binding site in a similar binding mode. [ABSTRACT FROM AUTHOR]

Succinate dehydrogenase (SDH, EC 1.3.5.1) is one of the most promising targets for fungicide development and has attracted great attention worldwide. However, existing commercial fungicides targeting SDH have led to the increasingly prominent problem of pathogen resistance, so it is necessary to develop new fungicides. Herein, we used a structure-based molecular design strategy to design and synthesize a series of novel SDHI fungicides containing an N-(alkoxy)diphenyl ether carboxamide skeleton. The mycelial growth inhibition experiment showed that compound M15 exhibited a very good control effect against four plant pathogens, with inhibition rates of more than 60% at a dose of 50 μg/mL. A structure–activity relationship study found that N-O-benzyl-substituted derivatives showed better antifungal activity than others, especially the introduction of a halogen on the benzyl. Furthermore, the molecular docking results suggested that π–π interactions with Trp35 and hydrogen bonds with Tyr33 and Trp173 were crucial interaction sites when inhibitors bound to SDH. Morphological observation of mycelium revealed that M15 could inhibit the growth of mycelia. Moreover, in vivo and in vitro tests showed that M15 not only inhibited the enzyme activity of SDH but also effectively protected rice from damage due to R. solani infection, with a result close to that of the control at a concentration of 200 μg/mL. Thus, the N-(alkoxy)diphenyl ether carboxamide skeleton is a new starting point for the discovery of new SDH inhibitors and is worthy of further investigation. [ABSTRACT FROM AUTHOR]

The Cp*Co(III) C−H allylation of (hetero)arenes with allyl aryl ethers has been developed using an amide as directing group (24 examples). DFT calculations have shed light on the mechanistic course and reactivity pattern, showing that strong electron releasing groups favour the reaction by reducing the activation barrier of the rate‐determining C−H activation step. However, the steric strain can increase the energy of the migratory insertion step to the point of completely preventing the reaction, as in the case of the 3,5‐dimethylbenzamide. The obtained allylated compounds have been transformed into a variety of interesting heterocyclic and carbocyclic structures, such as isoquinolones and isochromanones. [ABSTRACT FROM AUTHOR]