Acid Derivatives Research Articles

Cinnamic Acid Derivatives as Potential Multifunctional Agents in Cosmetic Formulations Used for Supporting the Treatment of Selected Dermatoses

Cinnamic acid and its natural derivatives were primarily used in cosmetics as fragrance materials as well as skin and hair conditioners. Nowadays, not only natural but also synthetic cinnamic acid derivatives are used as active ingredients of cosmetic formulations. They still serve as fragrance ingredients but also as active ingredients supporting the treatment of selected dermatoses such as acne vulgaris, atopic dermatitis, and hyperpigmentation. They are also commonly used in anti-aging cosmetic formulations. On the other hand, several cinnamic acid derivatives used as fragrances in cosmetic products are classified as potential allergens which can cause contact dermatitis. The main mechanisms of action proved for various cinnamic acid derivatives include antioxidant, antimicrobial, anti-inflammatory, and antimelanogenic properties. Most commonly used cinnamic acid derivatives in cosmetics products are hydroxy acids such as ferulic acid, caffeic acid, p-coumaric acid, and sinapic acid. Chemical synthesis led to several modified acids, esters, and amides, which also showed the potential to be used in cosmetic formulations.

Quantitative Structure Activity Relationship Analysis of Benzimidazole Derivatives as Aldose Reductase Inhibitors

Hyperglycemia is involved in the pathogenesis of diabetic neuropathy, retinopathy, nephropathy, and macro-vascular disease via multiple mechanisms, of which increased aldose reductase activity. Aldose reductase inhibitors, when administered from the onset of hyperglycemia, prevent the progression of polyol accumulation–linked complication. In this work, we report quantitative structure activity relationship analysis performed on the Triazino[4,3-α]benzimidazole acetic acid derivatives as aldose reductase inhibitors. The molecular modeling study was performed by using the software BioMed CAChe 6.0 and the regression analysis by SYSTAT 10.2. Various physicochemical parameters belonging to different classes viz. hydrophobic, steric and electronic etc. were calculated. QSAR models were generated using 17 compounds. The model showed a good correlative and predictive ability having convention coefficient (r2) of 0.846 and cross-validated correlation coefficient (q2) of 0.6866 by LOO external validation method. Based on the developed QSAR model, it may be concluded that aldose reductase inhibition activity of benzimidazole acetic acid derivatives is strongly influenced by the thermodynamic and electronic nature of the substituents. QSAR model shows that LOGP, LUMO energy, and steric energy are negatively affecting the biological activity. For a molecule to have higher aldose reductase activity, compound should be less lipophilic and should have more electronegative groups or atoms than electropositive groups or atoms present in the compound.

Three New Triterpene Glycosides from the Roots of Deutzia x Hybrida “Strawberry Fields” (Hydrangeaceae)

Three new triterpene glycosides were isolated from Deutzia x hybrida “Strawberry Fields” cultivar via aqueous–ethanolic extraction of the roots, including one derivative of sumaresinolic acid and two of echinocystic acid: 3-O-β-D-glucuronopyranosylsumaresinolic acid 28-O-β-D-xylopyranosyl-(1→4)-α-L-rhamnopyranosyl-(1→2)-α-L-arabinopyranosyl ester, 3-O-β-D-glucuronopyranosylechinocystic acid 28-O-β-D-xylopyranosyl-(1→4)-α-L-rhamnopyranosyl-(1→2)-α-L-arabinopyranosyl ester, and 3-O-α-L-arabinopyranosyl-(1→3)-β-D-glucuronopyranosylechinocystic acid 28-O-β-D-xylopyranosyl-(1→4)-α-L-rhamnopyranosyl-(1→2)-α-L-arabinopyranosyl ester. As none of the isolated saponins were previously documented in the literature, their structural elucidation required extensive 1D and homo- and heteronuclear 2D NMR spectroscopy, as well as mass spectrometry analysis. All three glycosides were tested for their stimulatory activity of the sweet taste receptor TAS1R2/TAS1R3. It is the first chemical and biological investigation of Deutzia x hybrida “Strawberry Fields” as well as the first report of sumaresinolic acid glycosides in Deutzia genus.

Antidiabetic Potential of Black Elderberry Cultivars Flower Extracts: Phytochemical Profile and Enzyme Inhibition

Black elderberry (Sambucus nigra L.) flowers are rich in polyphenolic compounds, including chlorogenic acid and quercetin derivatives, which are known for their health benefits, particularly their antioxidant and antidiabetic properties. This study aimed to optimize the extraction conditions using the Box–Behnken model to maximize polyphenol yields from different elderberry flower cultivars and to evaluate their potential for antidiabetic action. The extracts were analyzed for their phytochemical content and assessed for enzyme inhibition, specifically targeting enzymes critical in carbohydrate digestion and glucose regulation. The anti-inflammatory activity was also assessed. Results indicated that the Black Beauty, Obelisk, and Haschberg cultivars demonstrated significant inhibition of α-glucosidase, with a high inhibitory potential against α-amylase enzymes for the Obelisk cultivar. Additionally, high chlorogenic acid content was strongly correlated with enzyme inhibition and antioxidant activity, suggesting its substantial role in glucose regulation. This study underscores the potential of elderberry flower extracts, particularly those rich in chlorogenic acid, as natural agents for managing blood glucose levels, warranting further exploration of their use in antidiabetic applications.

Degradable poly(β-amino ester) microparticles for cleansing products and food fortification

AbstractMicroplastic pollution is a pressing global crisis caused by the extensive use of nondegradable microplastic materials in daily activities. One effective approach to mitigate this issue is to replace nondegradable plastics with degradable materials that have properties amendable for targeted applications. Here we present the development of a degradable microparticle (MP) platform based on a poly(β-amino ester) (PAE) that degrades into sugar and amino acid derivatives. This PAE MP platform showed functional replacement of nondegradable microplastics used in cleansing products and food fortification. In cleansing products, PAE MPs effectively enhanced the cleansing efficiency of a representative rinse-off product and showed effective removal of potentially toxic elements, as an alternative of traditional nondegradable microbeads. In food fortification, PAE MPs provided robust protection for multiple essential vitamins and minerals against extensive cooking and storage conditions with rapid nutrient release in a simulated human digestion system. Collectively, these PAE MPs present a potential platform to replace microplastic usage on a global scale in many applications.

Access to β-Keto Amino Acid Derivatives via Interrupted Polonovski Strategy Involving NHC-Catalyzed Aza Benzoin Reaction.

A general and practical route to the synthesis of β-keto amino acid derivatives from aldehydes and bench stable imine surrogates is presented. Following the interrupted Polonovski strategy, the imine formed in situ was trapped by the catalytically generated Breslow intermediate in an aza benzoin reaction. The present strategy has been extended to the formal synthesis of florfenicol and an intermediate en route to vancomycin. The functionalization of the synthesized β-keto amino acid derivatives highlights the practical applicability of the current methodology.

Machine learning-aided discovery of T790M-mutant EGFR inhibitor CDDO-Me effectively suppresses non-small cell lung cancer growth

BackgroundEpidermal growth factor receptor (EGFR) T790M mutation often occurs during long durational erlotinib treatment of non-small cell lung cancer (NSCLC) patients, leading to drug resistance and disease progression. Identification of new selective EGFR-T790M inhibitors has proven challenging through traditional screening platforms. With great advances in computer algorithms, machine learning improved the screening rates of molecules at full chemical spaces, and these molecules will present higher biological activity and targeting efficiency.MethodsAn integrated machine learning approach, integrated by Bayesian inference, was employed to screen a commercial dataset of 70,413 molecules, identifying candidates that selectively and efficiently bind with EGFR harboring T790M mutation. In vitro cellular assays and molecular dynamic simulations was used for validation. EGFR knockout cell line was generated for cross-validation. In vivo xenograft moues model was constructed to investigate the antitumor efficacy of CDDO-Me.ResultsOur virtual screening and subsequent in vitro testing successfully identified CDDO-Me, an oleanolic acid derivative with anti-inflammatory activity, as a potent inhibitor of NSCLC cancer cells harboring the EGFR-T790M mutation. Cellular thermal shift assay and molecular dynamic simulation validated the selective binding of CDDO-Me to T790M-mutant EGFR. Further experimental results revealed that CDDO-Me induced cellular apoptosis and caused cell cycle arrest through inhibiting the PI3K-Akt-mTOR axis by directly targeting EGFR protein, cross-validated by sgEGFR silencing in H1975 cells. Additionally, CDDO-Me could dose-depended suppress the tumor growth in a H1975 xenograft mouse model.ConclusionCDDO-Me induced apoptosis and caused cell cycle arrest by inhibiting the PI3K-Akt-mTOR pathway, directly targeting the EGFR protein. In vivo studies in a H1975 xenograft mouse model demonstrated dose-dependent suppression of tumor growth. Our work highlights the application of machine learning-aided drug screening and provides a promising lead compound to conquer the drug resistance of NSCLC.Graphical

A New Methylbutyric Acid Derivative with Pro-angiogenesis Activity from the Mangrove Fungus Penicillium polonicum M-3.

A new methylbutyric acid derivative penianoic acid A (1), along with fifteen known compounds (2-16), was isolated and identified from the culture extract of Penicillium polonicum M-3 sourced from Malaysian mangrove root soil. Their structures were determined by detailed spectroscopic analysis of NMR and MS data and quantum chemical calculations of ECD and NMR (with DP4+ probability analysis). The isolated compounds were evaluated for pro-angiogenesis activity using zebrafish in vivo model. Compounds 1, 3, 4, 6-10, and 12-15 showed potent in pro-angiogenic activity in transgenic zebrafish.

Supramolecular Gels Derived from Primary Ammonium salts of Naproxen and its Amino Acid Derivatives: Design, Synthesis, Structures and its Application as Anti-cancer Agent Against Melanoma Cell B16-F10.

Supramolecular synthon approach was employed to develop a self-drug-delivery system based on organic salt based supramolecular gelators. One such key gelator NAP-PHE∙PEA derived from naproxen-phenylalanine conjugate and phenethylamine showed ability to gel both water and organic solvents. Supramolecular interactions such as π-π and C-H…π were probed by variable-temperature 1H-NMR spectroscopy in the hydrogelation process of NAP-PHE∙PEA. Single crystal structures of nine out of twelve salts were determined and the supramolecular synthon present therein was carefully analyzed. Intriguing insights of the gel-network structure was also investigated by structure-property correlation based on single-crystal and powder X-ray diffraction analysis of gelator/nongelator salts. The gelator salt NAP-PHE∙PEA displayed significant anti-cancer property against cancer cells (B16-F10. HeLa and A375); it was found non-cytotoxic against normal cell lines (E.derm and HEK-293) at comparable concentrations as revealed by MTT assays. The gelator salt NAP-PHE∙PEA also displayed significant anti-cancer behaviour against B16-F10 (scratch assay) and HeLa (multi-cellular tumour spheroid). The methyl salicylate gel of NAP-PHE∙PEA displayed shape-sustaining, load-bearing, self-healing properties along with rheoreversibility, which are considered important for topical applications.

Undescribed and known phenolic acid derivatives with significant antioxidant activity from the Scorzonera parviflora Jacq. roots.

The antioxidant activity of Scorzonera parviflora Jacq. roots were assessed by measuring their ability to scavenge ABTS and DPPH radicals. Bioactivity-guided fractionation was utilized to identify the compound(s) responsible for this activity. The most active phase, ethyl acetate, was isolated using column chromatography. The resulting fractions were then purified using preparative TLC on reverse phase and semi-preparative HPLC. The structures of the pure compounds were elucidated by spectral analysis (MS and 1H, 13C, 2D-NMR). Three undescribed phenolic acid derivatives, namely parvifloric acid A (1), B (2), and C (3), and one new sesquiterpene lactone, parviflorin (4) together with seven known compounds were isolated and identified as scopolin (5), scopoletin (6), caffeic acid (7), protocatechuic acid (8), 4,5-O-dicaffeoylquinic acid (9) 3,5-O-dicaffeoylquinic acid (10), and 3,5-O-dicaffeoylquinic acid methyl ester (11). Finally, the pure compounds obtained were tested to evaluate their antioxidant capacities, using ABTS and DPPH radical scavenging potencies. The highest activity was observed with 3,5-O-dicaffeoylquinic acid (10), followed by its methyl ester.

Bioaccessibility of Cafestol from Coffee Brew: A Metabolic Study Employing an In Vitro Digestion Model and LC-HRMS.

Cafestol is an ent-kaurene skeleton diterpene that is present in coffee beans and brews. Although several biological activities have been described in the literature for cafestol, such as hypercholesterolemic, anti-inflammatory, anticerous, and antidiabetic effects, its metabolism within the human body remains poorly understood. Therefore, this study aimed to quantify cafestol in boiled coffee brew, assess its bioaccessibility using a static in vitro digestion model, and investigate the metabolites formed during the digestion process using liquid chromatography coupled to high-resolution mass spectrometry. Cafestol content in the boiled coffee brew ranged from 127.47 to 132.65 mg L-1. The bioaccessibility of cafestol from boiled coffee brew using the in vitro digestion model was 93.65%; additionally, in the intestinal phase, cafestol was mainly found in its alcohol form. Additionally, a novel carboxylic acid derivative metabolite from cafestol with m/z 331.1909 [M + H]+ formed in the oral digestion phase is proposed. This metabolite was also detected in other digestion phases. Thus, this is the first article to investigate the metabolism of cafestol during digestion using an in vitro digestion model. The results indicate that cafestol is bioaccessible, is available to absorption, in its alcohol form, and suffers an oxidation reaction during the oral phase of digestion.

Assessment of the cytotoxic effect of aerial parts of Gazania rigens hexane extract on HRT-18 and MCF-7 cell line and chemical composition analysis using GC/MS and LC/MS

Gazania rigens are cultivated for their vividly colored flowerheads. The herb, belonging to the Asteraceae family, displays various classes of secondary metabolites, including terpenes, phenols and fatty acid derivatives. Antioxidant, hepatoprotective, nephroprotective, and antimicrobial activities of the herb have been evaluated and have proven to benefit humans clinically specially in case of cancer affected people. Breast cancer is the second most frequent reason for female mortality, and the third most frequent reason in the world is colorectal cancer. A previous study stated the in vitro anticancer effect of the genus Gazania rigens on the MCF-7 breast cancer cell. N-hexane extract of Gazania rigens aerial parts was prepared by maceration, cold extraction methods and subjected to GC/MS and LC-MS analysis to characterize its constituents. In GC/MS, the total number of identified compounds were 2-pentadecanone, 6,10,14-trimethyl, hexadecanoic acid methyl ester, 11-octadecenoic acid methyl ester, methyl stearate hexanedioic acid, and bis(2-ethylhexyl) ester. LC/MS analysis revealed and confirmed the presence of lupeol. Based on the result, n-hexane extract was evaluated for its in vitro anticancer effect against the MCF-7 and HRT-18 cell lines using an MTT assay. Results from the MTT assay showed there is a significant cytotoxic effect for hexane extract against both cell line HRT-18 and MCF-7, the IC50 value for HRT-18 was 102.2±10 ug/ml, while the IC50 value for MCF-7 was 121.2±12 ug/ml.

Unlocking the Hidden Potential of Rosemary (Salvia rosmarinus Spenn.): New Insights into Phenolics, Terpenes, and Antioxidants of Mediterranean Cultivars

Rosemary (Salvia rosmarinus Spenn. syn. Rosmarinus officinalis L.) is a Mediterranean aromatic species used both as an official herb and as a spice. Different cultivars may exhibit diverse phytochemical compositions, making a comprehensive chemical characterization pivotal for a targeted selection of valuable cultivars. This study aimed to characterize and compare the phenolic and terpene composition and content of leaf extracts of six Mediterranean rosemary cultivars: ‘Alba’, ‘Arp’ ‘Ginger’, ‘Gorizia’, ‘Tuscan Blue’, and ‘Roseus’. HPLC-DAD analysis revealed a similar phenolic composition in all the cultivars, but quantitative differences were observed. The main compounds were carnosic acid derivatives, flavonoids (e.g., luteolin, apigenin, and quercetin glucosides), rosmarinic acid, caffeic acid, and other hydroxycinnamic acid derivatives. The highest phenolic content was found in ‘Alba’, with a predominance of carnosic acid derivatives, whereas the lowest was found in ‘Ginger’ and ‘Gorizia’. The GC-MS analysis evidenced quantitative differences among the cultivars. Particularly, ‘Alba’ contained the highest terpene content, whereas ‘Arp’ and ‘Gorizia’ showed the lowest values. Regarding the antioxidant activity, ‘Alba’ exhibited the highest values as regards phenols, while for terpenes, the highest ones were obtained for ‘Ginger’ and ‘Tuscan Blue’. Significant Pearson correlations were obtained between the total phenol/terpene content and the antioxidant activity. The chemical characterization of these cultivars provides relevant information to produce the rosemary phytocomplexes, finding multiple industrial applications.

A new cannabigerolic acid derivative and its unprenylated precursor produced through the reconstitution of cannabinoid biosynthesis in Streptomyces.

A new derivative of cannabigerolic acid, designated as iso-cannabigerolic acid (iso-CBGA), a member of the cannabinoid family, and its precursor iso-olivetolic acid (iso-OA) were discovered from the culture of the engineered Streptomyces avermitilis heterologously expressing the genes responsible for cannabigerolic acid biosynthesis. Structural determination revealed an iso-pentyl moiety, which may arise from the biosynthetic precursor pool present in S. avermitilis. We describe herein the culture, isolation, structure determination and antibacterial activities of iso-CBGA and iso-OA.

Copper(I)-Catalyzed Enantioselective α-Alkylation of 2-Acylimidazoles.

Catalytic asymmetric α-alkylation of simple carboxylic acid derivatives is a challenging issue due to the difficulties in achieving high catalytic efficiency and controlling the enantioselectivity. Herein, by using a copper(I)-(R)-DTBM-SEGPHOS complex as a catalyst and 2-acylimidazoles as pronucleophiles, a general method for the catalytic asymmetric α-alkylation of simple carboxylic acid derivatives is accomplished. Various alkyl electrophiles, including allyl bromides, benzyl bromides, propargyl bromide, and unactivated alkyl sulfonates, serve as efficient alkylation reagents. The reaction enjoys the advantages of an easy reaction protocol, good functional group tolerance, and high enantioselectivity. 2,4,6-Trimethylphenol is found as an effective additive to increase yields. Preliminary 1H NMR experiments indicate the precoordination of 2-acylimidazoles to a copper(I) catalyst, which might acidify the α-hydrogens of 2-acylimidazoles and allow facile generation of stabilized copper(I) enolates. Finally, the synthetic utility of the present method is demonstrated by the asymmetric formal synthesis of AZD2716, a potent secreted phospholipase A2 inhibitor.

Antitubercular potential and pH-driven mode of action of salicylic acid derivatives.

In the search for new antituberculosis drugs with novel mechanisms of action, we evaluated the antimycobacterial activity of a panel of eight phenolic acids against four pathogenic mycobacterial model species, including Mycobacterium tuberculosis. We demonstrated that salicylic acid (SA), as well as the iodinated derivatives 5-iodo-salicylic acid (5ISA) and 3,5-diiodo-salicylic acid (3,5diISA), displayed promising antitubercular activities. Remarkably, using a genetically encoded mycobacterial intrabacterial pH reporter, we describe for the first time that SA, 5ISA, 3,5diISA, and the anti-inflammatory drug aspirin (ASP) act by disrupting the intrabacterial pH homeostasis of M. tuberculosis in a dose-dependent manner under in vitro conditions mimicking the endolysosomal pH of macrophages. In contrast, the structurally related second-line anti-TB drug 4-aminosalicylic acid (PAS) had no pH-dependent activity and was strongly antagonized by l-methionine supplementation, thereby suggesting distinct modes of action. Finally, we propose that SA, ASP, and its two iodinated derivatives could restrict M. tuberculosis growth in a pH-dependent manner by acidifying the cytosol of the bacilli, therefore making such compounds very attractive for further development of antibacterial agents.

Corosolic acid derivative-based lipid nanoparticles for efficient RNA delivery

Lipid nanoparticles (LNPs) represent the most widely employed and clinically validated platform for in vivo RNA delivery. However, currently used LNP formulations, which consist of lipids and cholesterol, exhibit limited transfection efficiency and off-target hepatic transfection. These limitations necessitate higher dosage and pose potential safety concerns. In this study, three derivatives of corosolic acid (CA) were synthesized to create a library of cholesterol-free lipid nanoparticles, CAxLNPs. From this library, CAβLNP was identified as the most effective, exhibiting enhanced tumor cell uptake and superior endosomal membrane fusion capabilities compared to cholesterol-containing LNP formulations, leading to optimal endosomal escape and efficient cytoplasmic delivery of mRNA/siRNA. Following intratumoral injection, CAβLNP demonstrated significantly improved retention and penetration within tumor tissues while minimizing undesired hepatic transfection. This LNP formulation offers a safer, more effective carrier for RNA delivery, providing promising potential to expand the applications of RNA therapeutics.

Improving Retinoic Acid Efficacy: Lipase-Catalyzed Synthesis of Derivatives with Antiviral Activity.

An efficient enzymatic approach was applied to the synthesis of new derivatives of retinoic acid. Nine derivatives, four of them new compounds, were obtained through lipase-catalysis with excellent yield. In order to find the optimal reaction conditions, the influence of various parameters such as enzyme source, nucleophile : substrate ratio, enzyme : substrate ratio, solvent and temperature was studied. The excellent results obtained by lipase catalysis made the procedure very efficient considering their advantages such as mild reaction conditions and low environmental impact. In addition, several synthesized compounds exhibited lower cytotoxicity than the retinoic acid in Vero cells and a remarkably higher antiviral activity against Herpes simplex virus type 1 (HSV-1) and Herpes simplex virus type 2 (HSV-2).

The Combination of Graphitic Carbon Nitride (gC3N4) and Supercritical Carbon Dioxide for Green Photooxidation of Benzylic Alcohols

AbstractThe research focuses on the innovative use of graphite‐like carbon nitride (gC3N4) catalysts along with supercritical carbon dioxide (scCO2) for the green synthesis of valuable organic compounds. Having explored different synthetic routes for gC3N4 and the obtained samples efficiency in the photocatalytic oxidation of benzyl alcohol with molecular oxygen in scCO2, we identified the most effective catalyst bearing ether linkers between layers of a graphite‐like structure. This catalyst facilitates the production of benzaldehyde and benzoic acid derivatives, highlighting the potential for sustainable industrial applications. The study's emphasis on a metal‐free catalyst and a zero‐waste process underlines its contribution to environmentally friendly chemical practices. The proposed approach offers a more sustainable and efficient alternative to traditional processes in small‐scale chemical production.

Biosynthetic Incorporation of Non-native Aryl Acid Building Blocks into Peptide Products Using Engineered Adenylation Domains.

Nonribosomal peptides (NRPs), one of the most widespread secondary metabolites in nature, with therapeutically significant activities, are biosynthesized by modular nonribosomal peptide synthetases (NRPSs). Aryl acids contribute to the structural diversity of NRPs as well as nonproteinogenic amino acids and keto acids. We previously confirmed that a single Asn-to-Gly substitution in the 2,3-dihydroxybenzoic acid-activating adenylation (A) domain EntE involved in enterobactin biosynthesis accepts monosubstituted benzoic acid derivatives with nitro, cyano, bromo, and iodo functionalities at the 2 or 3 positions. Here, we showed that the mutant EntE (N235G) accommodates various disubstituted benzoic acid derivatives with halogen, methyl, methoxy, nitro, and cyano functionalities at the 2 and 3 positions and monosubstituted benzoic acid with an alkyne at the 3 position. Structural analysis of the mutant EntE (N235G) with nonhydrolyzable aryl-AMP analogues using 3-chloro-2-methylbenzoic acid and 3-prop-2-ynoxybenzoic acid revealed how bulky 3-chloro-2-methylbenzoic acid and clickable 3-prop-2-ynoxybenzoic acid are recognized by enlarging the substrate-binding pocket of the enzyme. When engineered EntE mutants were coupled with enterobactin and vibriobactin biosynthetic enzymes, 3-hydroxybenzoic acid-, salicylic acid-, and 3-bromo-2-fluorobenzoic acid-containing peptides were produced as early stage intermediates, highlighting the potential of NRP biosynthetic pathway engineering for constructing diverse aryl acid-containing metabolites.