Aryl Carboxamides Research Articles

An insight into the structure-activity relationship studies of anticancer medicinal attributes of 7-azaindole derivatives: a review.

In the current portfolio, there is a lot of interest in the 7-azaindole building block for drug discovery. The creation of synthetic, sophisticated methods for the modification of 7-azaindoles is a promising area of research. This review covers the structure-activity relationship of 7-azaindole analogs, which have been shown to beeffective anticancer agents in the literature of the past twodecades. Positions 1, 3and 5 of the 7-azaindole ring arethe most active sites. Disubstitution is used for the synthesis of a new analog of the 7-azaindole moiety. All positions are used to create novel molecules that areeffective anticancer agents. The alkyl, aryl carboxamide group and heterocyclic ring are the most successful types of substitution.

Carbon-Nitrogen Bond Formation Using Sodium Hexamethyldisilazide: Solvent-Dependent Reactivities and Mechanisms.

The solvent-dependent reactivity of sodium hexamethyldisilazide (NaHMDS) toward carbon-centered electrophiles reveals reactions that are poorly represented or unrepresented in the literature, including direct aminolysis of aromatic methyl esters to give carboxamides, nitriles, or amidines, depending on the choice of solvent. SNAr substitutions of aryl halides and opening of terminal epoxides are also examined. A combination of 1H and 29Si nuclear magnetic resonance (NMR) spectroscopic studies using [15N]NaHMDS, kinetic studies, and computational studies reveals the complex mechanistic basis of the preferences for simple aryl carboxamides in toluene and dimethylethylamine and arylnitriles or amidines in tetrahydrofuran (THF). A prevalence of dimer- and mixed dimer-based chemistry even starting from the observable NaHMDS monomer in THF solution is notable.

Regulating exchange dynamics in poly(β-hydrazide esters) via push-pull electronic effects towards covalent adaptable networks with fast reprocessing

Poly(β-hydrazide esters), prepared by the aza-Michael addition of a hydrazide to an acrylate moiety, have been used to accelerate the dissociation rates of dynamic aza-Michael adducts via push-pull electronic effects to create covalent adaptable networks (CANs) with faster reprocessing rates. Hydrazide precursors containing aryl groups that can conjugate with the carboxamide functionality can increase the electron density on the terminal amine of the hydrazide (push electronic effect). On the other hand, hydrazide precursors containing alkyl groups that cannot conjugate with the carboxamide will have terminal amines that are more electron-deficient since part of its electron density is donated to the carbonyl group (pull electronic effect). We used small molecule models of the CANs to show that the push electronic effect of the aryl carboxamide group accelerated the dissociation rates of the dynamic aza-Michael adducts and significantly increased the reversibility of the Michael addition. In contrast, the pull electronic effect of the alkyl carboxamide groups reduced the dissociation rates of the dynamic aza-Michael adducts. Likewise, when we examined the reprocessing of the CANs, the poly(β-hydrazide esters) with the push electronic effect had lower stress relaxation times (69–79 s) and reprocessing times than their congeners with the pull electronic effect (182–3760 s). They can be reprocessed at least 10 times when heated to 180 °C for 0.5 h. Regulating the thermal stability of the dynamic aza-Michael adducts can thus reduce the dependence of the reprocessing performance of the CANs on the boiling points of the monomers. In addition, these poly(β-hydrazide esters) show excellent heat resistance (Tg = 113 °C andTd-5% = 279 °C). Thus, the push-pull electronic effect of the carboxamide groups provides a useful strategy to regulate the reversibility of the dynamic covalent bonds to achieve thermosets that can be reprocessed rapidly.

C-H bond functionalization of aryl acids and amines by 'on-water' reaction: Bi-dentate directing group enabled synthesis of biaryl and m-teraryl carboxamides.

Herein, we report a palladium-catalyzed 'on-water' methodology for the synthesis of biaryl and m-teraryl derivatives of aryl carboxamides by selective mono and bis C-H bond functionalization. 8-aminoquinoline and 2-thiomethylaniline were used as directing groups for C-H bond functionalization of aryl carboxamides with various aryl and alkyl iodides using 3.0-4.0 mol% of Pd(OAc)2as catalyst and water as the solvent resulting in 45-97% isolated yields of the mono and bis C-H bond functionalized products. Using an 8-aminoquinoline carboxamide core, C-H bond functionalization of indole-3-carboxylic acid and a late-stage functionalization of aspirin molecule have also been carried out. Reactions of benzyl/naphthyl picolinamides with aryl iodides gave 60-96% yield of the arylated products using the picolinamide directing group. Moreover, the insoluble nature of products in an aqueous medium enabled us to explore the reusability of the solvent, i.e., water and the catalyst. Control experiments and structural studies were carried out which confirmed thein situformation of unique palladacycles during the reaction. Removal of the directing groups has been carried out to convert the functionalized products into amines and fluorenone compounds useful in industrial and pharmaceutical applications.

Design and Synthesis of Conformationally Flexible Scaffold as Bitopic Ligands for Potent D3-Selective Antagonists.

Previous studies have confirmed that the binding of D3 receptor antagonists is competitively inhibited by endogenous dopamine despite excellent binding affinity for D3 receptors. This result urges the development of an alternative scaffold that is capable of competing with dopamine for binding to the D3 receptor. Herein, an SAR study was conducted on metoclopramide that incorporated a flexible scaffold for interaction with the secondary binding site of the D3 receptor. The alteration of benzamide substituents and secondary binding fragments with aryl carboxamides resulted in excellent D3 receptor affinities (Ki = 0.8-13.2 nM) with subtype selectivity to the D2 receptor ranging from 22- to 180-fold. The β-arrestin recruitment assay revealed that 21c with 4-(pyridine-4-yl)benzamide can compete well against dopamine with the highest potency (IC50 = 1.3 nM). Computational studies demonstrated that the high potency of 21c and its analogs was the result of interactions with the secondary binding site of the D3 receptor. These compounds also displayed minimal effects for other GPCRs except moderate affinity for 5-HT3 receptors and TSPO. The results of this study revealed that a new class of selective D3 receptor antagonists should be useful in behavioral pharmacology studies and as lead compounds for PET radiotracer development.

Identification of Novel Aryl Carboxamide Derivatives as Death-Associated Protein Kinase 1 (DAPK1) Inhibitors with Anti-Proliferative Activities: Design, Synthesis, In Vitro, and In Silico Biological Studies.

Death-associated protein kinase 1 (DAPK1) is a serine/threonine protein kinase involved in diverse fundamental cellular processes such as apoptosis and autophagy. DAPK1 isoform plays an essential role as a tumor suppressor and inhibitor of metastasis. Consequently, DAPK1 became a promising target protein for developing new anti-cancer agents. In this work, we present the rational design and complete synthetic routes of a novel series of eighteen aryl carboxamide derivatives as potential DAPK1 inhibitors. Using a custom panel of forty-five kinases, a single dose of 10 µM of the picolinamide derivative 4a was able to selectively inhibit DAPK1 kinase by 44.19%. Further investigations revealed the isonicotinamide derivative 4q as a promising DAPK1 inhibitory lead compound with an IC50 value of 1.09 µM. In an in vitro anticancer activity assay using a library of 60 cancer cell lines including blood, lung, colon, CNS, skin, ovary, renal, prostate, and breast cancers, four compounds (4d, 4e, 4o, and 4p) demonstrated high anti-proliferative activity with mean % GI ~70%. Furthermore, the most potent DAPK1 inhibitor (4q) exhibited remarkable activity against leukemia (K-562) and breast cancer (MDA-MB-468) with % GI of 72% and 75%, respectively.

Crystal engineering studies of a series of pyridine-3,5-dicarboxamide ligands possessing alkyl ester arms, and their coordination chemistry

Five pyridine-3,5-dicarboxamide, 3,5-pda, ligands were synthesised and characterised. All of these ligands possess pendant arms with terminal carboxylic esters. The crystal structures of several of these ligands were obtained, these demonstrating various degrees of supramolecular interactions depending on the structural nature of the pendant arms. Discrete complexes and coordination networks from these ligands with d-block metal ions were also investigated; with manganese(II) and cadmium(II) four new coordination polymer species were obtained, while reactions with cobalt(II) and platinum(II) gave a non-crystalline polymer and a discrete complex, respectively. X-ray powder diffraction was used to determine the phase purity, while the morphological properties of some of these ligands and metal complexes were also probed using AFM and SEM imaging and physical properties were investigated using techniques such as EDX and DSC. The results herein demonstrate that these 3,5-pda ligands and their transition metal complexes possess structural properties analogous to popular aryl carboxamide building blocks that can be harnessed in crystal engineering and supramolecular chemistry.

Palladium-catalyzed oxidative annulation of N-(8-quinolinyl) aryl carboxamides with 1-aryl-2-tosyloxy ethanones

A novel and facile palladium-catalyzed annulation reaction between N-(8-quinolinyl) aryl carboxamides and 1-aryl-2-tosyloxy ethanones was herein demonstrated. The practical transformation took place readily in the presence of Pd(OAc)2 without any ligands, offering the desired 3-aryl-2-(8-quinolinyl) isoquinolin-1(2H)-ones with good functional groups tolerance (29 examples) and high efficiencies (up to 90% yields). The mechanism of the protocol was proposed to take place through a C-H/N-H activation pathway, which was verified by the control reactions.

A facile method for Rh-catalyzed decarbonylative ortho-C-H alkylation of (hetero)arenes with alkyl carboxylic acids.

A facile and effective method for Rh-catalyzed direct ortho-alkylation of C–H bonds in (hetero)arenes with commercially available carboxylic acids has been developed. This strategy was initiated by in situ conversion of carboxylic acids to anhydrides which, without isolation, underwent Rh-catalyzed direct decarbonylative cross-coupling of aryl carboxamides containing 8-aminoquinoline. The reaction proceeds with high regioselectivity and exhibits a broad substrate scope as well as functional group tolerance.

Discovery of Novel Aryl Carboxamide Derivatives as Hypoxia-Inducible Factor 1α Signaling Inhibitors with Potent Activities of Anticancer Metastasis.

In order to discover novel hypoxia-inducible factor 1 (HIF-1) inhibitors for the cancer metastasis treatment, 68 new aryl carboxamide compounds were synthesized and evaluated for their inhibitory effect by dual luciferase-reporter assay. Based on five rounds of investigation on structure-activity relationships step by step, compound 30m was discovered as the most active inhibitor (IC50 = 0.32 μM) with no obvious cytotoxicity (CC50 > 50 μM). It effectively attenuated hypoxia-induced HIF-1α protein accumulation and reduced transcription of vascular epidermal growth factor in a dose-dependent manner, which was further demonstrated by its inhibitory potency on capillary-like tube formation, angiogenesis of zebrafish as well as cellular migration and invasion. Importantly, compound 30m exhibited antimetastatic potency in breast cancer lung metastasis in the mice model, indicating its promising therapeutic potential for prevention and treatment of tumor metastasis. These results definitely merit attention for further rational design of more efficient HIF-1 inhibitors in the future.

Cyclic acyl amidines as unexpected C4-donors for fully substituted pyridine ring formation in the base mediated reaction with malononitrile

A new one-step, pseudo four-component approach for the synthesis of fully substituted pyridines via ring-opening of the cyclic acyl amidine of 3-amino-1H-isoindol-1-one and its aza-analogues during the reaction with malononitrile in the presence of sodium methoxide, followed by pyridine ring closure is reported. This method allows the one-step preparation of previously unknown 2-(pyridin-4-yl)(hetero)aryl carboxamides in good yields under mild reaction conditions.

Palladium-Catalyzed C(sp2)−H Olefination/Annulation Cascades of Aryl Carboxamides Assisted by N,S-Bidentate Auxiliary

A palladium(II)-catalyzed olefination/annulation of aryl carboxamides, assisted by an N, S-bidentate auxiliary, with methyl acrylate is described. Various carboxamides with a number of functional groups were compatible with this reaction to afford, regioselectively and in moderate yield, (E)-3-methyleneisoindolin-1-one derivatives bearing an alkyl(aryl)thio group.

Copper-Catalyzed C–H Carbamoyloxylation of Aryl Carboxamides

Copper-Catalyzed C–H Carbamoyloxylation of Aryl Carboxamides

Copper-Catalyzed C-H Carbamoyloxylation of Aryl Carboxamides with CO2 and Amines at Ambient Conditions.

A copper-catalyzed, 8-aminoquinoline-assisted, one-pot three-component coupling of aryl carboxamides, CO2, and amines has been developed. This protocol proceeds smoothly in the presence of inexpensive CuI and MnO2 at room temperature under atmospheric CO2 pressure, leading to simultaneous construction of C-O and C-N bonds. The reaction displays a broad substrate scope, high functional group tolerance, and excellent monoselectivity, providing an operationally simple method for the synthesis of various O-aryl carbamates.

Ni(II)-catalyzed C(sp2) [sbnd]H alkynylation/annulation cascades: Regioselective access to 3-methyleneisoindoline-1-one using N,S-bidentate auxiliary

A nickel(II)-catalyzed alkynylation/annulation of aryl carboxamides assisted by an N, S-bidentate directing group with terminal alkynes is described. This protocol provides an effective method to selectively furnish a series of biologically 3-methyleneisoindolin-1-one derivatives bearing methylthio group. Various carboxamides and terminal alkynes with a number of functional groups were compatible in this reaction to afford the corresponding products in moderate to good yields.

Synthesis and profiling of benzylmorpholine 1,2,4,5-tetraoxane analogue N205: Towards tetraoxane scaffolds with potential for single dose cure of malaria

A series of aryl carboxamide and benzylamino dispiro 1,2,4,5-tetraoxane analogues have been designed and synthesized in a short synthetic sequence from readily available starting materials. From this series of endoperoxides, molecules with in vitro IC50s versus Plasmodium falciparum (3D7) as low as 0.84 nM were identified. Based on an assessment of blood stability and in vitro microsomal stability, N205 (10a) was selected for rodent pharmacokinetic and in vivo antimalarial efficacy studies in the mouse Plasmodium berghei and Plasmodium falciparum Pf3D70087/N9 severe combined immunodeficiency (SCID) mouse models. The results indicate that the 4-benzylamino derivatives have excellent profiles with a representative of this series, N205, an excellent starting point for further lead optimization studies.

Pd-Catalyzed C(sp2)-H aminocarbonylation using the Langlois reagent as a carbonyl source.

A Pd-catalyzed C(sp2)-H aminocarbonylation of aryl carboxamides assisted by an N,S-bidentate directing group was developed, in which cheap and stable sodium trifluoromethanesulfinate was first utilized as a carbonyl source. The reaction can be applicable to a wide range of carboxamides with good functional group tolerance and afford isoindole-1,3-diones in moderate to good yields.

Design, synthesis and biological evaluation of new pyrrolidine carboxamide analogues as potential chemotherapeutic agents for hepatocellular carcinoma

The successful targeting of different malignancies by OSU-2S, encouraged us to design and synthesize a novel series of pyrrolidine aryl carboxamide derivatives. In this context, we found that, the amide nature and tether length were found to be key determinant elements for the anticancer activity of these new and rigid analogues of OSU-2S. The most effective analogues induced apoptosis in cancer cells by a similar mechanism to that of OSU-2S, possibly via the activation of PKCδ in addition to their ability to induce cell cycle arrest and inhibition of cancer cell migration. Compound 10m, possesses anticancer potency comparable to that of OSU-2S when tested against cancer cell lines under study, and was found to be safer on normal cells. Furthermore, compound 10m, was found to be about 2-folds more potent than the anticancer drug Sorafenib in hepatocellular carcinoma (HCC). The newly developed compounds represent a therapeutically promising approach for the treatment of HCC.

Polysubstituted 2-aminoimidazoles as anti-biofilm and antiproliferative agents: Discovery of potent lead

Most of the human bacterial infections are associated with the biofilm formation and the natural tolerance of biofilms to antibiotics challenges treatment. Because of their low immunity, cancer patients are especially susceptible to bacterial infections. Compounds with anti-biofilm activity could therefore become a useful adjunct to chemotherapy, in particular if they also show antiproliferative activities. Taking this into consideration and as a result of our continuous interest in 2-aminoimidazole derivatives, we have designed and synthesized a series of novel polysubstituted 2-aminoimidazoles (20a-x). The compounds were evaluated against a panel of three bacterial strains for their biofilm and planktonic growth inhibitory activity and most of them show promising results. Furthermore, the synthesized compounds were evaluated against various cancer cell lines and almost all the compounds were found to possess potent antiproliferative activity. The substitution pattern at the C-4 position and the aryl carboxamide ring at the N-1 position have major effects on the biofilm inhibitory and antiproliferative activity. Especially, the introduction of a p-methyl group at the carboxamide ring remarkably enhances both the anti-biofilm and antiproliferative activity. The two most potent compounds (20i &20r) were further studied for their antiproliferative activity and a flow cytometer-based cell cycle experiment was performed, which revealed their capability to induce G2/M phase cell cycle arrest. Based on these results, these two new compounds having potential to target both cancer proliferation and microbial biofilms might be used in single drug monotherapy.

Highly Selective Synthesis of Carboxamides via Transition Metal Catalysed Aminocarbonylation

This short review summarises the most important results obtained during the past decade in the field of palladium catalysed aminocarbonylation. In this reaction, using amines as N-nucleophiles, the carbonylation of enol-triflates/aryl-triflates or their synthetic surrogates, alkenyl halides/aryl halides takes place resulting in the formation of unsaturated carboxamides or aryl carboxamides. In the latter case, 2-ketocarboxamides are also formed via double carbon monoxide insertion. The efficiency of aminocarbonylation is illustrated by several high-yielding syntheses including transformation of both simple model substrates and skeletons of biological importance. As green chemistry aspects of this reaction, the ambient conditions, high activity, low catalyst loading, the possibility of tuning selectivities and high functional group tolerance should be mentioned. Keywords: Amide, carbonylation, palladium, chemoselectivity, environmentally benign reaction.