Acid Ester Analogues Research Articles

Synthesis and Study of the Structure-Activity Relationship of Antiproliferative N-Substituted Isosteviol-Based 1,3-Aminoalcohols.

Starting from isosteviol, a series of diterpenoid 1,3-aminoalcohol derivatives were prepared via stereoselective transformations. The acid-catalysed hydrolysis and rearrangement of natural stevioside produced isosteviol, which was transformed into the key intermediate methyl ester. In the next step, an 1,3-aminoalcohol library was prepared by the reductive amination of the intermediate 3-hydroxyaldehyde obtained from isosteviol in a two-step synthesis. To study the effect of the carboxylate ester function at position 4, the free carboxylic acid, benzyl ester and acryloyl ester analogues were prepared as elongated derivatives in comparison with our earlier results in this field. The antiproliferative activity of compounds against human tumour cell lines (A2780, HeLa, MCF-7 and MDA-MB-231) was investigated. In our preliminary study, the 1,3-aminoalcohol function with N-benzyl or (1H-imidazol-1-yl)-propyl substitution and benzyl ester moiety seemed essential for the reliable antiproliferative activity. The results obtained could be a good starting point to further functionalisation towards more efficient antiproliferative diterpenes.

Chromone-3-acrylic acid ester analogues: Design, synthesis and biological evaluation as potential pancreatic lipase inhibitors

A novel series of 21 chromone-3-acrylic acid ester analogues (5aa-5cm) were designed, synthesized and evaluated for PL inhibitory activity. The molecular docking study indicate that all the designed chromone analogues have the good binding ability (MolDock score: -115.86 to -160.07 kcal/mol) in the active site of PL enzyme (PDB ID: 1LPB), showing interactions with essential amino acid residues (Phe77, Tyr114, Ser152, Phe215, Arg256). Also, all the analogues were checked for in silico drug likeness property and all were found to have drug like properties, obeying Lipinski rule of 5, with no PAINS alerts. Analogue 5am, with the best docking score, was stable in molecular dynamics simulation for 100 ns (maximum RMSD of 6.4 Å), showing crucial amino acid interactions for more than 60% of the simulation time. The structure of the synthesized analogues were then confirmed by NMR, HRMS and IR spectroscopy. Among the synthesized analogues, 5am and 5ad exhibited potent PL inhibition with IC50 of 5.16 ± 0.287 & 5.82 ± 0.933 µM, respectively, as compared with orlistat (IC50 = 0.86 ± 0.09 µM). The inhibition kinetics and in silico studies confirmed competitive type of inhibition of analogue 5am. The current work highlights the importance of chromone analogues as potential PL inhibitors. Further, the lead optimization may lead to much more potential PL inhibitors.

Aromatic sulphonamides of aziridine-2-carboxylic acid derivatives as novel PDIA1 and PDIA3 inhibitors

In this study, we report a series of newly synthesised sulphonamides of aziridine-2-carboxylic acid (Az-COOH) ester and amide analogues as potent protein disulphide isomerase (PDI, EC 5.3.4.1) inhibitors. The inhibitory activity on PDI was determined against recombinant human PDIA1 and PDIA3 proteins using an insulin reduction assay. These compounds in low micromolar to low nanomolar concentrations showed the effective in vitro inhibitory properties of PDIA1 with weaker effects on PDIA3. Complexes of 15N- and 15N,13C- uniformly labelled recombinant human PDIA1a with two PDIA1 inhibitors were produced and investigated by a protein nuclear magnetic resonance (NMR) spectroscopy. It was found that both C53 and C56 of the PDIA1 enzyme were involved in covalent binding. Finally, in a range of pharmacological studies, we demonstrated that investigated compounds displayed anti-cancer and anti-thrombotic activity. These findings demonstrate that sulphonamides of Az-COOH derivatives are promising candidates for the development of novel anti-cancer and anti-thrombotic agents.

Ferrocenoyl-substituted quinolinone and coumarin as organometallic inhibitors of SARS-CoV-2 3CLpro main protease.

The 3-chymotrypsin-like protease 3CLpro from severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) is a potential target for antiviral drug development. In this work, three organometallic ferrocene-modified quinolinones and coumarins were compared to their benzoic acid ester analogues with regard to inhibition of 3CLpro using an HPLC-based assay with a 15mer model peptide as the substrate. In contrast to FRET-based assays, this allows direct identification of interference of buffer constituents with the inhibitors, as demonstrated by the complete abolishment of ebselen inhibitory activity in the presence of dithiothreitol as a redox protectant. The presence of the organometallic ferrocene moiety significantly increased the stability of the title compounds towards hydrolysis. Among the studied compounds, 4-ferrocenyloxy-1-methyl-quinol-2-one was identified as the most stable and potent inhibitor candidate. IC50 values determined for ebselen and this sandwich complex compound are (0.40±0.07) and (2.32±0.21) μM, respectively.

Recent Advances in Chiral Aldehyde Catalysis for Asymmetric Functionalization of Amines

AbstractAsymmetric functionalization of amines and their derivatives is of great significance in synthetic chemistry and is widely used in the preparation of natural products and pharmaceuticals. In recent years, chiral aldehyde catalysis has emerged as a well-established and recognized tool, providing excellent catalytic activation and stereoselective control in asymmetric reactions of N-unprotected amino acid esters and amino acid ester analogues. In this short review, recent advances in enantioselective aldehyde catalysis, including chiral aldehydes as organocatalysts and co-catalysis combined with transition metals, will be summarized. Lastly, continued development of enantioselective aldehyde catalysis is prospected in the future.1 Introduction2 Chiral Aldehyde Catalysis for Tethering Strategy3 Chiral Aldehyde Catalysis for Imine Activation4 Chiral Aldehyde/Transition Metal Cooperative Catalysis5 Conclusion

Biting deterrency of undecanoic acid and dodecanoic acid ester analogs against Aedes aegypti.

Mosquitoes remain one of the most significant threats to the health of humans throughout the world. This study was designed to evaluate the biting deterrent effects of a series of ester analogs of undecanoic acid (C:11:0) and dodecanoic acid (C:12:0) against Aedes aegypti (L), (Diptera: Culicidae), the yellow fever mosquito, using Klun and Debboun (K&D) and Ali and Khan (A&K) bioassay systems. In the K&D bioassays, C:11:0 esters methyl undecanoate, propyl undecanoate, butyl undecanoate, and pentyl undecanoate, and the C:12:0 esters methyl dodecanoate, ethyl dodecanoate, propyl dodecanoate, octyl dodecanoate, and dodecyl dodecanoate were most active. All of these esters were as effective as N,N-diethyl-m-toluamide (DEET) and as effective as the parent acids undecanoic acid and dodecanoic acid with biting deterrence index values ranging from 0.80 to 0.99. In the in vitro A&K bioassay undecanoic acid with a minimum effective dose (MED) of 3.125 μg cm-2 was the most active compound and showed higher activity than DEET (MED of 25 μg cm-2 ). The most active synthetic analog was butyl undecanoate with a MED of 12.5μg cm-2 . The next most active analogs are the methyl ester analogs methyl undecanoate and methyl dodecanoate, both with MED values of 25 μg cm-2 . Fatty acid synthetic esters and structural analogs are a promising source of new mosquito repelling compounds and should be investigated further. Published 2020. This article is a U.S. Government work and is in the public domain in the USA.

A strategy for developing effective orally-delivered nanoparticles through modulation of the surface "hydrophilicity/hydrophobicity balance".

Efficient oral delivery of macromolecules by nanoparticles is greatly limited by epithelial cells and the mucus layer that covers the surface of the intestinal epithelium. Worse still, to overcome both the mucus and epithelium barriers, opposite surface properties of the nanocarriers are required. Hydrophilic properties are necessary for mucus permeation, while hydrophobic ones are preferable for epithelium internalization. Thus, it is supposed that there must be a balance between the hydrophilicity and hydrophobicity of the surface of nanoparticles (NPs), which would provide NPs with a rapid mucus penetrating ability and satisfactory cellular uptake efficiency. In the current study, we have synthesized a series of copolymers (HPMA-FAs) composed of hydrophilic N-(2-hydroxypropyl) methacrylamide (HPMA) and four hydrophobic methacrylamido fatty acid ester (FA) analogues. By changing the amount of HPMA-octyl methacrylate (HPMA-C8) or applying different FAs on polymerization of the HPMA-FA copolymers for the NP formulation, we have formulated NPs with varied surface hydrophilicity/hydrophobicity properties. It was observed that the NPs coated with a 20% amount of the HPMA-C8 copolymers could result in a satisfactory mucus penetrating ability and cellular uptake efficiency, while the NPs coated with a 20% amount of the HPMA-cetyl methacrylate copolymer (NPs-C16 (20%)) presented the best results compared with the other HPMA-FA formulated NPs. The in vivo study showed that insulin-loaded NPs-C16 (20%) generated an obvious hypoglycemic effect, with a maximal 46% reduction of the blood glucose level. Moreover, no histopathology lesions or serum chemistry parameter changes were observed based on the in vivo toxicity test. Therefore, we hope that these results will provide a new perspective for the design of mucus-penetrating and epithelium-absorbed NPs for oral drug delivery systems.

Structure–activity relationships of vanillic acid ester analogs in inhibitory effect of antigen-mediated degranulation in rat basophilic leukemia RBL-2H3 cells

Methyl vanillate (1) showed strong degranulation inhibitory activity among vanillin derivatives tested. In order to find structure–activity relationships for developing anti-allergic agents with simple structures and potent activity, we synthesized several vanillic acid (VA) ester derivatives with C1–C4 and C8 alkyl chains and evaluated their degranulation inhibitory activities. The most active compound of VA ester derivatives was derivative 5 with a C4 straight alkyl chain, and derivative 5 exhibited approximately three-fold greater inhibitory activity than that of 1. Moreover, we designed 8 types of analogs based on 5, and we found that the minimum structure for potent degranulation inhibitory activity requires direct connection of the butyl ester moiety on the benzene ring and at least one hydroxyl group on the benzene ring. Butyl meta or para hydroxyl benzoate (10 or 11) has a simpler structure than that of 5 and exhibited more potent degranulation inhibitory activity than that of 5.

Synthesis of Itaconic Acid Ester Analogues via Self-Aldol Condensation of Ethyl Pyruvate Catalyzed by Hafnium BEA Zeolites

Lewis acidic zeolites are used to synthesize unsaturated dicarboxylic acid esters via aldol condensation of keto esters. Hafnium-containing BEA (Hf-BEA) zeolites catalyze the condensation of ethyl pyruvate into diethyl 2-methyl-4-oxopent-2-enedioate and diethyl 2-methylene-4-oxopentanedioate (an itaconic acid ester analogue) with a selectivity of ca. 80% at ca. 60% conversion in a packed-bed reactor. The catalyst is stable for 132 h on stream, reaching a turnover number of 5110 molEP molHf–1. Analysis of the dynamic behavior of Hf-BEA under flow conditions and studies with Na-exchanged zeolites suggest that Hf(IV) open sites possess dual functionality for Lewis and Bronsted acid catalysis.

Syntheses and biological activities of deoxy-d-allose fatty acid ester analogs.

We describe the syntheses of three different deoxy-D-allose analogs [2-deoxy-d-allose (2-DOAll), 1,2-dideoxy-d-allose (1,2-DOAll), and 1,2-didehydro-1,2-dideoxy-d-allose (1,2-DHAll)] and their fatty acid esters via regioselective lipase-catalyzed transesterification. Among them, 2-DOAll and its decanoate (2-DOAll-C10) showed higher inhibitory activity on plant growth, which is similar to d-allose (All) [corrected] and its decanoate (All-C10). Bioassay results of deoxy-All-C10 on four plant species suggest that the hydroxy group at the C-1 position might be important showing growth inhibitory activity. In addition, co-addition of gibberellin (GA3) with 1,2-DHAll-C10 and 2-DOAll-C10 recovered plant growth, suggesting that they might mainly inhibit biosynthesis of gibberellin.

Caffeic Acid Phenethyl Ester (CAPE) in Romanian Propolis

Introduction. Propolis is an important bee product, rich in biologically active compounds (MAƒrghitaș et al ., 2013). It is collected by the bees from buds and exudates of different trees and plants and it has been used since ancient times as a natural remedy or in embalming process. Caffeic acid phenethyl ester (CAPE) is one of the main medicinal components of propolis, possessing important biological activities, such as anti-bacterial, anti-oxidant anti-inflammatory and the most important anti-cancer properties (Son and Lewis, 2002). Aims. Taking into account that CAPE is an excellent compound in cancer, hepatitis and other oxidative stress diseases treatment; we consider that knowing the amount of this compound in Romanian propolis is a very challenging proposal. Materials and Methods. Different propolis samples were harvested in Transilvania, Romania, freeze immediately after harvest, finely ground, extracted with 70% ethylic alcohol and analyzed by high performance liquid chromatography. The measurements were done on a Shimadzu equipment, using acetonitril:water as mobile phase. To calculate the amount of CAPE in the samples, a calibration curve of different concentrations of standard compound was constructed. Results were expressed as mg/g propolis. Results: The analyzed propolis samples show that beside different phenolic acids and flavonoiuds, Romanian propolis is also rich in CAPE. Concentrations ranging from 0.86 to 3.87mgCAPE/g was measured and correlated with high amounts of chrysin. High concentrations of caffeic acid  (1.4 mg/ml) and pinocembrin (2.85 mg/g) were also determined in the analyzed samples. Conclusion. HPLC analysis of propolis samples from different locations in Romania, has highlighted the fact that they contain large amounts of CAPE. This propolis may be used successfully in the treatment of various diseases, including cancer. References MAƒrghitaș L., Dezmirean D. and Bobiș O. (2013). Important developments in Romanian propolis research, Evid. Based Complement. Alternat. Med., 2013:159392. Son S. And Lewis B.A. (2002). Free radical scavenging and antioxidative activity of caffeic acid amide and ester analogues: structure-activity relationship. J.Agric.Food Chem. 50:468-472.

Clinical potential of elacytarabine in patients with acute myeloid leukemia.

Acute myeloid leukemia (AML) has been treated for over four decades with standard induction chemotherapy including seven days of cytosine arabinoside (cytarabine, ara-C) infusion. Cytarabine, while effective in killing leukemic cells, is subject to development of several resistance mechanisms rendering the drug ineffective in many patients. Elacytarabine, a lipophilic 5'-elaidic acid ester or nucleoside analogue of cytosine arabinoside, was created with the intent of overcoming resistance mechanisms including reduced expression of the human equilibrative nucleoside transporter 1 (hENT1) required for cytarabine entry into cells, as well as increased activity of cytidine deaminase (CDA) which breaks down the active metabolite of cytarabine, ara-CTP. Elacytarabine enters cells independently of transporters, has a longer half life compared with cytarabine and is not subject to deactivation by CDA. Preclinical data were encouraging although subsequent clinical studies have failed to show superiority of elacytarabine compared with standard of care as monotherapy in patients with AML. Clinical trials utilizing elacytarabine in combination with anthracyclines are ongoing. Use of hENT1 expression as a predictive marker for cytarabine or elacytarabine response has been studied with no conclusive validation to date. Despite promising early results, the jury is still out in regards to this novel agent as an effective alternative to standard cytarabine therapy in acute leukemias, especially in combination with additional agents such as anthracyclines.

Bilayer interaction and protein kinase C-C1 domain binding studies of kojic acid esters

Synthesis of kojic acid ester analogues and their lipid bilayer interaction and PKC-C1 domain binding properties have been demonstrated in this present work.

Intermolecular interaction of voriconazole analogues with model membrane by DSC and NMR, and their antifungal activity using NMR based metabolic profiling

The development of novel antifungal agents with high susceptibility and increased potency can be achieved by increasing their overall lipophilicity. To enhance the lipophilicity of voriconazole, a second generation azole antifungal agent, we have synthesized its carboxylic acid ester analogues, namely p-methoxybenzoate (Vpmb), toluate (Vtol), benzoate (Vbz) and p-nitrobenzoate (Vpnb). The intermolecular interactions of these analogues with model membrane have been investigated using nuclear magnetic resonance (NMR) and differential scanning calorimetric (DSC) techniques. The results indicate varying degree of changes in the membrane bilayer’s structural architecture and physico-chemical characteristics which possibly can be correlated with the antifungal effects via fungal membrane. Rapid metabolite profiling of chemical entities using cell preparations is one of the most important steps in drug discovery. We have evaluated the effect of synthesized analogues on Candida albicans. The method involves real time 1H NMR measurement of intact cells monitoring NMR signals from fungal metabolites which gives Metabolic End Point (MEP). This is then compared with Minimum Inhibitory Concentration (MIC) determined using conventional methods. Results indicate that one of the synthesized analogues, Vpmb shows reasonably good activity.

In search of a novel antifungal agent: probing molecular interactions of fluconazole and its analogues with model membranes by NMR and DSC techniques

In search of a novel antifungal agent with high susceptibility and increased antifungal potency it is necessary to increase the overall lipophilicity of these agents. In view of that, we have synthesized different carboxylic acid ester analogues of fluconazole, such as fluconazole-benzoate, fluconazole-p-nitrobenzoate, fluconazole-p-methoxybenzoate and fluconazole-toluate, with varying degrees of lipophilicity. In order to probe molecular level interactions of these molecules with biomembrane, lipid bilayers prepared from l-α-dipalmitoyl phosphatidyl choline (DPPC) as the model membrane were used. Multinuclear and multidimensional nuclear magnetic resonance, differential scanning calorimetry and transmission electron microscopy was used to investigate the changes in the thermotropic properties, organization of the membrane and intermolecular interactions. Fluconazole and its analogues show varying degrees of changes in the DPPC bilayer's architecture and physico-chemical characteristics. This might influence important biological features of fungal biomembranes that could be responsible for their respective antifungal effects. The study indicates that fluconazole-p-methoxybenzoate is the most active among all analogues and therefore could be the most promising antifungal candidate.

ChemInform Abstract: Phenyl‐, Benzyl‐, and Unsymmetrical Hydroxy‐Methylenebisphosphonates as Dronic Acid Ester Analogues from α‐Oxophosphonates by Microwave‐Assisted Syntheses.

ChemInform Abstract: Phenyl‐, Benzyl‐, and Unsymmetrical Hydroxy‐Methylenebisphosphonates as Dronic Acid Ester Analogues from α‐Oxophosphonates by Microwave‐Assisted Syntheses.

Synthesis of N-hydroxycinnamoyl amino acid ester analogues and their free radical scavenging and antioxidative activities

Hydroxycinnamic acids have a variety of biological activities, including antioxidant activity. To find more active antioxidants with hydroxycinnamoyl moiety, we synthesized a series of N-hydroxycinnamoyl amino acid esters and evaluated their antioxidative activities by 2,2-diphenyl-1-picryl hydrazyl (DPPH) radical scavenging and human red blood cells (RBCs) haemolysis methods. It was found that N-caffeoyl amides exhibited the highest DPPH-scavenging activities, whereas N-feruloyl amides demonstrated the highest antihaemolysis activities among the three different hydroxycinnamamides (caffeoyl, feruloyl, and p-coumaroyl), and that hydroxycinnamoyl amides were more effective than their corresponding free acid and ester compounds in both DPPH and RBC haemolysis tests.

Phenyl‐, benzyl‐, and unsymmetrical hydroxy‐methylenebisphosphonates as dronic acid ester analogues from α‐oxophosphonates by microwave‐assisted syntheses

AbstractThe microwave (MW)‐assisted addition of dialkyl phosphites to α‐oxophosphonates was investigated and optimized under solventless conditions to provide the phenyl‐ and benzyl‐hydroxy‐methylenebisphosphonates efficiently by suppressing the rearrangement side reaction. Methyl‐hydroxy‐methylenebisphosphonates with mixed ester functionalities and an analogous diester‐diacid were also synthesized. It was found that the α‐oxophosphonates may also be converted to hydroxy‐methylenebisphosphonates and/or rearranged products without using dialkyl phosphite as the reagent and with the careful exclusion of water, simply on standing at room temperature, on thermal treatment, or on MW irradiation. These novel reactions taking place via the controlled decomposition of the precursor and resulting in the intermediate formation of dialkyl phosphite were also studied in detail. © 2011 Wiley Periodicals, Inc. Heteroatom Chem 22:640–648, 2011; View this article online at wileyonlinelibrary.com. DOI 10.1002/hc.20727

Inhibitory Effects of Caffeic Acid Ester Analogues on Free Radicals and Human Liver Microsome CYP1A2 Activities

Ethyl caffeate (EC), octyl caffeate(OC), benzyl caffeate(BC) and phenethyl caffeate(PC) were synthesized and evaluated for scavenging of superoxide anion, nitric oxide radical and 1,1-diphenyl-1-picrylhydrazyl radical (DPPH). Antioxidant activity was investigated with reducing power method. Pooled human liver microsome was used for investigating the effects on cytochrome P450 1A2 (CYP1A2) catalytic activities by using phenacetin as a substrate. Dixon and Cornish-Bowden plots were used for enzyme kinetic analysis. The EC, OC, BC and PC potentially inhibited superoxide anion, nitric oxide and DPPH radicals. IC(50) values of superoxide anion scavenging of EC, OC, BC and PC were 16.42, 79.83, 123.69 and 123.69 µg/ml, respectively. EC was more potent than OC and BC in terms of nitric oxide radical scavenger: IC(50) values of EC, OC and BC were 24.16, 37.34 and 52.64 µg/ml, respectively. In addition, the IC(50) values of EC, OC, BC and PC on DPPH radical scavenging were 70.00, 184.56, 285.34 and 866.54 µg/ ml, respectively. The IC(50) values of EC, OC, BC and PC on phenacetin O-deethylation were 124.98, 111.86, 156.68 and 31.05 µg/ml, respectively. Enzyme kinetics showed that the type of inhibition mechanism was mixed-type. The result of this study shows that caffeic acid ester analogues potentially scavenge free radicals and inhibit catalytic activity of CYP1A2. This may lead to important implications in the prevention of CYP1A2-mediated chemical carcinogenesis.

Synthesis and Biological Evaluation of 9Z-Retinoic Acid Analogs Having 2-Substituted Benzo[b]furan

Palladium-catalyzed cross-coupling reactions of a 2-substituted 3-iodobenzo[b]furans and stannanyl ester afforded the stereoselective production of 9Z-retinoic acid ester analogs in good yields. These esters were then converted to the corresponding acids via basic hydrolysis in excellent yields, and their biological activities were evaluated. The analog changed the connected position of polyene side chain from 2-position to 3-position of benzo[b]furan decreased the biological activities dramatically, and the introduction of various substituents at 2-position afforded almost no effect on the activities.