Anilides Research Articles

Novel 4-triazole phenyl amide (4-TPA) molecules: Potent promoters of α-synuclein fibril disassembly

Parkinson's disease profoundly compromises patients' daily lives, and the disassembly of α-synuclein aggregates, a primary pathological factor, represents a promising therapeutic approach. In this study, we conducted a systematic screening and optimization process to identify the novel scaffold B37, a 4-triazolyl-phenylamine derivative, exhibiting a potent disassembly activity of 1.1 μM against α-synuclein preformed fibrils. Notably, B37 demonstrated significant neuroprotective effects, ameliorated autophagic dysfunction induced by preformed fibrils, mitigated oxidative stress, and restored the co-localization of preformed fibrils with lysosomes. Transmission electron microscopy corroborated its in vitro disassembly function. Pharmacokinetic profiling revealed favorable parameters with a receptible blood-brain barrier permeability. B37 emerges as a promising lead compound for further optimization, aiming to develop a highly effective agent targeting the disassembly of α-synuclein aggregates to treat neurodegenerative diseases like Parkinson's disease.

Mechanism Analysis of Antimicrobial Peptide NoPv1 Related to Potato Late Blight through a Computer-Aided Study.

Phytophthora infestans (Mont.) de Bary, the oomycotic pathogen responsible for potato late blight, is the most devastating disease of potato production. The primary pesticides used to control oomycosis are phenyl amide fungicides, which cause environmental pollution and toxic residues harmful to both human and animal health. To address this, an antimicrobial peptide, NoPv1, has been screened to target Plasmopara viticola cellulose synthase 2 (PvCesA2) to inhibit the growth of Phytophthora infestans (P. infestans). In this study, we employed AlphaFold2 to predict the three-dimensional structure of PvCesA2 along with NoPv peptides. Subsequently, utilizing computational methods, we dissected the interaction mechanism between PvCesA2 and these peptides. Based on this analysis, we performed a saturation mutation of NoPv1 and successfully obtained the double mutants DP1 and DP2 with a higher affinity for PvCesA2. Meanwhile, dynamics simulations revealed that both DP1 and DP2 utilize a mechanism akin to the barrel-stave model for penetrating the cell membrane. Furthermore, the predicted results showed that the antimicrobial activity of DP1 was superior to that of NoPv1 without being toxic to human cells. These findings may offer insights for advancing the development of eco-friendly pesticides targeting various oomycete diseases, including late blight.

The behaviour of grapevine growers in the decision-making of using Plant Protection Products (PPP) from Palmela region

In current days, the major challenges for farmers are the impact of plant protection products (PPP) on the public health, the environment protection, residues reduction, bees and non-target organisms, as well as, the withdrawal of many active ingredients and climate changes. Given the current situation, sustainable use of PPP is a main objective and priority. The decisions making of using PPP of 235 winegrowers from Palmela region, which do not have regular technical assistance, were assessed during 2016 until 2019. The data analysed included the number of applications, the dosages used and the compliance of pre-harvest interval (PHI). For each year, it was observed that a winegrower, on average, made seven treatments, although the tendency is a decrease to reduce the number of treatments. The PPP most used belong to the groups 3 (Triazoles), M02 (Inorganic) and M04 + 4 (Phthalimides + Phenyl Amides) according FRAC Code. Regardless of the climatic conditions and the disease pressure in the vineyard, the winegrowers used PPP every 14 days. Fear and “empiric experience” sometimes overtake knowledge and technology. That could only be changed with trust between technical assistance and farmers. That could be the solution to face the mentioned challenges and to offer sustainable wines from Palmela region.

Intrinsically Stretchable, Highly Efficient Organic Solar Cells Enabled by Polymer Donors Featuring Hydrogen-Bonding Spacers.

Intrinsically stretchable organic solar cells (IS-OSCs), consisting of all stretchable layers, are attracting significant attention as a future power source for wearable electronics. However, most of the efficient active layers for OSCs are mechanically brittle due to their rigid molecular structures designed for high electrical and optical properties. Here, a series of new polymer donors (PD s, PhAmX) featuring phenyl amide (N1 ,N3 -bis((5-bromothiophen-2-yl)methyl)isophthalamide, PhAm)-based flexible spacer (FS) inducing hydrogen-bonding (H-bonding) interactions is developed. These PD s enable IS-OSCs with a high power conversion efficiency (PCE) of 12.73% and excellent stretchability (PCE retention of >80% of the initial value at 32% strain), representing the best performances among the reported IS-OSCs to date. The incorporation of PhAm-based FS enhances the molecular ordering of PD s as well as their interactions with a Y7 acceptor, enhancing the mechanical stretchability and electrical properties simultaneously. It is also found that in rigid OSCs, the PhAm5:Y7 blend achieves a much higher PCE of 17.5% compared to that of the reference PM6:Y7 blend. The impact of the PhAm-FS linker on the mechanical and photovoltaic properties of OSCs is thoroughly investigated.

Synthesis, biological evaluation, and molecular modeling studies of new benzoxazole derivatives as PARP-2 inhibitors targeting breast cancer

Many benzoxazole-based and similar scaffolds were reported to have wide-range of anticancer activities. In this study, four series of benzoxazole derivatives were designed by combining benzoxazole scaffold with different amines via a reversed phenyl amide linker to produce the compounds of series A, B and C. A fourth new hybrid of benzoxazole with 1,2,3 triazole ring (series D) was also designed. The designed compounds were synthesized and screened for their anti-breast cancer activity against MDA-MB-231 and MCF-7 cell lines using MTT assay. The most potent cytotoxic compounds; 11–14, 21, 22, 25–27 were further evaluated for their in vitro PARP-2 enzyme inhibition. Compounds 12 and 27 proved to be the most active PARP-2 inhibitors with IC50 values of 0.07 and 0.057 µM, respectively. Compounds 12 and 27 caused cell cycle arrest in mutant MCF-7 cell line at G2/M and G1/S phase, respectively and they possessed significant apoptosis-promoting activity. Docking results of compounds 12 and 27 into PARP-2 pocket demonstrated binding interactions comparable to those of olaparib. Their predicted pharmacokinetic parameters and oral bioavailability appeared to be appropriate. Collectively, it could be concluded that compounds 12 and 27 are promising anti-breast cancer agents that act as PARP-2 inhibitors with potent apoptotic activity.

Dual Role of Phenyl Amides from Hempseed on BACE 1, PPARγ, and PGC-1α in N2a-APP Cells.

In Alzheimer’s disease (AD) the accumulation of amyloid β (Aβ) plaques in the brain leads to neuroinflammation, neuronal cell dysfunction, and progressive memory loss. Therefore, blocking the formation of Aβ plaques has emerged as one of the most promising strategies to develop AD treatments. Hempseed is widely used as a food, and recently its compounds have shown beneficial effects on neuroinflammation. The objective of this study was to investigate whether a fraction rich in phenyl amide compounds, N-trans-caffeoyltyramine (CAFT) and N-trans-coumaroyltyramine (CUMT), can affect gene expression: β-site amyloid-precursor-protein-cleaving enzyme 1 (BACE 1), peroxisome proliferator-activated receptor gamma (PPAR γ), and PPARγ-coactivator-1α (PGC-1α) in N2a-APP cells. The mRNA levels were measured using RT-qPCR. The ethyl acetate fraction and CAFT were found to reduce BACE1 gene expression and are promissory PPARγ and PGC-1α natural agonists. The results show that hempseed compounds can inhibit the expression of BACE 1, which is involved in the accumulation of Aβ plaques and positively affect transcription factors involved in complex and diverse biological functions.

Developing A Novel Coumarone-Phenyl Amide Functionalized [Gd(III)-Pt(IV)] Complex as High T1, T2 Relaxive M-MRI Contrast Agent for Cancer Diagnosis

Pt(IV) cored Gd(III) metal complex as a multimodal MRI contrast agent for cancer diagnosis is reported. The hetero nuclear complex [Pr-(DO3-Ch-Ph-Am-Gd(III))2Pt(II)] is highly soluble in water and stable at room temperature. The complex shows high longitudinal (r1p = 24.43 mM-1 s-1) and transversal (r2p = 38.61 mM-1 s-1) relaxivity values in neat aqueous solution at pH =7 and at 27 oC. The relaxivity value of the complex is greater than the low molecular weight, FDA approved MRI contrast agents. The presence of two water molecules in the first coordination sphere and a replaceable hydrogen atom in the linker enhances the proton relaxation rate and gives a huge relaxivity value. The r2p/r1P ratio of 1.58 confirms that the complex is a T1-weighted contrast agent. The presence of high polar coumarone pendant arm and high rigid acridone moieties in the complex make the complex as better anticancer agent for ovarian cancer. The high polar nature of the coumarone, phenyl amide, acridone moiety will show better binding efficiency with ovarian cancer creating CA125 glycoprotein.

Design, Synthesis and Enzymatic Inhibition of Novel Unusual Amino Acids as a Transition State Analogue of Amyloid Precursor Protein Peptide

β-secretase 1 (BACE1) plays a pivotal role in the pathology of Alzheimer׳s disease via accumulation beta amyloid in the brain. In this context, identifying new scaffolds that block BACE1 is of great importance despite all pharmacokinetic drawbacks that peptide-like structures have. Here, we report a new core structure based on novel unusual amino acids by substituting phenyl amide group in the P1 position and small alkyl groups in the P1′ site that results in the formation of new biological active peptides in micromolar level. Three different scaffolds were designed based on docking studies to efficiently interact with critical Asp32 residue in the active site of BACE1 and incorporated in peptides synthesis by Fmoc solid-phase peptide synthesis (SPPS) methodology to achieve desired compounds in good yield. The inhibitory activity of all synthesized peptides was examined by FRET-based enzymatic assay. The peptide 7 showed the best inhibitory activity with IC50 = 98.14 µM. Results of this investigation revealed that utilizing unusual amino acids as building blocks for the synthesis of peptidomimetics would be an option for the development and optimization of pharmaceutical structures. The inhibition of β-secretase 1 (BACE1) is potentially important approach to treatment of Alzheimer disease (AD). Novel series of peptides coupled to the new unusual amino acids scaffold were investigated as BACE1 inhibitors in this study. The design of these peptides was mostly affected by OM00-3. Based on observations, in good agreement between BACE-1 inhibition assessment and docking methodology, peptide 7 was the most potent compound between all and could be the basis of future studies.

Fungicide Sensitivity Survey of Plasmopara viticola Populations in Georgia Vineyards

Grapevine downy mildew, caused by Plasmopara viticola, is among the most damaging diseases of grapes globally and in the viticultural regions of Georgia (U.S.A.). Although management of this disease typically involves fungicide applications, resistance development in P. viticola can render chemical management ineffective. The objective of this study was to survey fungicide sensitivities of P. viticola populations in vineyards across three regions in Georgia. Samples were collected from eight vineyards in 2017 and four in 2018 and tested phenotypically for sensitivity to quinone outside inhibitor (QoI), carboxylic acid amide (CAA), and phenylamide (PA) fungicides using leaf disc bioassays. In addition, DNA was extracted from P. viticola samples collected from 2015 through 2018 in these 12 vineyards and six others for a total of 18 vineyards sampled. All available DNA samples were tested for the presence of the known resistance-causing mutations G143A (QoI) and G1105S (CAA) using polymerase chain reaction (PCR). This study documented widespread occurrence of QoI resistance in P. viticola in Georgia, with 83.0% of isolates collected in 2017 and 2018 testing positive for QoI resistance based on bioassay and 82.9% of isolates collected from 2015 to 2018 testing positive for QoI resistance through PCR testing. In total, 94.4% (17/18) of surveyed vineyards had confirmed QoI resistance by the conclusion of the survey period. No reduced sensitivity to CAA or PA fungicides was identified. Due to widespread QoI resistance, these fungicides should not be relied upon for downy mildew management in Georgia vineyards with a long history of their use.

Microwave Assisted Synthesis of Some Novel Thiazine Derivatives and Prediction of Their Bioactivity

In present work first we synthesized different chalcones by using Claisen-Schmidt condensation of substituted acetophenones and different aromatic aldehydes in basic medium. Then by irradiating these chalcones to microwaves in scientific microwave oven at 30% (160 watts) power, condensed with different hydrazides & isothiocyanates and gives different 2-phenyl-2,5-dihydropyrazole-1-carbothionic acid phenyl amide derivatives. These derivatives were further condensed in microwave with substituted acetophenones and different aromatic aldehydes to give pyrazolyl thiazine derivatives which were subjected to web-based computer programme PASS to find out their probable biological activity

Evaluation of fungicides against foot and stem rot and Phoma leaf spot of roselle and their impact on fibre yield

Foot and stem rot (FSR) and Phoma leaf spot caused by Phytophthora parasitica var. sabdariffae and Phoma sabdariffae are the two major diseases, affecting the roselle cultivation across India and worldwide. The efficacy of different group of fungicides like, Acetamida-Dithiocarbamate, Methoxyacrylates, Trifloxystrobin and Tebuconazole, Phenyl amide and Copper compound were assessed under field conditions against FSR and Phoma leaf spot. Duncan’s multiple range test (DMRT) was used to determine significant difference (p < 0.05) between the treatments. Seed treatment with cymoxanil 8% + mancozeb 64% WP @ 3 g kg−1 seed + prophylactic foliar spraying of cymoxanil 8% + mancozeb 64% WP @ 0.3% at 30 and 45 days of crop age showed lowest disease incidence (3.66 and 2.93%) against FSR and Phoma leaf spot disease as compared to the untreated control (9.73 and 7.66%) and exhibited higher plant height (350 cm), high basal diameter (17.51 cm), highest benefit–cost ratio (2.1), more incremental benefit–cost ratio (15.6) and highest fibre yield (26.53 q/ha) over untreated control.

Experimental and theoretical spectroscopic analysis, chemical reactivity and fungicidal activity study on benalaxyl along with quantum chemical computation on metalaxyl and furalaxyl

Abstract Structural activity, spectroscopic analysis and fungicidal activity plays an important role in understanding the nature of phenylamide fungicides. The objective of the study was to combine experimental spectroscopic and computational methodology together with bioactivity study in order to investigate the structure activity and fungicidal activity of phenyl amide fungicide benalaxyl. Computational study was done on other phenylamide fungicides metalaxyl and furalaxyl using B3LYP/6-311G(d,p) basis set. The complete vibrational distributions were performed on the basis of the potential energy distribution by vibrational energy distribution analysis program. The UV–visible spectrum of benalaxyl in water solvent was taken and analyzed in comparison with TD-DFT method. The potential energy surface scan analysis was performed. The 1H and 13C NMR spectra were recorded and analyzed. Benalaxyl was screened for its antifungal activity. Molecular docking studies were conducted to predict its fungicidal activity. The MIC value of benalaxyl was performed.

Anti-proliferative potential of cyclotetrapeptides from Bacillus velezensis RA5401 and their molecular docking on G-Protein-Coupled Receptors

Elucidation of bioactive chemical compounds from rhizobacteria is highly utilized in pharmaceuticals and naturopathy, due to their health benefits to human and plants. In current study, four cyclopeptides along with one phenyl amide were isolated from the ethyl acetate extract of Bacillus velezensis sp. RA5401. Their structures were determined and characterized as cycle (L-prolyl-L-leucyl)2 (1), cyclo (L-prolyl-l-valine)2 (2), cycle (L-phenylanalyl-L-propyl)2 (3), cyclo (D-pro-L-tyr-L-pro-L-tyr)2 (4) and N-(2-phenylethyl)acetamide (5) on the basis of electron spray ionization mass spectrometry (ESI-MS), nuclear magnetic resonance (NMR) techniques and comparison with the literature data. The five compounds have been isolated for the first time from this species. The effect of various concentrations of these compounds on the proliferation of MDA-MB-231 breast cancer cells was examined. It was found that 1 and 2 induced concentration-independent anti-proliferative effects, while 3, 4 and 5 inhibited cancer cell proliferation in a concentration-dependent manner. Furthermore, to determine the suitable binding targets of these compounds within cancer cell line, detailed target prediction and comparative molecular-docking studies were performed. The compounds 1 and 2 hit intracellular anti-cancer targets of proteases family, while compounds 3, 4 and 5 interacted with different membrane receptors of G-Protein-Coupled Receptors (GPCRs). In conclusion, the Bacillus velezensis RA5401 can be an ideal strain to produce anti-proliferative constituents at industrial scale.

The Design, Synthesis, and Characterizations of Spore Germination Inhibitors Effective against an Epidemic Strain of Clostridium difficile.

Clostridium difficile infections (CDI), particularly those caused by the BI/NAP1/027 epidemic strains, are challenging to treat. One method to address this disease is to prevent the development of CDI by inhibiting the germination of C. difficile spores. Previous studies have identified cholic amide m-sulfonic acid, CamSA, as an inhibitor of spore germination. However, CamSA is inactive against the hypervirulent strain R20291. To circumvent this problem, a series of cholic acid amides were synthesized and tested against R20291. The best compound in the series was the simple phenyl amide analogue which possessed an IC50 value of 1.8 μM, more than 225 times as potent as the natural germination inhibitor, chenodeoxycholate. This is the most potent inhibitor of C. difficile spore germination described to date. QSAR and molecular modeling analysis demonstrated that increases in hydrophobicity and decreases in partial charge or polar surface area were correlated with increases in potency.

Corrigendum: Iterative C-H Functionalization Leading to Multiple Amidations of Anilides.

Corrigendum: Iterative C-H Functionalization Leading to Multiple Amidations of Anilides.

Conformational selectivity and high-affinity binding in the complexation of N-phenyl amides in water by a phenyl extended calix[4]pyrrole.

We describe the synthesis of a tetrapyridinium phenyl extended calix[4]pyrrole that is soluble in neutral water solution at mM concentrations. We show that, in pure water, the synthesized calix[4]pyrrole receptor selectively binds the cis-(E) conformers of secondary N-phenyl-amides and tertiary N-methyl-N-phenyl-formamide with binding affinities larger than 103 M-1. The conformational selectivity is remarkable owing to the energetic preference of amides to adopt the trans-(Z) conformation in solution. In this respect, we used two binding models for the mathematical analyses of the titration data and calculated apparent and intrinsic binding constants. The combined action of hydrogen bonding and the hydrophobic effect that operates in the binding of the amides in water is responsible for the large affinities displayed by the receptor.

Solid-state entrapment of water clusters by 26-membered pentamide unclosed cryptands – probing the para-substituent effect

Twenty six membered unclosed cryptands end-capped with nitrophenyl (1), phenyl (2), and methoxyphenyl (3) amide substituent (lariat arm) were characterized by single crystal X-ray analysis to reveal the role of para-substituent on the solid-state stabilization of water clusters. Host molecules 1 and 3 crystallize in the same space group (P-1) forming isostructural assemblies with the same entrapped octameric water cluster build from a cyclic tetramer connected with four up-and-down positioned pendulous water molecules. In striking contrast, the host molecule 2 bearing the unsubstituted amido-phenyl group crystallizes in P21/c space group in which two host molecules stabilize acyclic water chain. This distinct crystallization behavior may be rationalized by differences in the electrostatic potential surfaces between hosts 1 and 3 as compared with 2 (para-substituent effect).

A Modern Twist to a Classic Synthetic Route: Ph3Bi-Based Redox Transmetalation Protolysis (RTP) for the Preparation of Barium Metalorganic Species.

This paper reports advances in redox transmetalation/protolysis (RTP) utilizing the readily available Ph3Bi for the synthesis of a series of barium metal-organic species. On the basis of easily available starting materials, an easy one-pot procedure, and workup, we have obtained BaL2 compounds (L = bis(trimethylsilyl)amide, phenyl(trimethylsilyl)amide, pentamethylcyclopentadienide, fluorenide, 2,6-di-isopropylphenolate, and 3,5-diphenylpyrazolate) quantitatively by sonication of an excess of barium metal with triphenylbismuth and HL in perdeuterotetrahydrofuran, as established by NMR measurements. Rates of conversion are affected by both pKa and bulk of HL. Competition occurs from direct reaction of Ba with HL, thereby enhancing the overall conversion, the effect being pronounced for the less bulky and more acidic ligands. Overall, the method significantly adds to the synthetic armory for barium metal-organic/organometallic compounds.

Synthesis of benzo[d]pyrrolo[2,1-b][1,3]oxazines by intramolecular cyclization of 2,4-dioxabutanoic acids 2-(hydroxymethyl)phenylamides

(Z)-4-Aryl-N-[2-(2-hydroxymethyl)phenyl]-2,4-dioxo-3-[3-oxo-3,4-dihydroquinoxalin-2(1Н)-ylidene]butanamide heated in Dowthem A at 200°С quickly underwent cyclization into 3а-aryl-2-hydroxy-3-(3-oxo-3,4-dihydroquinoxalin-2-yl)-3a,5-dihydro-1H-benzo[d]pyrrolo[2,1-b][1,3]oxazin-1-ones.

An Unprecedented Synthesis of N‐Phenyl Amides via Cleavage of Benzotriazole Ring under Free Radical Condition

AbstractAn attempt of Bu3SnH mediated cyclization of acylbenzotriazoles (RCOBt) to corresponding benzoxazole failed; instead, corresponding N‐phenylamides were achieved in good yield. The reactions proceed via reductive cleavage of benzotriazole ring with consequent evolution of molecular nitrogen (N2). A diverse range of amide has been achieved in high yields. Structures of all the compounds have been elucidated using IR, MS, 1H and 13C NMR, while four of them (3 o, 3 w, 4 and 5) have also been characterized by single crystal X‐ray analysis.