Heterocyclic Carboxamides Research Articles

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

Structure–activity relationships study of <i>N</i> -ethylene glycol-comprising alkyl heterocyclic carboxamides against A549 lung cancer cells

Heterocyclic (pyrazine)carboxamide Ru(ii) complexes: structural, experimental and theoretical studies of interactions with biomolecules and cytotoxicity.

Treatments of N-(1H-benzo[d]imidazol-2-yl)pyrazine-2-carboxamide (HL1) and N-(benzo[d]thiazol-2-yl)pyrazine-2-carboxamide carboxamide ligands (HL2) with [Ru(p-cymene)Cl2]2 and [Ru(PPh3)3Cl2] precursors afforded the respective Ru(ii) complexes [Ru(L1)(p-cymene)Cl] (Ru1), [Ru(L2)(p-cymene)Cl] (Ru2), [Ru(L1)(PPh3)2Cl] (Ru3), and [Ru(L2)(PPh3)2Cl] (Ru4). These complexes were characterized by NMR, FT-IR spectroscopies, mass spectrometry, elemental analyses, and crystal X-ray crystallography for Ru2. The molecular structure of complex Ru2 contains one mono-anionic bidentate bound ligand and display pseudo-octahedral piano stool geometry around the Ru(ii) atom. The interactions with calf thymus DNA (CT-DNA) and bovine serum albumin (BSA) were investigated by spectroscopic techniques. The experimental binding studies suggest that complexes Ru1-Ru4 interact with DNA, primarily through minor groove binding, as supported by molecular docking results. Additionally, these complexes exhibit strong quenching of the fluorescence of tryptophan residues in BSA, displaying static quenching. The in vitro cytotoxicity studies of compounds Ru1-Ru4 were assessed in cancer cell lines (A549, PC-3, HT-29, Caco-2, and HeLa), as well as a non-cancer line (KMST-6). Compounds Ru1 and Ru2 exhibited superior cytotoxicity compared to Ru3 and Ru4. The in vitro cytotoxicity and selectivity of compounds Ru1 and Ru2 against A549, PC-3, and Caco-2 cell lines surpassed that of cisplatin.

Recent Advances in the Development of Sulfamoyl-Based Hepatitis B Virus Nucleocapsid Assembly Modulators.

Hepatitis B virus (HBV) is the primary contributor to severe liver ailments, encompassing conditions such as cirrhosis and hepatocellular carcinoma. Globally, 257 million people are affected by HBV annually and 887,000 deaths are attributed to it, representing a substantial health burden. Regrettably, none of the existing therapies for chronic hepatitis B (CHB) have achieved satisfactory clinical cure rates. This issue stems from the existence of covalently closed circular DNA (cccDNA), which is difficult to eliminate from the nucleus of infected hepatocytes. HBV genetic material is composed of partially double-stranded DNA that forms complexes with viral polymerase inside an icosahedral capsid composed of a dimeric core protein. The HBV core protein, consisting of 183 to 185 amino acids, plays integral roles in multiple essential functions within the HBV replication process. In this review, we describe the effects of sulfamoyl-based carboxamide capsid assembly modulators (CAMs) on capsid assembly, which can suppress HBV replication and disrupt the production of new cccDNA. We present research on classical, first-generation sulfamoyl benzocarboxamide CAMs, elucidating their structural composition and antiviral efficacy. Additionally, we explore newly identified sulfamoyl-based CAMs, including sulfamoyl bicyclic carboxamides, sulfamoyl aromatic heterocyclic carboxamides, sulfamoyl aliphatic heterocyclic carboxamides, cyclic sulfonamides, and non-carboxamide sulfomoyl-based CAMs. We believe that certain molecules derived from sulfamoyl groups have the potential to be developed into essential components of a well-suited combination therapy, ultimately yielding superior clinical efficacy outcomes in the future.

Single-tailed heterocyclic carboxamide lipids for macrophage immune-modulation.

The discovery of new immune-modulating biomaterials is of significant value to immuno-engineering and therapy development. Here, we discovered that single-tailed heterocyclic carboxamide lipids preferentially modulated macrophages - but not dendritic cells - by interfering with sphingosine-1-phosphate-related pathways, consequently increasing interferon alpha expression. We further performed extensive downstream correlation analysis and determined key factors in physicochemical properties likely to modulate pro-inflammatory and anti-inflammatory immune responses. These properties will be useful for the rational design of the next generation of cell type-specific immune-modulating lipids.

Structural and electronic impacts on corrosion inhibition activity of novel heterocyclic carboxamides derivatives on mild steel in 1 M HCl environment: Experimental and theoretical approaches

To study the corrosion mitigation on mild steel (MS) in 1 M HCl, the carboxamide derivatives namely: N–(1–benzyl piperidin–4–yl)pyridine–4–carboxamide (N–BPPC), N–(4–(pyridin–4–ylmethyl) phenyl)pyridine–4–carboxamide (N–PMPPC), (4–methylpiperazin–1–yl)pyrazin–2–yl) methanone (4–MPPM) were synthesized and characterized by spectroscopy techniques like FT-IR, LC-MS, and 1H &13C NMR. Experimental techniques like the weight-loss method, potentiodynamic, electrochemical impedance studies, and surface analysis were performed at 303 K. Their anti-corrosion efficiency was proportional to their concentration. Electrochemical techniques revealed that they acted as mixed-type inhibitors and proceeded via single charge transfer at the metal–electrolyte interface. Strong adsorption of carboxamide derivatives on mild steel (MS) was supported by surface morphology studies and obeyed the Langmuir model of the isotherm. The thermodynamic and activation parameters were measured to study the temperature effect, revealing that physicochemical adsorption took place. Anti-corrosion efficiencies were decreased with temperature rise. DFT and molecular dynamics studies have been utilized in their neutral and protonated form of inhibitors in the aqueous phase to study inhibitors’ structural and electronic impacts on the corrosion process. The optimized structure and spatial configuration exposed the influence of the molecule's alignment with the metal plane on corrosion mitigation. The molecules' bulk and local reactivity parameters show that the electron density of atoms of molecules coordinates with the metal surface. Finally, the order of corrosion retardation effect was found to be 4–MPPM > N–BPPC > N–PMPPC from experimental and theoretical studies.

Evaluation of Heterocyclic Carboxamides as Potential Efflux Pump Inhibitors in Pseudomonas aeruginosa.

The ability to rescue the activity of antimicrobials that are no longer effective against bacterial pathogens such as Pseudomonas aeruginosa is an attractive strategy to combat antimicrobial drug resistance. Herein, novel efflux pump inhibitors (EPIs) demonstrating strong potentiation in combination with levofloxacin against wild-type P. aeruginosa ATCC 27853 are presented. A structure activity relationship of aryl substituted heterocyclic carboxamides containing a pentane diamine side chain is described. Out of several classes of fused heterocyclic carboxamides, aryl indole carboxamide compound 6j (TXA01182) at 6.25 µg/mL showed 8-fold potentiation of levofloxacin. TXA01182 was found to have equally synergistic activities with other antimicrobial classes (monobactam, fluoroquinolones, sulfonamide and tetracyclines) against P. aeruginosa. Several biophysical and genetic studies rule out membrane disruption and support efflux inhibition as the mechanism of action (MOA) of TXA01182. TXA01182 was determined to lower the frequency of resistance (FoR) of the partner antimicrobials and enhance the killing kinetics of levofloxacin. Furthermore, TXA01182 demonstrated a synergistic effect with levofloxacin against several multidrug resistant P. aeruginosa clinical isolates.

New Sulfanilamide Derivatives Incorporating Heterocyclic Carboxamide Moieties as Carbonic Anhydrase Inhibitors.

Carbonic Anhydrases (CAs) are ubiquitous metalloenzymes involved in several disease conditions. There are 15 human CA (hCA) isoforms and their high homology represents a challenge for the discovery of potential drugs devoid of off-target side effects. For this reason, many synthetic and pharmacologic research efforts are underway to achieve the full pharmacological potential of CA modulators of activity. We report here a novel series of sulfanilamide derivatives containing heterocyclic carboxamide moieties which were evaluated as CA inhibitors against the physiological relevant isoforms hCA I, II, IX, and XII. Some of them showed selectivity toward isoform hCA II and hCA XII. Molecular docking was performed for some of these compounds on isoforms hCA II and XII to understand the possible interaction with the active site amino acid residues, which rationalized the reported inhibitory activity.

Сationic carboxamide derivatives of tricyclic heteroaromatic compounds: synthesis and preliminary evaluation of antiproliferative activity

This research was aimed at the synthesis and study of biological activity of the carboxamides of tricyclic heteroaromatic systems, acridone, phenazine and thioxanthone, containing the aliphatic and aromatic cationic substituents at amide fragment. These heterocyclic cores are DNA intercalating agents, whereas the introduction of cationic groups provides additional ionic interactions of the ligands with their biological targets, such as DNA and enzymatic complexes of the system of nucleic acids biosynthesis. A convenient way of the introduction of such groups is a modification of heterocyclic carboxamides. A small library of new cationic amide derivatives of acridone-4-, phenazine-1- and thioxanthone-4-carboxylic acids was obtained. They were synthesized in 37-81% yield by mild and selective quaternization of the nitrogen atoms at N,N-dimethylaminoalkyl (alkyl = ethyl, propyl) and pyridylmethyl fragments of the neutral N-functionalized carboxamides with methyl iodide. Tricyclic heteroaromatic cores were not affected. Convenient protocol for the synthesis of thioxanthone-4-carboxylic acid (TCA) based on the reaction of 2-mercaptobenzoic and 2-iodobenzoic acids followed by cyclization of the intermediate was developed (yield 79%). A series of new N-functionalized neutral amides of TCA, the precursors of corresponding cationic carboxamide, were also obtained via the reaction of acyl chloride with amines. Preliminary in vitro testing of four compounds as potential antitumor agents in U87MG tumor cell culture (human malignant glioma) demonstrated their significant antiproliferative activity at low micromolar concentrations, with growth inhibition values GI50 in the range 1.7-11 µM. These results suggest that cationic carboxamides of tricyclic heteroaromatic systems are promising scaffolds for the design of new antitumor drugs.

Discovery of fused heterocyclic carboxamide derivatives as novel α7-nAChR agonists: Synthesis, preliminary SAR and biological evaluation

The α7 nicotinic acetylcholine receptor (α7 nAChR) has emerged as a promising therapeutic target for schizophrenia. In our previous work, a novel series of α7-nAChR agonists bearing scaffold of indolizine were discovered. To explore the effect of aromaticity on the activity and find more active agents, herein, fused heterocyclic carboxamide derivatives were designed and synthesized in this study. Based on the evaluation by two-electrode voltage clamp in Xenopus oocytes, 27 of the synthesized compounds showed obvious agonism of α7 nAChR. Particularly, compounds 10a and 10e showed significantly higher Emax than EVP-6124. The result illustrated the importance of aromaticity to the activity of agonism. Compound 10a, which showed EC50 of 1.88 μM and Emax of 72.4%, was further characterized comprehensively, including co-application with type II positive allosteric modulator PNU-120596, selectivity with other closely related ligand-gated ion channel, etc. The results showed that 10a showed moderate selectivity over other subtypes such as α4β2 and α3β4 nAChR. 10a evoked α7-like currents that were inhibited by MLA and enhanced in the presence of the α7 PAM PNU-120596. The analysis of binding mode and understanding of structure-activity relationship provided insights to develop more potent novel α7-nAChR agonists.

Synthesis and Pharmacological Evaluation of Heterocyclic Carboxamides: Positive Allosteric Modulators of the M1 Muscarinic Acetylcholine Receptor with Weak Agonist Activity and Diverse Modulatory Profiles.

Targeting allosteric sites at M1 muscarinic acetylcholine receptors is a promising strategy for the treatment of Alzheimer's disease. Positive allosteric modulators not only may potentiate binding and/or signaling of the endogenous agonist acetylcholine (ACh) but also may possess direct agonist activity (thus referred to as PAM-agonists). Recent studies suggest that PAM-agonists with robust intrinsic efficacy are more likely to produce adverse effects in vivo. Herein we present the synthesis and pharmacological evaluation of a series of pyrrole-3-carboxamides with a diverse range of allosteric profiles. We proposed structural modifications at top, core, or pendant moieties of a prototypical molecule. Although generally there was a correlation between the degree of agonist activity and the modulatory potency of the PAMs, some derivatives displayed weak intrinsic efficacy yet maintained strong allosteric modulation. We also identified molecules with the ability to potentiate mainly the affinity or both affinity and efficacy of ACh.

Strong influence of intramolecular Si⋯O proximity on reactivity: Systematic molecular structure, solvolysis, and mechanistic study of cyclic N -trimethylsilyl carboxamide derivatives

A comparative alcoholysis study of N-silylated derivatives of simple heterocyclic carboxamides (lactams, imides, ureas) is presented. The second-order rate constant values span a range as wide as three orders of magnitude. On the basis of DFT calculations, a good correlation between reactivity and the Si⋯O distance was found within each family of compounds. The viability of two different reaction pathways was evaluated using a detailed computational mechanistic study of the methanolysis of cyclic urea homologues. Peculiarities in the single-crystal X-ray diffraction structures of the trimethylsilyl and trimethylsiloxy phthalimides are also discussed.

Pd/C-catalyzed synthesis of N-aryl and N-alkyl isoquinolones via C[sbnd]H/N[sbnd]H activation

Pd/C-catalyzed direct synthesis of N-aryl and N-alkyl isoquinolones was developed via the annulation reactions of benzamides and alkynes in high yields (up to 99%) through the cleavage of CH/NH bonds. The reaction was ligand-free and air was used as oxidant. High regioselectivities were found when unsymmetrical alkynes or meta-benzamides were used as substrates. The heterocyclic carboxamide substrates, such as furan and thiophene derivatives, also afforded the corresponding products in high yields.

Universal Readers Based on Hydrogen Bonding or π-π Stacking for Identification of DNA Nucleotides in Electron Tunnel Junctions.

A reader molecule, which recognizes all the naturally occurring nucleobases in an electron tunnel junction, is required for sequencing DNA by a recognition tunneling (RT) technique, referred to as a universal reader. In the present study, we have designed a series of heterocyclic carboxamides based on hydrogen bonding and a large-sized pyrene ring based on a π-π stacking interaction as universal reader candidates. Each of these compounds was synthesized to bear a thiolated linker for attachment to metal electrodes and examined for their interactions with naturally occurring DNA nucleosides and nucleotides by 1H NMR, ESI-MS, computational calculations, and surface plasmon resonance. RT measurements were carried out in a scanning tunnel microscope. All of these molecules generated electrical signals with DNA nucleotides in tunneling junctions under physiological conditions (phosphate buffered aqueous solution, pH 7.4). Using a support vector machine as a tool for data analysis, we found that these candidates distinguished among naturally occurring DNA nucleotides with the accuracy of pyrene (by π-π stacking interactions) > azole carboxamides (by hydrogen-bonding interactions). In addition, the pyrene reader operated efficiently in a larger tunnel junction. However, the azole carboxamide could read abasic (AP) monophosphate, a product from spontaneous base hydrolysis or an intermediate of base excision repair. Thus, we envision that sequencing DNA using both π-π stacking and hydrogen-bonding-based universal readers in parallel should generate more comprehensive genome sequences than sequencing based on either reader molecule alone.

Antiviral effect of theaflavins against caliciviruses.

Caliciviruses are contagious pathogens of humans and various animals. They are the most common cause of viral gastroenteritis in humans, and can cause lethal diseases in domestic animals such as cats, rabbits and immunocompromised mice. In this study, we conducted cytopathic effect-based screening of 2080 selected compounds from our in-house library to find antiviral compounds against three culturable caliciviruses: feline calicivirus, murine norovirus (MNV) and porcine sapovirus (PoSaV). We identified active six compounds, of which two compounds, both related to theaflavins, showed broad antiviral activities against all three caliciviruses; three compounds (abamectin, a mixture of avermectin B1a and B1b; avermectin B1a; and (-)-epigallocatechin gallate hydrate) were effective against PoSaV only; and a heterocyclic carboxamide derivative (BFTC) specifically inhibited MNV infectivity in cell cultures. Further studies of the antiviral mechanism and structure-activity relationship of theaflavins suggested the following: (1) theaflavins worked before the viral entry step; (2) the effect of theaflavins was time- and concentration-dependent; and (3) the hydroxyl groups of the benzocycloheptenone ring were probably important for the anti-calicivirus activity of theaflavins. Theaflavins could be used for the calicivirus research, and as potential disinfectants and antiviral reagents to prevent and control calicivirus infections in animals and humans.

Discovery and Synthesis of Heterocyclic Carboxamide Derivatives as Potent Anti-norovirus Agents.

There is an urgent need for structurally novel anti-norovirus agents. In this study, we describe the synthesis, anti-norovirus activity, and structure-activity relationship (SAR) of a series of heterocyclic carboxamide derivatives. Heterocyclic carboxamide 1 (50% effective concentration (EC50)=37 µM) was identified by our screening campaign using the cytopathic effect reduction assay. Initial SAR studies suggested the importance of halogen substituents on the heterocyclic scaffold and identified 3,5-di-boromo-thiophene derivative 2j (EC50=24 µM) and 4,6-di-fluoro-benzothiazole derivative 3j (EC50=5.6 µM) as more potent inhibitors than 1. Moreover, their hybrid compound, 3,5-di-bromo-thiophen-4,6-di-fluoro-benzothiazole 4b, showed the most potent anti-norovirus activity with a EC50 value of 0.53 µM (70-fold more potent than 1). Further investigation suggested that 4b might inhibit intracellular viral replication or the late stage of viral infection.

Computational Docking Studies of Novel Heterocyclic Carboxamides as Potential PI3Kα Inhibitors

Computational Docking Studies of Novel Heterocyclic Carboxamides as Potential PI3Kα Inhibitors

Synthesis and Preliminary Biological Evaluation of New Heterocyclic Carboxamide Models

The heterocyclic system is a promising core nucleus in many bioactive compounds. This work describes our effort to synthesize and characterize a set of new biphenyl, benzofuran and benzothiophene carboxamide derivatives. Our biological studies showed that compounds 10 and 17 have antifungal activity against C. galabrate more potent than fluconazole compounds 9, 10, and 17 exerted cytotoxic activities in immortalized embryonic mouse fibroblast cells (3T3) and a human cervical cancer cell line (HeLa); in particular, the cyclic amidine derivative 17 showed selective toxicity against HeLa. This study showed that the tested compounds have the potential to be useful as antitumor drugs after further optimization. Keywords: Antifungal activity, cervical cancer cell, cytotoxicity, heterocyclic compounds, NMR, Synthesis.

Structure-activity relationships of positional isomers in aromatic heterocyclic carboxamide fungicides

Positional isomers of various aromatic heterocyclic carboxamides were synthesized and their fungicidal activity was examined. Among them, N-(biphenyl-2-yl) and N-[2-(1,3-dimethylbutyl)-3-thienyl]-1-methyl-3-CF3-pyrazole-4-carboxamides showed high activity against gray mold, while their corresponding 5-CF3 carboxamide isomers showed no fungicidal activity. Similar results were observed for carboxamide isomers containing CF3-thiazole as well as methyl-substituted thiophene and furan derivatives. Docking studies were performed on these carboxamides with a fungus succinate dehydrogenase homology model. Based on our docking study, we proposed a model for the interaction between carboxamides and a conserved histidine residue in succinate dehydrogenase.

Synthesis, characterization, and antibacterial activity of the ligands including thiophene/furan ring systems and their Cu(II), Zn(II) complexes

Carboxamide complexes having general formula as [ML]Cl2·nH2O (where M = Cu(II), Zn(II); n = 0, 1/2) were synthesized using heterocyclic carboxamide ligands: 1,4-bis[3-(2-thiophenecarboxamido)propyl]piperazine (L1) and 1,4-bis[3-(2-furancarboxamido) propyl]piperazine (L2). Their structures were characterized with elemental analysis, molar conductivity, magnetic susceptibility, and spectral methods (1H-NMR, 13C-NMR, FT-IR, LC-MS). TGA and DTA curves were also performed. The structure–activity relationship for the ligands was investigated using PM3 semi-empirical method. The antibacterial activities of the carboxamides and their complexes were investigated against bacteria; Staphylococcus aureus ATCC 25923, Escherichia coli ATCC 11230, Bacillus magaterium RSKK 5117, B. cereus RSKK 863, Salmonella enteritidis ATCC 13076, B. subtilis RSKK 244 using microdilution method.

ChemInform Abstract: Rhodium‐Catalyzed Oxidative Cycloaddition of Benzamides and Alkynes via C—H/N—H Activation.

AbstractIn the presence of a copper(II) salt as oxidant, benzamides as well as heterocyclic carboxamides undergo the title reaction with a variety of internal alkynes to give isoquinolinones or the corresponding heteroaryl‐fused pyridine analogues.