Heterocyclic Carboxylic Acids Research Articles

Enzymatic Synthesis of Austroeupatol Esters with Enhanced Antiprotozoal Activity.

Austroeupatol, the principal diterpene isolated from the invasive shrub Austroeupatorium inulifolium, holds promise for structural diversification and biological assessment of its derivatives due to its abundant availability and high yield isolation. We propose an efficient enzymatic synthesis of a series of austroeupatol esters derived from aliphatic and heterocyclic carboxylic acids. Systematic optimization of reaction parameters, including enzyme type and quantity, acylating agent amount, solvent, and temperature, was conducted. Thermomyces lanuginosus lipase in cyclohexane at 55 °C, yielded esters with favorable conversion rates. Through enzymatic catalysis, mono- and diacylated derivatives were obtained, with a diacylation-monoacylation ratio influenced by temperature and acylating agent amount. The antiprotozoal activity of austroeupatol and all synthesized derivatives was evaluated, observing that acylation improved it. The 19-valeroyl, 19-indolylpropyl, and 19-octyl derivatives were the most potent compounds against Trypanosoma cruzi and Leishmania infantum, highlighting this approach as a valuable method for synthesizing austroeupatol derivatives as potential antiparasitic agents.

Nucleophilic Functionalization of Tropylium Salts with Heterocyclic Amines and Carboxylic Acid Amides and Hydrazides

Nucleophilic Functionalization of Tropylium Salts with Heterocyclic Amines and Carboxylic Acid Amides and Hydrazides

A metal-catalysed functional group metathesis approach to the carbon isotope labelling of carboxylic acids.

The distribution, metabolism and ultimate fate of molecules within the body is central to the activity of pharmaceuticals. However, the introduction of radioisotopes into the metabolically stable carbon sites on drugs to probe these features typically requires toxic, radioactive gases such as [14C]CO and [14C]CO2. Here we describe an approach to directly carbon-label carboxylic-acid-containing pharmaceuticals via a metal-catalysed functional group exchange reaction, forming 14C-labelled carboxylic-acid-containing drugs without radioactive gases, in one pot, using an easily available and handled carboxylic acid 14C source. To enable this process, a functional group metathesis of carbon-carbon covalent bonds in acid chloride functionalities is developed, exploiting the ability of nickel catalysts to both reversibly activate carbon-chloride bonds and exchange functionalities between organic molecules. The drug development applicability is illustrated by the direct incorporation of the 14C label or 13C label into an array of complex aryl, alkyl, vinyl and heterocyclic carboxylic acid drugs or drug candidates without gases or a special apparatus, at ambient conditions and without loss of the radiolabel.

Novel organic–inorganic hybrid dimethyltin(IV) complexes of heterocyclic carboxylic acid and N-phthaloyl amino acids: Design, synthesis, spectroscopic characterization, DFT calculations and their anti-oxidant potential

Four new organic–inorganic hybrid dimethyltin(IV) complexes (1–4) having general formula Me2SnAL which were generated by the reaction of dimethyltin(IV) dichloride with sodium salts of indole-3-acetic acid (AH) and flexible N-phthaloyl amino acids (LH) in 1:1:1 molar ratio in refluxing dry THF. The plausible structure of newly generated complexes has been elucidated on the basis of spectroscopic [IR, NMR (1H,13C,119Sn), HRMS] studies. The suggested five coordinated geometry of the hybrid dimethyltin(IV) complexes have been further supported by computational calculations using density functional theory (DFT). DFT calculations were carried out using B3LYP/6-31G* functional basis set. DFT calculations furnish an insight into the optimized geometry, optimized energy, stability, global reactivity descriptors and frontier molecular orbital (FMO) analysis of newly synthesized organic–inorganic hybrid dimethyltin(IV) complexes. These newly synthesized complexes were also evaluated for their anti-radical activity by DPPH free radical scavenging assay. All the dimethyltin(IV) complexes acted as efficient radical scavengers.

Synthesis and biological evaluation of several new heterocyclic carvacrol esters

In this work, five novel esters (E4, E5, E6, E7, and E8) were synthesized through the condensation of carvacrol with heterocyclic carboxylic acids. The structures of the newly synthesized compounds were identified by FT-IR and 1H NMR analysis. The new carvacrol-based compounds and their original natural product (carvacrol) were screened for their in vitro biological activities against various types of bacteria and cancer cells. Results showed a strong inhibitory effect of ester E4 against all studied types of bacteria, and ester E4 with a MIC of 62.5 μg/mL was more effective than carvacrol with a MIC of 125 μg/mL against the gram-negative bacteria K. pneumoniae.

A stable N-containing heterocyclic carboxylic acid ligand Co-MOF for photoelectric performance and anionic dyes adsorption

Metal-organic frameworks (MOFs) are crystalline porous hybrid materials with periodic network structure and abundant active sites, which are promising adsorbents for organic pollutants. Herein, a novel Co(II)-based organic framework (Co-MOF) [Co2(L1)2(L2)] (L1 = 3-(3-carboxylphenyl) isonicotinic acid, L2 = 4, 4′-Azopyridin) was developed for selective dyes adsorption. Experiments suggest that the Co-MOF exhibits high stability, good photoelectricity and high selectivity for dyes adsorption. For dyes adsorption, the Co-MOF shows a strong adsorption to methyl orange achieving a high capacity up to 440.5 mg g−1, but shows a weak adsorption to methylene blue or rhodamine, indicating its better selectivity for anionic dyes. An insight into the selective removal of the methyl orange is being accounted for by acid-base attraction, anion-π and π–π stacking interactions, involving the Co ion, phenyl rings, and ocarboxylate of L, and the phenyl rings, and osulfonate of MO. The current work contributes to the development of future multifunctional MOF materials with the application in environment protection.

A one-step base-free synthesis of N-arylamides via modified pivaloyl mixed anhydride mediated amide coupling.

Pivalic anhydride is shown to be an effective reagent for direct amidation of carboxylic acids with N-alkyl anilines. The only by-product of this reaction is nontoxic pivalic acid, which can be easily removed by aqueous workup. The reactions are conducted under mild conditions and found to be compatible with a range of carboxylic acids, including aromatic, heterocyclic, acrylic, and aliphatic carboxylic acids and amino acids generating the desired amides in short reaction times.

Nipecotic Acid Derivatives as Potent Agents against Neurodegeneration: A Preliminary Study.

Alzheimer’s Disease (AD) is a common neurodegenerative disorder characterized by memory loss and cognitive impairment. Its pathology has not been fully clarified and therefore highly effective treatments have not been obtained yet. Almost all the current treatment options aim to alleviate only the symptoms and not to eliminate the disease itself. Acetylcholinesterase inhibitors are the main therapeutic agents against AD, whereas oxidative stress and inflammation have been found to be of great significance for the development and progression of neurodegeneration. In this work, ethyl nipecotate (ethyl-piperidine-3-carboxylate), a heterocyclic carboxylic acid derivative, which acts as a GABA reuptake inhibitor and has been used in research for diseases involving GABAergic neurotransmission dysfunction, was amidated with various carboxylic acids bearing antioxidant and/or anti-inflammatory properties (e.g., ferulic acid, sinapic acid, butylated hydroxycinnamic acid). Most of our compounds have significant antioxidant potency as lipid peroxidation inhibitors (IC50 as low as 20 μΜ), as oxidative protein glycation inhibitors (inhibition up to 57%), and act as DPPH reducing agents. Moreover, our compounds are moderate LOX inhibitors (up to 33% at 100 μΜ) and could reduce rat paw edema induced by carrageenan by up to 61%. Finally, some of them possessed inhibitory activity against acetylcholinesterase (IC50 as low as to 47 μΜ). Our results indicate that our compounds could have the potentiality for further optimization as multi-targeting agents directed against AD.

Decarbonylative Pd-Catalyzed Suzuki Cross-Coupling for the Synthesis of Structurally Diverse Heterobiaryls.

Heteroaromatic biaryls are core scaffolds found in a plethora of pharmaceuticals; however, their direct synthesis by the Suzuki cross-coupling is limited to heteroaromatic halide starting materials. Here, we report a direct synthesis of diverse nitrogen-containing heteroaromatic biaryls by Pd-catalyzed decarbonylative Suzuki cross-coupling of widely available heterocyclic carboxylic acids with arylboronic acids. The practical and modular nature of this cross-coupling enabled the straightforward preparation of >45 heterobiaryl products using pyridines, pyrimidines, pyrazines, and quinolines in excellent yields. We anticipate that the modular nature of this protocol will find broad application in medicinal chemistry and drug discovery research.

Bipyridine carboxylic acid as a high-performance anode material for lithium- and sodium-ion batteries

Commercial lithium-ion batteries with carbon-based anodes exhibit low specific capacities and pose potential safety risks of lithium plating. As possible alternatives, conjugated carboxylic acid-based electrode materials have attracted extensive attention owing to their suitable discharge potential, low solubility in electrolytes, and low-cost reproducibility. However, their theoretical capacities are limited by the number of active sites. In this paper, we introduce 2,2′-bipyridine-5,5′-dicarboxylic acid (H2bpy) as a new anode material demonstrating high specific capacity, good cycle stability, and remarkable rate performance in both lithium- and sodium-ion batteries. In particular, H2bpy possesses an ultrahigh initial capacity of lithium-ion battery of 1200 mAh g−1 at a current density of 200 mA•g−1, and the specific capacity can maintain 550 mAh•g−1 after 100 cycles. Whereas the sodium-ion battery retains a specific capacity of 258 mAh•g−1 under the same conditions. We find, through density functional theory analysis, that the superior performance is due to the molecular structure and stacking form of H2bpy. Furthermore, we perform an ex situ spectroscopic analysis and find that the H2bpy electrode has good electrochemical stability. These findings suggest that bipyridine carboxylic acids can effectively broaden the application of heterocyclic carboxylic acids as anode materials.

Equilibrium study on the reactive extraction of heterocyclic monocarboxylic acids from the aqueous solution using Alamine 300/diluent composite solvent: Optimization and modeling of the solvent effect

AbstractExperiments were conducted to optimize the extraction equilibrium of reactive systems (water + heterocyclic carboxylic acid + Alamine 300/diluent) at T = 298.2 K and P = 101.3 kPa. The uptake capacity of the commercial composite solvent Alamine 300/diluent approximates the order: 2‐furoic acid ≥ alpha‐oxo‐2‐furanacetic acid > tetrahydro‐2‐furoic acid, and n‐heptane < 1,2‐dichloroethane < 1‐heptanol ≤ 2‐heptanone. Four differentiable models featuring the effects of separation ratio R and synergistic enhancement SE factors are stringently tested to identify global optimization ranges by derivative variation method as follows: 0.2 < R < 0.8 and 4 < SE < 7 for 1‐heptanol and 2‐heptanone, 1.2 < R < 3.5 and 4 < SE < 6.5 for 1,2‐dichloroethane, 2 < R < 80 and 4 < SE < 80 for n‐heptane, and Alamine 300 concentration 0.12–0.18 mol dm−3. Consecutively, the optimum mass transfer stages of a countercurrent extraction are calculated by Kremser–Souders–Brown equation. The equilibrium properties are estimated precisely according to linear solvation energy relation with substantial improvement linear solvation energy relation with substantial improvement (LSER‐si), solvation probability relation solvation probability relation (SPR) and Chemodel‐modified yielding mean relative errors of 7.0%, 0.08% and 20.4%, respectively.

Three bismuth(III) complexes constructed by N-containing heterocyclic carboxylic acids: Synthesis, crystal structure and photocatalytic activity

Three novel bismuth(III) complexes of the formulae [Bi(3-apac)2(H2O)Cl3](3-apac)2 (1), [Bi(μ-pda)(H2O)Cl]n (2) and [Bi(6,6′-bpdc)(H2O)(μ-Cl)] (3) (where 3-apac ​= ​3-aminopyrazine-2-carboxylic acid, H2pda ​= ​pyridine-2,6-dicarboxylic acid, 6,6′-H2bpdc ​= ​2,2′-bipyridine-6,6′-dicarboxylic acid) were synthesized. The X-ray crystallographic investigation reveals that 1 is a mononuclear compound and offers the first example of Bi(III) complex which proton transfer occurs in ligand molecules. 2 is a dinuclear coordination polymer, which consists of two [Bi(μ-pda)(H2O)Cl] units via two bridging O atoms of two pda2− ions. And the dinuclear complex 3 is built up from two Bi3+ ion cores which are bridged through two Cl– ions. Furthermore, the photocatalytic activity of 1–3 toward the degradation of Rhodamine B (RhB) was explored, and the mechanism of the photocatalytic degradation was discussed. The results indicate that 2 and 3 are good candidates for the photocatalytic degradation of RhB.

Highly Chemoselective Esterification from O-Aminoallylation of Carboxylic Acids: Metal- and Reagent-Free Hydrocarboxylation of Allenamides.

Metal-free hydrocarboxylation of allenamides with various functionalized carboxylic acids were achieved with complete regio- and stereocontrol (>49:1). This environmentally compatible transformation affords γ-acyloxyenamides with exclusive E-selectivity. Electron rich, electron poor, aliphatic, aryl, and heterocyclic carboxylic acids all gave excellent yields (avg. 89 %, 47 examples). We demonstrate the synthetic potential of this transformation in the late-stage modification of complex natural carboxylic acids and simple modification of the products to three-carbon synthons with ample opportunity for further diversification. DFT studies revealed that the reaction occurs in a stepwise manner through the intermediacy of a conjugated iminum species, which is rapidly captured by the carboxylate ion, resulting in the observed linear selectivity.

Specific Features of the Reactions of Pentaphenylantimony with Polyfunctional Heterocyclic Carboxylic Acids

Pyridine-2,6- and 2,5-dicarboxylic acids have acted as bifunctional compounds in the reactions with pentaphenylantimony, forming bis(tetraphenylantimony)pyridine-2,6- and 2,5-dicarboxylate, respectively. The interaction of pentaphenylantimony with 2-[(6-hydroxy-5-nitroso-4(3H)-oxopyrimidin-2-yl)sulfanyl]acetic acid involving carboxyl and hydroxyl groups in the pyrimidine ring has afforded 2-{[5-nitroso-4(3H)-oxo-6-(tetraphenylstiboxy)pyrimidin-2-yl]sulfanyl}tetraphenylantimony acetate. The structural features of the synthesized compounds have been established by means of X-ray diffraction analysis.

Synthesis, structures, magnetic and electric properties of four new coordination polymers constructed with heterocyclic nitrogen ligands and multidentate organic acid

Four new coordination polymers based on heterocyclic nitrogen and aromatic carboxylic acids, namely [Co(L1)(2,5-TDC)(H2O)]n (1), [Co(L1)(1,3-BDC)]n (2), [Cu(L2)(1,4-NDC)]n (3), and [Mn(L2)2(2-AIOC)(H2O)]n (4) [L1 = 3,6-bis(1H-imidazol-1-yl)pyridazine, L2 = 3,6-bis(1H-benzo[d]imidazol-1-yl) pyridazine, 1,2-H2TDC = 2,5-thiophenedicarboxylic acid, 1,3-H2BDC = benzenedicarboxylic acid, 1,4-H2NDC = 1,4-naphthalenedicarboxylic acid, 2-H2AIOC = 2-aminoterephthalic acid] have been hydro-/solvothermally prepared and further characterized. 1 and 2 show 2D plane structure which belong to typical sql and sp topological net, respectively. 3 is a six-connected 3D framework with a pcu topological net and 4 belongs to a 3D supramolecular structure constructed via hydrogen bonds. Magnetic tests revealed that 1–3 presence the antiferromagnetic behavior, while 4 displays a ferrimagnetic behavior. The electrochemical measurements explained that 3 possesses excellent cycling stability that it can retain about 91.1% of original capacitance after cycling 10,000 times at 3 A g−1 in 2 mol L−1 KOH aqueous electrolyte.

Biological evaluation, molecular docking and DFT studies of charge transfer complexes of quinaldic acid with heterocyclic carboxylic acid

The quinaldic acid based charge transfer (CT) complexes with the ionic counterpart of furan (QCFC), thiophene (QCTC) and pyridine-2-carboxylic acid (QCPC) were prepared and successfully characterized by 1H NMR, 13C NMR, FT-IR spectroscopic techniques. In addition, the QCFC was characterized by Dept-135 and 2D NMR (Cosy, HQSC and HMBC) techniques. The electrical conductivity of synthesized CT complexes has also been investigated. The in vitro anti-inflammatory and antidiabetic activities were studied and the results were compared with reference drugs. The QCFC exhibited better anti-inflammatory and antidiabetic activity than QCTC and QCPC. Good stability under physiological conditions was observed for the CT complexes synthesized. The molecular docking studies were also performed with an α-amylase enzyme (1HNY.pdb) to identify the probable binding site of the complexes. All the CT complexes have similar binding score and the QCFC showed 4 hydrogen bonding interactions with α-amylase enzyme. Also, the 3D structure of the complexes was optimized using the Gaussian09 W program and DFT calculations were performed to find the significant regions that are necessary for enzyme inhibition.

Highly Selective and Sensitive Detection of PO4 3- Ions in Aqueous Solution by a Luminescent Terbium Metal-Organic Framework.

A luminescent terbium metal–organic framework [Tb(HPIA–)(PIA2–)(H2O)2] (Tb-MOF), synthesized by a lanthanide metal ion (Tb3+) and nitric heterocyclic carboxylic acid ligands H2PIA (H2PIA = 5-(1H-pyrazol-3-yl)isophthalic-acid), was structurally characterized as a three-dimensional skeleton structure in which layered coordination frameworks are connected by hydrogen bonds. Based on the antenna effect, Tb-MOF can emit bright green fluorescence under 254 nm excitation, and the fluorescence emission presents excellent durability in aqueous solutions among a wide pH range. Moreover, the structure of Tb-MOF also possesses outstanding thermal stabilities. In some ways, PO43– and its derivatives are thought to be a kind of pollutant ion causing series environmental and health problems. The as-synthesized Tb-MOF exhibits prominent selectivity and remarkable sensitivity for detecting PO43– as an easy-to-use fluorescent probe with low detection limit, fast response, and wide detection range. Therefore, Tb-MOF has significant applications in the fields of human health and environmental monitoring.

Regioselective Synthesis of Fused Furans by Decarboxylative Annulation of α,β‐Alkenyl Carboxylic Acid with Cyclic Ketone: Synthesis of Di‐Heteroaryl Derivatives

Abstractα,β‐Alkenyl carboxylic acids undergo CuII‐mediated decarboxylative annulation reactions with aliphatic cyclic ketones to provide synthetically valuable di‐heterocycles. The annulation process tolerates a variety of aliphatic ketones and heterocyclic alkenyl carboxylic acids, producing substituted fused furan derivatives with complete regioselectivity. The current protocol offers a synthetically applicable pathway to construct a variety of oligo‐heterocycles through Cu‐mediated single‐electron transfer and decarboxylation. Notably, synthesis of relatively inaccessible di‐heterocycles has been achieved successfully using this protocol.

Regioselective Synthesis of Fused Furans by Decarboxylative Annulation of α,β-Alkenyl Carboxylic Acid with Cyclic Ketone: Synthesis of Di-Heteroaryl Derivatives.

α,β-Alkenyl carboxylic acids undergo CuII -mediated decarboxylative annulation reactions with aliphatic cyclic ketones to provide synthetically valuable di-heterocycles. The annulation process tolerates a variety of aliphatic ketones and heterocyclic alkenyl carboxylic acids, producing substituted fused furan derivatives with complete regioselectivity. The current protocol offers a synthetically applicable pathway to construct a variety of oligo-heterocycles through Cu-mediated single-electron transfer and decarboxylation. Notably, synthesis of relatively inaccessible di-heterocycles has been achieved successfully using this protocol.

Solvent‐Free One‐Pot Tandem Multicomponent Synthesis of Triazolothiadiazinyl Coumarins and Their Antimicrobial Properties

AbstractHere, we report the synthesis, characterization and antimicrobial activity evaluation of a series of triazolo‐thiadiazinyl coumarin derivatives 4 (a–j) and 6 (a–j). The triazolo thiadiazinyl coumarins were synthesized in a facile tandem solvent free one‐pot multi component reaction approach by taking various aliphatic/ aromatic/ heterocyclic carboxylic acids 1 (a–c) and 5 (a&b), Thiocarbohydrazide (2) and substituted 3‐(2‐bromoacetyl)coumarins 3 (a–h). The newly synthesized molecules were confirmed on the basis of physical, analytical and single crystal X‐ray diffraction data. The triazolo thiadiazinyl coumarins exhibited excellent antimicrobial activity against Gram positive, Gram negative and fungi microbial strains. Among the tested compounds, compounds 4 f (6‐Bromo), 4 g (6,8‐Dibromo), 6e (6,8‐Dichloro), 6 f (6‐Bromo) and 6 g (6,8‐Dibromo) exhibited potent antimicrobial activity at 25 μg / mL concentration against Gram positive and Gram negative bacterial strains.