Design, Synthesis, and Antifungal Activity of Acrylamide Derivatives Containing Trifluoromethylpyridine and Piperazine.

In this study, a series of acrylamide derivatives containing trifluoromethylpyridine or piperazine fragments were rationally designed and synthesized. Subsequently, the in vitro antifungal activities of all of the synthesized compounds were evaluated. The findings revealed that compounds 6b, 6c, and 7e exhibited >80% antifungal activity against Phomopsis sp. (Ps) at the concentration of 50 µg/mL. Furthermore, the EC50 values for compounds 6b, 6c, and 7e against Ps were determined to be 4.49, 6.47, and 8.68 µg/mL, respectively, which were better than the positive control with azoxystrobin (24.83 µg/mL). At the concentration of 200 µg/mL, the protective activity of compound 6b against Ps reached 65%, which was comparable to that of azoxystrobin (60.9%). Comprehensive mechanistic studies, including morphological studies with fluorescence microscopy (FM), cytoplasmic leakage, and enzyme activity assays, indicated that compound 6b disrupts cell membrane integrity and induces the accumulation of defense enzyme activity, thereby inhibiting mycelial growth. Therefore, compound 6b serves as a valuable candidate for the development of novel fungicides for plant protection.

Acrylamide derivatives: A dynamic nuclear magnetic resonance study.

Substituted acrylamides have found an extensive application in organic and medical chemistry; therefore, it is very important to get insight into their features such as electronic structure, spectral properties, and stereochemical transformations. A correct interpretation of the chemical behavior and biological activity of these heteroatomic systems is impossible without knowledge of the structure of stereodynamic forms and factors determining their relative stability. The structure and peculiarities of stereodynamic behavior of substituted acrylamides and their model compounds were studied by dynamic and multinuclear 1 H, 13 C, and 15 N nuclear magnetic resonance (NMR) spectroscopy in CDCl3 and DMSO-d6 solution. It has been established that acrylamides in solution are realized as Z- and E-isomers, with the E-rotamer being somewhat predominant. The obtained experimental values of the free activation energy of rotamers vary within 15-17 kcal/mol, depending on the stereochemical structure of the molecule. 15 N NMR spectroscopy is the most reliable and fastest method for determining the structural and stereochemical features of nitrogen-containing compounds.

A Study of the Synthesis and Characterization of New Acrylamide Derivatives for Use as Corrosion Inhibitors in Nitric Acid Solutions of Copper.

The objective of this research was to explore the impact of corrosion inhibition of some synthetic acrylamide derivatives 2-cyano-N-(4-hydroxyphenyl)-3-(4-methoxyphenyl)acrylamide (ACR-2) and 2-cyano-N-(4-hydroxyphenyl)-3-phenylacrylamide (ACR-3) on copper in 1.0 M nitric acid solution using chemical and electrochemical methods, including mass loss as a chemical method and electrochemical impedance spectroscopy (EIS) and potentiodynamic polarization (PP) as electrochemical methods. By Fourier-transform infrared spectroscopy (FTIR), proton nuclear magnetic resonance (1HNMR), and mass spectroscopy (MS) methods, the two compounds were verified and characterized. There is evidence that both compounds were effective corrosion inhibitors for copper in 1.0 M nitric acid (HNO3) solutions, as indicated by the PP curves, which show that these compounds may be considered mixed-type inhibitors. With the two compounds added, the value of the double-layer capacitance was reduced. In the case of 20 × 10-5 M, they reached maximum efficiencies of 84.5% and 86.1%, respectively. Having studied its behavior during adsorption on copper, it was concluded that it follows chemical adsorption and Langmuir isotherm. The theoretical computations and the experimental findings were compared using density functional theory (DFT) and Monte Carlo simulations (MC).

Design, synthesis and antitumor activity evaluation of novel indole acrylamide derivatives as IMPDH inhibitors.

Inosine 5'-monophosphate dehydrogenase (IMPDH; EC1.1.1.205) is the rate-limiting enzyme of GMP biosynthesis. The inhibition of IMPDH limits the growth and survival of tumors. Based on the systematic summary of clinical IMPDH inhibitors, 38 acrylamide derivatives with differently substituted indoles at the 3-position as the core scaffold were designed and synthesized. In addition, the actions of these compounds at the enzyme and cellular levels were evaluated. An MTT assay with different kinds of cells was used to assess the cytotoxic activities of compounds 14e and 14n, which displayed potent hIMPDH2 inhibitory activities (IC50 = 4.207 and 2.948 µM, respectively). Biological evaluation indicated that target compounds 14e and 14n displayed the most significant effects on SW480 human colon cancer cells (IC50 = 15.34 ± 0.06 and 15.31 ± 0.09 µM, respectively), and it was determined that these compounds are effective and valuable IMPDH inhibitors for cancer intervention.

Design, synthesis and biological evaluation of novel N-(3-amino-4-methoxyphenyl)acrylamide derivatives as selective EGFRL858R/T790M kinase inhibitors.

On the basis of N-(3-amino-4-methoxyphenyl)acrylamide scaffold, a series of novel compounds containing 3-substitutional-1-methyl-1H-indole, 2-substitutional pyrrole or thiophene moieties were synthesized and their in vitro antiproliferation activities against A549 and H1975 cell lines were evaluated. The results indicated that most of the compounds showed moderate to excellent antitumor activities. Especially, compounds 9a (A549 IC50 = 1.96 µM, H1975 IC50 = 0.095 µM), 17i (A549 IC50 = 4.17 µM, H1975 IC50 = 0.052 µM), 17j (A549 IC50 = 1.67 µM, H1975 IC50 = 0.061 µM) exhibited comparable antitumor activities and selectivity ratios compared to the positive control osimertinib (A549 IC50 = 2.91 µM, H1975 IC50 = 0.064 µM). In vitro inhibitory activities against EGFR kinases containing different mutations were also tested. Compound 17i showed remarkable inhibitory activity (with IC50 value of 1.7 nM) to EGFRL858R/T790M kinase and selectivity (22-folds compared to EGFRWT kinase). Furthermore, acridine orange/ethidium bromide (AO/EB) staining assay, cell apoptosis assay, cell cycle distribution assay and wound-healing assay of the compounds 9a and 17i were performed on H1975 cell line. The results showed dose-dependent activities of the induction of apoptosis, G0/G1-phase arrestation and inhibition of migration, which were similar to the positive control osimertinib. Additionally, molecular docking analysis was performed to seek the possible binding mode between the selected compounds (9a, 17i-17j) and EGFRL858R/T790M kinase. The results demonstrated that compound 17i is a promising candidate and worth further study.

Synthesis and evaluation of new phenyl acrylamide derivatives as potent non-nucleoside anti-HBV agents.

As a continuation of our previous work, a series of new phenyl acrylamide derivatives (4Aa-g, 4Ba-t, 5 and 6a-c) were designed and synthesized as non-nucleoside anti-HBV agents. Among them, compound 4Bs could potently inhibit HBV DNA replication in wild-type and lamivudine (3TC)/entecavir resistant HBV mutant strains with IC50 values of 0.19 and 0.18 µM, respectively. Notably, the selective index value of 4Bs was above 526, indicating the favorable safety profile. Interestingly, unlike nucleoside analogue 3TC, 4Bs could significantly inhibit 3.5 kb pgRNA expression. Molecular docking study revealed that 4Bs could fit well into the dimer-dimer interface of HBV core protein by hydrophobic, π-π and H-bond interactions. Considering the potent anti-HBV activity, low toxicity and diverse anti-HBV mechanism from that of nucleoside anti-HBV agent 3TC, compound 4Bs might be a promising lead to develop novel non-nucleoside anti-HBV therapeutic agents, and warranted further investigation.

Design, synthesis, molecular modeling, and biological evaluation of acrylamide derivatives as potent inhibitors of human dihydroorotate dehydrogenase for the treatment of rheumatoid arthritis.

Human dihydroorotate dehydrogenase (DHODH) is a viable target for the development of therapeutics to treat cancer and immunological diseases, such as rheumatoid arthritis (RA), psoriasis and multiple sclerosis (MS). Herein, a series of acrylamide-based novel DHODH inhibitors as potential RA treatment agents were designed and synthesized. 2-Acrylamidobenzoic acid analog 11 was identified as the lead compound for structure-activity relationship (SAR) studies. The replacement of the phenyl group with naphthyl moieties improved inhibitory activity significantly to double-digit nanomolar range. Further structure optimization revealed that an acrylamide with small hydrophobic groups (Me, Cl or Br) at the 2-position was preferred. Moreover, adding a fluoro atom at the 5-position of the benzoic acid enhanced the potency. The optimization efforts led to potent compounds 42 and 53‒55 with IC50 values of 41, 44, 32, and 42 nmol/L, respectively. The most potent compound 54 also displayed favorable pharmacokinetic (PK) profiles and encouraging in vivo anti-arthritic effects in a dose-dependent manner.

pH Behavior of Polymer Complexes between Poly(carboxylic acids) and Poly(acrylamide derivatives) Using a Fluorescence Label Technique.

In order to clarify the local environment during interpolymer complex formation between poly(carboxylic acids) and poly(acrylamide derivatives) with different N-substitutions, a fluorescence label technique was used. 3-(2-propenyl)-9-(4-N,N-dimethylaminophenyl) phenanthrene (VDP) was used as an intramolecular fluorescence probe. All polymers were synthesized by free radical polymerization. Interpolymer complexation was monitored by charge transfer emission from the VDP unit. Both of the poly(carboxylic acids) formed interpolymer complexes with poly(N,N-dimethylacrylamide) (polyDMAM). The micro-environments around the VDP unit in the acidic pH region for the poly(methacrylic acid) (polyMAAc) and polyDMAM mixed systems were more hydrophobic than those of the poly(acrylic acid) (polyAAc) and polyDMAM mixed systems, as the α-methyl group of the MAAc unit contributed to hydrophobicity around the polymer chain during hydrogen bond formation. This suggests that, when the poly(carboxylic acids) and poly(acrylamide derivatives) were mixed, with a subsequent decrease in the solution pH, a hydrogen bond was partially formed, following which the hydrophobicity of the micro-environment around the polymer chains was changed, resulting in the formation of interpolymer complexes. Moreover, the electron-donating ability of the carbonyl group in the poly(acrylamide derivatives) had an effect on complexation with poly(carboxylic acids).

Design, Synthesis, and Evaluation of Acrylamide Derivatives as Direct NLRP3 Inflammasome Inhibitors.

NLRP3 inflammasome plays a key role in the intracellular activation of caspase-1, processing of pro-inflammatory interleukin-1ß (IL-1ß), and pyroptotic cell death cascade. The overactivation of NLRP3 is implicated in the pathogenesis of autoinflammatory diseases, known as cryopyrin-associated periodic syndromes (CAPS), and in the progression of several diseases, such as atherosclerosis, type-2 diabetes, gout, and Alzheimer's disease. In this study, the synthesis of acrylamide derivatives and their pharmaco-toxicological evaluation as potential inhibitors of NLRP3-dependent events was undertaken. Five hits were identified and evaluated for their efficiency in inhibiting IL-1ß release from different macrophage subtypes, including CAPS mutant macrophages. The most attractive hits were tested for their ability to inhibit NLRP3 ATPase activity on human recombinant NLRP3. This screening allowed the identification of 14, 2-(2-chlorobenzyl)-N-(4-sulfamoylphenethyl)acrylamide, which was able to concentration-dependently inhibit NLRP3 ATPase with an IC50 value of 74 µm. The putative binding pose of 14 in the ATPase domain of NLRP3 was also proposed.