Carboxamide Compounds Research Articles

Investigation of substituent effects on the electronic structure and antiviral activity of favipiravir derivatives for Covid-19 treatment using DFT and molecular docking

In this study, Density-functional theory/Time-dependent density-functional theory (DFT/TDDFT) and Molecular docking method was used to investigate the effect of methyl acetate, tetrahydrofuran and cyanobenzylidene substituents on the electronic structure and antiviral activity of favipiravir for treating COVID-19. The DFT and TDDFT computations were employed using the Gaussian 09 software package. The values were calculated using the 6-311++G(d, p) basis set and the hybrid B3LYP functional method. Autodock vina software was used for simulations to better predictions and to validate the modified compounds' binding affinities and poses. Results of the study indicate that compounds 1 to 6 all displayed a planar structure, where the pyrazine ring, carboxamide, hydroxyl groups, and other substituents are all situated within the same plane. In addition, the energy gaps (Egap) of these six compounds (Cpd 1, 2, 3, 4, 5, and 6) were compared. The significant dipole moment and binding affinity achieved implies a particular orientation for binding within the target protein, signaling the anticipated strength of the binding interaction. In all six compounds, the electrophilic domain is situated in the vicinity of the amine functional group within the carboxamide compound, whereas the nucleophilic domain encompasses both the carbonyl and hydroxyl groups. The most negatively charged sites are susceptible to electrophilic interactions. In conclusion, compounds 5 and 6 exhibit a high binding affinity of the target protein, while compound 6 has a high energy gap, which could enhance its antiviral activity against the COVID-19 virus.

Molecular structures, DFT calculations, in silico molecular docking, predicted pharmacokinetics and biological activities of N-(quinolin-8-yl)-2- pyridine/pyrazine carboxamide compounds

New N-(quinolin-8-yl)pyrazine/pyridine-2-carboxamide derivatives were prepared through condensation reaction of 8-amino-quinoline with the appropriate carboxylic acids to afford 5-methyl-N-(quinolin-8-yl)pyrazine-2-carboxamide (HL1) and 5‑chloro-N-(quinolin-8-yl)pyridine-2-carboxamide (HL2). Single crystal X-ray crystallography analysis unambiguously reveals that the asymmetric units of C15H12N4O (HL1) and C15H10ClN3O (HL2) belong to the monoclinic system with P121/1space group. Density functional theory (DFT) reveals that the chemically active sites of HL1-HL3 are situated on the O-atoms and N-atoms. Molecular docking of the compounds with calf thymus DNA (CT-DNA) and bovine serum albumin (BSA) receptors demonstrated favourable binding scores within the active binding sites. In silico pharmacokinetic results suggest that the compounds obey Lipinski rule, which is a key requirement for a potential drug candidate

Synthesis, insecticidal activity, and in silico study of novel carboxamide compounds containing benzoxazole moiety

Synthesis, insecticidal activity, and in silico study of novel carboxamide compounds containing benzoxazole moiety

Solvent effects on spectroscopic, electronic, and topological analyses, Hirshfeld surface, ADME, and molecular docking studies on antiviral pyridine carboxamide derivatives

A theoretical study of three pyridine carboxamide derivatives in conjunction with the Density Functional Theory (DFT) approach at the 6-311+G(d,p) basis set is presented along with X-ray results. The pyridine carboxamide derivatives were analyzed with the help of FT-IR, UV–Vis, 1H and 13C NMR investigation. The spectral characterizations were made by vibrational energy distribution analysis (VEDA4), which helps to assign vibrational frequencies to specific molecular vibrations. A comparative analysis of computed 1H and 13C NMR chemical shift values with experimental chemical shifts for the pyridine carboxamide compounds by applying the gauge-including atomic orbitals method in chloroform and acetone solvents was carried out. UV–Vis spectroscopy and electronic transitions were conducted on both chloroform and acetone solvents through the assistance of the TD-DFT methodology. Hirshfeld Surface analysis was employed to analyze the intermolecular hydrogen bonds of the type N-H⋯N to the crystal packing. The chemical properties of frontier molecular orbital and global reactivity descriptors were analyzed for the different solvents such as chloroform and acetone. The Fukui functions were used to identify reactive sites in a molecule, including those susceptible to nucleophilic and electrophilic outbreaks. The weak interactions were analyzed using reduced density gradient (RDG) analysis, a computational method used to study noncovalent interactions, including hydrogen bonding. The Absorption, Distribution, Metabolism, and Excretion (ADME) attributes of the studied compounds have been evaluated for drug discovery initiatives. Molecular docking studies with antiviral SARS-CoV-2 Mpro and Omicron variant containing the Q493R mutation proteins of three pyridine carboxamide derivatives (L3–L5) have been performed, and L5 has maximum binding energy values of −7.13 kcal/mol for 6LU7.

Novel indole retinoid derivative induces apoptosis and cell cycle arrest and modulates AKT and ERK signaling in HL-60 cells.

Chemotherapy with targeted drugs is the first line therapy option for acute and chronic myeloid leukemia. However, hematopoietic stem cell transplantation may be used in high-risk patients or patients with failed responses to chemo drugs. Discovery and development of more effective new agents with lower side effects is the main aim of leukemia treatment. In this study, a novel retinoid compound with tetrahydronaphthalene ring was synthesized and evaluated for anticancer activity in human chronic and acute myeloid leukemia cell lines K562 and HL-60. Novel N-(1H-indol-1-yl)-5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalene-2-carboxamide was synthesized based on molecular hybridization of the two different bioactive structures retinoid head and indole. The effects of the synthesized carboxamide compound, which was referred to as compound 5, were determined in K562 chronic myeloid leukemia and HL-60 acute myeloid leukemia cell lines and L929 fibroblast cell line, which served as a control. Colorimetric MTT and caspase3 activity tests, flow cytometry, western blot, and microscopic examinations were used to evaluate biological activity. Compound 5 more effectively induced cell death in HL60 cells in comparison to K562 cells and L929 fibroblast cells. Therefore, further mechanism of cell death was investigated in HL60 cell line. It was found that compound 5 induced remarkable cytotoxicity, caspase3 activation, and PARP fragmentation in HL60 cells. Flow cytometric staining showed that the percentage of cells arrested in G0/G1 was also increased with compound 5 treatment. Important modulator proteins of cell proliferation p-ERK, p-AKT, and p-m-TOR were also found to be inhibited with compound 5 treatment. Collectively, our results reveal compound 5, which is a novel indole retinoid compound as a potential active agent for the treatment of acute promyelocytic leukemia.

ELECTROPHYLIC REACTIONS OF CHLOROCARBOXYLIC ANHYDRIDE OF 1-METHYL-CYCLOHEX-3-ENE WITH 3-OXINDOLE AND N-PHENYLACETIC ACID

The properties of various functionally substituted nitrogen-organic com- pounds depend on their structure, the state and nature of the functional group in their molecule. Functionally substituted proteins obtained on the basis of the peptide bond of substituted heterocyclic compounds from various amino acids perform a physiological function that is widespread in nature and is important for the vital activity of the body. The direct acidification reaction of aromatic amines with aromatic carboxylic acids takes place under severe conditions at temperatures above 2800 C, the product is obtained with low yield, and at the same time additional products are formed. Among carbonaceous compounds, chloranhydrides of carbonic acids have the strongest electrophilic properties. The reaction of acylation with chloranhydrides proceeds in mild conditions and the reaction product is obtained with a high yield. Relevant carboxamide compounds have been obtained by acidification of N-phenylacetic acid and 3-oxindole with chlorocarboxylic anhydride of 1-methyl-cyclo- hex-3-ene. It has been found that the carboxamide compound obtained on the basis of N-phenylacetic acid formes carboxamide compound of 3-oxindole in the basic medium cycling intramolecularly.

Polymorphism in carboxamide compounds with high-Z′ crystal structures

Repetitivity of 21-axis symmetry element in three polymorphic crystal structures of carboxamide compound with highZ′ packing problem.

Antifungal potential of Azotobacter species and its metabolites against Fusarium verticillioides and biodegradation of fumonisin.

In the study, seven Plant Growth Promoting Rhizobacteria (PGPR) Azotobacter species were screened against three strains of Fusarium verticillioides to test its antifungal activity. Azotobacter strains were tested for the degradation of fumonisin produced by F. verticillioides. Secondary metabolites were isolated and characterized from the Azotobacter strains for the first time. Potential seven Azotobacter species antifungal activity was tested following the dual culture assay against three strains of Fusarium verticillioides namely FVM-42, FVM-86 and MTCC156 estimating the substantial zone of inhibition. Azotobacter species AZT-31 and AZT-50 strains significantly inhibited the growth of F. verticillioides recording drastic growth enhancement of maize under in-vitro conditions by calculating the infection incidence, vigour index and germination percentage. As confirmation, dereplication studies were conducted for the reconfirmation of Azotobacter strains by isolating from rhizoplane. Azotobacter strains played a key role in the degradation of fumonisin produced by F. verticillioides reporting 98% degradation at 2h of incubation with the pathogen. Furthermore, in the study first time, we have tried to isolate and characterize the secondary metabolites from the Azotobacter strains exhibiting six compounds from the species AZT-31 (2) and AZT-50 (4). Preliminary in-vitro experiments were carried out using the compounds extracted to check the reduction of infection incidence (90%) and increase in germination percentage upto 50 to 70% when compared to the test pathogen. Azotobacter strains referred as PGPR on influencing the growth of plant by producing certain substances that act as stimulators on inhibiting the growth of the pathogen. The future perspective would be the production of an active combination of carboxamide compound and Azotobacter species for preventively controlling the phytopathogenic fungi of plants and crops and also towards the treatment of seeds.

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.

Discovery of a Novel Class of Norovirus Inhibitors with High Barrier of Resistance.

Human noroviruses (HuNoVs) are the most common cause of viral gastroenteritis resulting in ~219,000 deaths annually and a societal cost of ~USD60 billion. There are no antivirals or vaccines available to treat and/or prevent HuNoV. In this study, we performed a large-scale phenotypical antiviral screening using the mouse norovirus (MNV), which included ~1000 drug-like small molecules from the Drug Design and Synthesis Centre (Sapienza University, Rome). Compound 3-((3,5-dimethylphenyl)sulfonyl)-5-chloroindole-N-(phenylmethanol-4-yl)-2.carboxamide (compound 1) was identified as an inhibitor of MNV replication with an EC50 of 0.5 ± 0.1 µM. A series of 10 analogs were synthesized of which compound 6 showed an improved potency/selectivity (EC50 0.2 ± 0.1 µM) against MNV; good activity was also observed against the HuNoV GI replicon (EC50 1.2 ± 0.6 µM). Time-of-drug-addition studies revealed that analog 6 acts at a time point that coincides with the onset of viral RNA replication. After six months of selective pressure, two compound 6res variants were independently selected, both harboring one mutation in VPg and three mutations in the RdRp. After reverse engineering S131T and Y154F as single mutations into the MNV backbone, we did not find a markedly compound 6res phenotype. In this study, we present a class of novel norovirus inhibitors with a high barrier to resistance and in vitro antiviral activity.

Study on Phenanthroline Carboxamide for Lanthanide Separation: Influence of Amide Substituents

Phenanthroline carboxamide compounds are promising for lanthanide intra-series separation. This paper presents a study on the effect of structure modification of phenanthroline carboxamides on the extraction of the whole lanthanide series. The study consists of theoretical calculations, extraction experiments of the 14 stable lanthanides, and extended X-ray absorption fine structure (EXAFS) analyses of Nd and Dy complexes. Tridentate monocarboxamides and tetradentate dicarboxamides show different trends in series extraction, although both preferentially extract the light lanthanides. The amide substituents, although not directly coordinating the metal ions, were also found to impact the distribution ratio, most probably due to a modification in the internal polarity of the molecules. This latter effect, if extrapolated to other nitrogen-based ligands such as pyridines or triazines, can be used to further fine-tune extractants for a process improvement.

Radioiodination and in vivo assessment of the potential of newly synthesized pyrrolizine-5-carboxamides derivative in tumor model

Recently, pyrrolizine derivatives have been reported to possess numerous anticancer activities. In a previous study, (EZ)-6-((4-chlorobenzylidene)-amino)-7-cyano-N-(p-tolyl)-2,3-dihydro-1H-pyrrolizine carboxamide (EZPCA) compound was synthesized and the cytotoxic activity of EZPCA toward COX-2 enzyme (overexpressed in cancer cells) was reported. In order to assess the suitability of this compound as a promising pilot structure for in vivo applications, EZPCA was radiolabeled with radioiodine-131 (131I) and various factors affecting radiolabeling process were studied. Quality control studies of [131I]iodo-EZPCA were performed using paper chromatography and HPLC was used as a co-chromatographic technique for confirming the radiochemical yield. Biodistribution studies of [131I]iodo-EZPCA were undertaken in normal and tumor bearing mice. The radiochemical yield percentage of [131I]iodo-EZPCA was 94.20 ± 0.12%. The biodistribution results showed evident tumor uptake of [131I]iodo-EZPCA with promising target/non-target (T/NT) ratios. As a conclusion, these data suggest that [131I]iodo-EZPCA had high binding efficiency, high tumor uptake and sufficient stability to be used be used in diagnostic studies.

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.

Novel N-(1-thia-4-azaspiro[4.5]decan-4-yl)carboxamide derivatives as potent and selective influenza virus fusion inhibitors.

Hemagglutinin is the surface protein of the influenza virus that mediates both binding and penetration of the virus into host cells. We here report on the synthesis and structure-activity relationship of some novel N-(1-thia-4-azaspiro[4.5]decan-4-yl)-carboxamide compounds carrying the 5-chloro-2-methoxybenzamide structure, designed as influenza virus fusion inhibitors. The carboxamides (1a-h, 2a-h) have a similar backbone structure as the fusion inhibitors that we reported on previously. Compounds 2b and 2d displayed inhibitory activity against influenza A/H3N2 virus replication (average antiviral EC50 : 2.1 µM for 2b and 3.4 µM for 2d). Data obtained in the hemolysis inhibition assay supported that these compounds act as inhibitors of the influenza virus hemagglutinin-mediated fusion process.

4-Quinolone-Carboxamide and Carbothioamide Compounds as Fluorescent Sensors. New Fluorimetric Methods for Cu2+ and Fe3+ Determination in Tap Water and Soil.

Ion sensor properties of the carboxamide and carbothioamide compounds carrying 4-quinolone group were investigated by means of emission spectrometry in methanol-water (1:1). The compounds were selectively complexed with Cu2+, Pd2+, and Fe3+ among many metal ions. The complex stoichiometry and the stability constant were determined by fluorimetric measurements. The carboxamide compound having phenyl group (QPO) showed sensitivity for Fe3+ ion with a linear range between 0.1 and 0.7mg/L. The new method was applied in the determination of iron in the spiked tap water samples and the sandy-soil reference material. A modified standard addition method was used to remove the matrix effect. Limit of detection was 0.03mg/L for the Fe3+ determination method. The carboxamide compound with benzyl group (QBO)showed sensitivity for Cu2+ ion with linear range 0-0.4mg/L. There was no matrix effect for copper determination in the spiked tap water samples. The detection limit of the method for Cu2+ ion was 0.05mg/L. The quantification limits of the methods were low enough to determine iron and copper amount in drinking water samples according to EPA.

Transient Dipnictyl Analogues of Acrylamides, R-E=E'-CONR2 , and a Related Diphosphadigalletane from Na[OCP] and (R2 N)2 ECl (E, E'=P, As, Ga).

The reaction of Na[OCP] with (R2 N)2 ECl (E=P or As; R=alkyl) granted direct access to transient amine-substituted diphospha- and arsaphospha-acrylamide analogues, (R2 N)E=P(CONR2 ) 1. Their facile formation allowed for a comprehensive reactivity study. Dimerization yielded the four-membered rings (R2 N)2 E2 P2 (CONR2 )2 , whereas in the presence of excess Na[OCP], a stepwise [2+2] cycloaddition occured, leading to the sodium salts of carboxotripnictides [(R2 N)EP2 CO(CONR2 )]- . These salts served as a reservoir of 1, either by extrusion of Na[OCP] or by reaction with the appropriate (R2 N)2 ECl, giving the [4+2]-cycloaddition products (R2 N)EP(C6 H10 )(CONR2 ) in the presence of 2,3-dimethylbutadiene. The formal conjugate addition product K[(tBuO)(R2 N)PP(CONR2 )] was obtained by reaction of Na[(R2 N)PP2 CO(CONR2 )] with tBuOK. In addition, a rare diphosphadigalletane with a ladder-type (R2 N)2 Ga2 P2 (CONR2 )2 core was isolated from the reaction of Na[OCP] with (R2 N)2 GaCl (R=alkyl). The unprecedented pnictogenyl carboxamide compounds were thoroughly characterized, including single-crystal X-ray structure determinations, and mechanisms for their formation were investigated by DFT calculations.

Supramolecular synthon and conformational polymorphism in thiazole carboxamide compound

Supramolecular synthon and conformational polymorphism in thiazole carboxamide compound

In vivo Piroxicam Metabolites: Possible Source for Synthesis of Central Nervous System (CNS) Acting Depressants

Piroxicam has been reported to be convertible to Central Nervous System (CNS) acting agents. It has serious depressant effects at high doses. In view of this, structures of piroxicam metabolites were assessed for possible conversion to CNS depressants. Literature search was carried out with intent to identifying piroxicam metabolites and the possibility of converting them to CNS acting depressants. Piroxicam is convertible to hydroxymethylated metabolite which may be converted to barbiturates such as thiopentone and thiamylal. Whereas cyclodehydrated metabolite may be converted to acetylcyclodehydrated compound that may be in turn converted to acetylacetone and cyclohexamide. However, carboxybenzothiazine metabolite may be converted to carboxamide compound, benzolactone which is convertible to phenazone. Carboxybenzothiazine is also convertible to 2-aminopyridine mepyramine and triplenamine. Conversion of carboxybenzothiazine to gamma aminobutyric acid and phenothiazines such as chlorpromazine, thioridazine, fluphenazine and perphenazine is highly possible. Structurally, barbituric compounds, carboxamide, cyclodehydrated, benzothiazine and carboxybenzothiazine metabolites may act via dopamine and adrenergic receptors causing depression of CNS activities. Piroxicam metabolites may also act via histamine, melatonin and potassium channel receptors causing CNS depression.

Modulation of the splicing regulatory function of SRSF10 by a novel compound that impairs HIV-1 replication.

We recently identified the 4-pyridinone-benzisothiazole carboxamide compound 1C8 as displaying strong anti-HIV-1 potency against a variety of clinical strains in vitro. Here we show that 1C8 decreases the expression of HIV-1 and alters splicing events involved in the production of HIV-1 mRNAs. Although 1C8 was designed to be a structural mimic of the fused tetracyclic indole compound IDC16 that targets SRSF1, it did not affect the splice site shifting activity of SRSF1. Instead, 1C8 altered splicing regulation mediated by SRSF10. Depleting SRSF10 by RNA interference affected viral splicing and, like 1C8, decreased expression of Tat, Gag and Env. Incubating cells with 1C8 promoted the dephosphorylation of SRSF10 and increased its interaction with hTra2β, a protein previously implicated in the control of HIV-1 RNA splicing. While 1C8 affects the alternative splicing of cellular transcripts controlled by SRSF10 and hTra2β, concentrations greater than those needed to inhibit HIV-1 replication were required to elicit significant alterations. Thus, the ability of 1C8 to alter the SRSF10-dependent splicing of HIV-1 transcripts, with minor effects on cellular splicing, supports the view that SRSF10 may be used as a target for the development of new anti-viral agents.

Rapid and sensitive screening and confirmation of thirty-four aminocarbonyl/carboxamide (NACA) and arylindole synthetic cannabinoid drugs in human whole blood.

We describe the development and validation of a method for the screening and confirmation of a range of chemically diverse synthetic cannabinoid drugs in human whole blood. The method targets the better known arylindole compounds as well as the emerging aminocarbonyl/ carboxamide (NACA) compounds. The approach consists of two separate extraction procedures designed to optimize recovery of each of these two classes, followed by analysis by liquid chromatography-tandem mass spectrometry (LC-MS/MS). The most significant novel compounds added were AB-FUBINACA, ADBICA, 5 F-ADBICA, ADB-PINACA, ADB-FUBINACA, ADB-FUBINACA, 5 F-ADB-PINACA, 5 F-ADB-PINACA, AB-PINACA, AB-CHMINACA, and ADB-CHMINACA. A third procedure is described for the quantitative confirmation of those compounds for which deuterated internal standards permitted quantitative analysis, including JWH-018, JWH-122, JWH-081, JWH-210, AM-2201, XLR-11, and UR-144. The methods were successfully validated according to Scientific Working Group in Forensic Toxicology (SWGTOX) protocol for 34 compounds in common use in the United States in the period of 2014 and 2015, although other substances, unknown at the time may have been introduced to the market over the same time period. The method was determined to be free from carry-over between samples, and no interference was found from other common therapeutic abused or novel psychoactive drugs. The methods were applied to the analysis of 1142 blood samples from forensic investigations, including post-mortem examinations and driving impairment cases. The drugs most frequently detected were AB-CHMINACA (18.6%), ADB-CHMINACA (15%), XLR-11 (5.5%), AB-FUBINACA (4.5%), AB-PINACA (3.9%), and ADB-FUBINACA (2.3%). Copyright © 2016 John Wiley & Sons, Ltd.