Esters 3a Research Articles

Improving the catalytic performance of carbonyl reductase based on the functional loops engineering.

Vibegron functions as a potent and selective β3-adrenergic receptor agonist, with its chiral precursor (2S,3R)-aminohydroxy ester (1b) being crucial to its synthesis. In this study, loop engineering was applied to the carbonyl reductase (EaSDR6) from Exiguobacterium algae to achieve an asymmetric reduction of the (rac)-aminoketone ester 1a. The variant M5 (A138L/A190V/S193A/Y201F/N204A) was obtained and demonstrated an 868-fold increase in catalytic efficiency (kcat/Km = 260.3 s-1 mM-1) and a desirable stereoselectivity (>99% enantiomeric excess, e.e.; >99% diastereomeric excess, d.e.) for the target product 1b in contrast to the wild-type EaSDR6 (WT). Structural alignment with WT indicated that loops 137-154 and 182-210 potentially play vital roles in facilitating catalysis and substrate binding. Moreover, molecular dynamics (MD) simulations of WT-1a and M5-1a complex illustrated that M5-1a exhibits a more effective nucleophilic attack distance and more readily adopts a pre-reaction state. The interaction analysis unveiled that M5 enhanced hydrophobic interactions with substrate 1a on cavities A and B while diminishing unfavorable hydrophilic interactions on cavity C. Computational analysis of binding free energies indicated that M5 displayed heightened affinity towards substrate 1a compared to the WT, aligning with its decreased Km value. Under organic-aqueous biphasic conditions, the M5 mutant showed >99% conversion within 12 h with 300 g/L substrate 1a (highest substrate loading as reported). This study enhanced the catalytic performance of carbonyl reductase through functional loops engineering and established a robust framework for the large-scale biosynthesis of the vibegron intermediate.

Exploring Border Conditions for Spontaneous Emergence of Chirality in Allylboration of 1,2,3-Triazolic Aldehydes.

A case of spontaneous chirality generation was observed during a synthetic project studying the allylboration of 1,2,3-triazolic aldehydes. Here, we present computational studies supported by experimental findings targeting the elucidation of border conditions required for the observation of spontaneous chirality generation in the reaction of 1-Ar-1H-1,2,3-triazole-4-carbaldehydes 1a,b with triallylborane. Three possible sources of symmetry breaking were found computationally. Thus, dimerization of the initial reaction products, alcoholates 4a,b, gives dimers 5a,b (homochiral) and 6a,b (heterochiral). The latter were computed to be more stable thermodynamically, which can lead to amplification of the initial stochastic imbalance of the enantiomers of 4a,b via the reservoir mechanism. Furthermore, enantiomeric excess can be increased during the transfer of the second allylic group in the reaction of optically active boronates 4a,b with 1a,b, which was computed to be enantioselective due to the strong activating and stereoregulating properties of the 1,2,3-triazole group. In addition, reactions of borinic esters 8a,b, products of the previous reaction with triallylborane, recovered in each case two molecules of 4a,b of the same handedness, which can lead to additional chirality amplification. Experimentally, reactions of optically active alcohols (+)-R-2a,b with triallylborane provided chiral alcoholates 4a,b, which were reacted with equivalent amounts of corresponding aldehydes 1a,b. Unexpectedly, in two series of 10 experiments each, preferential formation of both enantiomers of the newly formed product was observed: seven times S and three times R in the case of 1a and six times S and four times R in the case of 1b.

Rapid and selective detection of Gram-positive bacteria using new dual emissive and non-cytotoxic organoboron esters

In this work, we report the green synthesis of five emissive organoboron esters, obtained by a condensation reaction via one-pot three-component reaction under microwave irradiation in just 5 min, yielding quantitative yields. The molecular structure proposed in solution (1H, 11B and high-resolution mass spectrometry) was corroborated through X-ray diffraction analysis for 3c, where the boron ion resides in distorted tetrahedral geometry. The photophysical properties of organoboron esters were obtained in solution state, revealing that these molecular materials could be classified as semiconductors with a fluorescence quantum yield in the 0.70–32 % range. Furthermore, organoboron ester 3a demonstrated a non-hazardous selective fluorescent yellow stain against Staphylococcus aureus and Bacillus subtills strains. To the best of our knowledge, this is the first report of the use of a non-toxic organoboron ester compound as a selective fluorescent dye against Gram-positive bacterial.

Pyridine Derivatives as Insecticides. Part 5. New Thieno[2,3-b]pyridines and Pyrazolo[3,4-b]pyridines Containing Mainly Ethyl Nicotinate Scaffold and Their Insecticidal Activity toward Aphis gossypii (Glover,1887).

Ethyl 5-cyano-1,6-dihydro-2-methyl-4-(2'-thienyl)-6-thioxonicotinate (A) was synthesized and reacted with ethyl chloroacetate in the presence of sodium acetate or sodium carbonate to give ethyl 5-cyano-6-((2-ethoxy-2-oxoethyl)thio)-2-methyl-4-(2'-thienyl)nicotinate (1a) or its isomeric thieno[2,3-b]pyridine 2a. 3-Aminothieno[2,3-b]pyridine-2-carboxamide 2b was also synthesized by the reaction of A with 2-chloroacetamide. The reaction of 1a with hydrazine hydrate in boiling ethanol gave acethydrazide 3. Heating ester 1a with hydrazine hydrate under neat conditions afforded 3-amino-1H-pyrazolo[3,4-b]pyridine 10. Compounds 2b, 3, and 10 were used as precursors for synthesizing other new thieno[2,3-b]pyridines and pyrazolo[3,4-b]pyridines containing mainly the ethyl nicotinate scaffold. Structures of all new compounds were confirmed by elemental and spectral analyses. Most of the obtained compounds were evaluated for their insecticidal activity toward the nymphs and adults of Aphis gossypii (Glover,1887). Some compounds such as 4, 9b, and 9c showed promising results. The effect of some sublethal concentrations, less than LC50, of compounds 4, 9b, and 9c on the examined Aphis was subjected to a further study. The results demonstrated that exposure of A. gossypii nymphs to sublethal concentrations of compounds 4, 9b, and 9c had noticeable effects on their biological parameters, i.e., nymphal instar duration, generation time, and adult longevity. The highest concentration C1 of all three compounds increased the nymphal instar duration and generation time and decreased adult longevity and vice versa.

Multisite Amino‐Allylidene Ligands from Thermal CO Elimination in Diiron Complexes and Catalytic Activity in Hydroboration Reactions

AbstractThe new diiron(I) complexes [Fe2Cp2(μ‐CO){μ‐k3C,kN‐C(R1)C(R2)C(CN)NMe(R)}], 3 a–o (R=alkyl or 4‐C6H4OMe; R1=alkyl, aryl, ferrocenyl (Fc), thiophenyl, CO2Me or SiMe3; R2=H, Me or CO2Me) were synthesized in moderate to high yields from the thermal decarbonylation of the bis‐carbonyl precursors 2 a–o, and were structurally characterized by IR and NMR spectroscopy, and single crystal X‐ray diffraction in four cases. Electrochemical behavior of one complex was also investigated. Complexes 3 a–o comprise a highly functionalized, multisite amino‐(cyano)allylidene ligand, including metal coordination of a tertiary amine group. Selected complexes displayed negligible to moderate catalytic activity in CO2/propylene oxide coupling, working under ambient conditions. Additionally, they were investigated as catalysts for the conversion of benzaldehyde to the corresponding borate ester 6 a, using pinacolborane (HBpin) as the borylating agent. Most complexes achieved good conversions at room temperature with 1 % catalyst loading, and data highlight the significant influence of the multisite ligand substituents on the catalytic performance. Notably, complex 3 m (featuring R=4‐methoxyphenyl, R1=Fc, R2=H) displayed the highest activity and effectively catalyzed the hydroboration of various aldehydes and ketones. A plausible mechanistic cycle involves metal coordination of the carbonyl substrate, its activation being possibly facilitated by intramolecular interactions.

Synthesis, anti-HIV and cytotoxicity evaluation of chiral 2,5-disubstituted 1,3,4-thiadiazole derivatives bearing the sulfonamide scaffold

Abstract In the present study, chiral 2-(4-substiuted phenyl)amino-5-[1-(4-substituted benzenesulphonamido)alkyl]-1,3,4-thiazdiazoles 5a–x were synthesized from enantiopure l-amino acids in a multistep sequence. The starting acids were reacted with arylsulphonyl chlorides to produce N-arylsulfonyl amino acids 1a–h, followed by esterification to obtain the corresponding esters 2a–h. Treatment of esters with hydrazine hydrate afforded the corresponding hydrazides 3a–h. The coupling of hydrazides with aryl isothiocyanates followed by cyclization gave the target thiadiazoles 5a–x in good yields. The new synthesized compounds were assayed against HIV-1 and HIV-2 in MT-4 cells using MTT assay. Compounds 5s, 5v and 5w showed IC50 values of > 1.58, >1.98 and > 2.04 μm with SI > 1, respectively, indicating that these compounds were cytotoxic at concentrations values of 1.58, 1.98 and 2.04 μm, respectively.

3-Substituted 2-Aminonaphthalene Photocages for Carboxylic Acids and Alcohols; Decaging Mechanism and Potential Applications in Synthesis.

3-Hydroxymethyl-2-aminonaphthalene photocage (photoremovable protecting group) 2 was synthesized and transformed to different ethers and esters to investigate the applicability to decage alcohols and carboxylic acids, respectively. The photoelimination of carboxylic acids takes place relatively efficiently (ΦR = 0.11) upon excitation with near-visible light, contrary to the elimination of alcohols. The scope of the decaging of both alcohols and esters was demonstrated on several examples, including aliphatic and aromatic substrates, carbohydrates, and nonsteroidal anti-inflammatory drugs. The photophysical properties of the photocage and its models, methyl ether 4a and acetyl ester 5a, were investigated. The fluorescence quantum yields (Φf = 0.40-0.002) were found to be reversely proportional to the efficiency of elimination of OH, alcohols, or carboxylic acids. The decaging photochemical reaction mechanism was investigated experimentally by transient absorption techniques with time scales from femtoseconds to seconds and computationally on the TD-DFT level of theory. The photoelimination of carboxylates takes place directly in the singlet excited state by a homolytic cleavage producing a radical pair within 1 ns. The subsequent electron transfer gives rise to aminonaphthalene carbocation and the carboxylate. A wide scope of substrates that can be decaged relatively efficiently with near-visible light and the chromo-orthogonal compatibility of aminonaphthalene and aniline derivatives render these photocages potentially applicable in organic synthesis or biology.

Synthesis and Characterization of Edaravone Analogues as Remyelinating Agents and Putative Mechanistic Probes.

Edaravone (EDA), an antioxidant drug approved for the treatment of ischemic stroke and amyotrophic lateral sclerosis, was recently proposed as a remyelinating candidate for the treatment of multiple sclerosis. Here, we synthesized twelve EDA analogues 2b-4c showing three substitution patterns A-C, searching for improved remyelinating agents and putative molecular targets responsible for their regenerative activity. We profiled them in three primary assays to determine their stimulation of oligodendrocyte progenitor cell metabolism (tetrazolium MTT assay), their antioxidant potential (2,2-diphenyl-1-picrylhydrazyl-DPPH assay) and to predict their bioavailability (virtual ADME profile). Active 4'-carboxylate 2b, 4'-ester 2c and N1-carbamate-4'-ester 4a were further characterized, justifying their in vitro effects and selecting 4a as a putative EDA 1 prodrug suitable for in vivo testing.

Daphnepedunins G and H, anti-HIV macrocyclic 3,4-seco-daphnane orthoesters from Daphne pedunculata.

Daphnepedunins G (1) and H (2) with unusual macrocyclic 3,4-seco-daphnane orthoester structure were isolated from Daphne pedunculata. Their structures were determined by physicochemical and spectroscopic analyses combined with synthetic methods, including methyl esterification, derivatization reaction using a chiral anisotropic agent, and biomimetic conversion. Compounds 1 and 2 along with their methyl esters 1a and 2a were evaluated for anti-HIV activity, among which 1a and 2a exhibited potent activity with IC50 values of 1.08 and 1.17μM, respectively.

Tinopanoids K-T, clerodane diterpenoids with anti-inflammatory activity from Tinospora crispa

A total of 17 structurally diverse clerodane diterpenoids, including ten undescribed clerodane diterpenoids (tinopanoids K-T, 1–10) and seven known compounds (11–17), were isolated from the vines and leaves of Tinospora crispa. Compound 3 has not only bear the dominant substituents of γ-hydroxy-α, β-unsaturated-γ-lactone with anti-inflammatory activity, but also a ternary epoxy structure at C-3/C-4. The planar structures and relative configurations of the clerodane diterpenoids were elucidated by spectroscopic data interpretation. The absolute configurations of compounds 1, 4, 8 and 13 were determined by single-crystal X-ray crystallographic, while that of compound 3 was determined using computed ECD data and single crystal X-ray diffraction of related p-bromobenzoate ester (3a). Subsequently, all compounds were evaluated for their inhibitory effect on nitric oxide (NO) production of LPS-activated BV-2 cells, and compounds 3 and 8 exhibited better NO inhibitory potency, with IC50 values of 5.6 and 13.8 μM than the positive control minocycline (Mino, IC50 = 22.9 μM). The corresponding results of western blot analysis and qRT-PCR revealed that compound 3 can significantly inhibit the inducible nitric oxide synthase (iNOS) and cyclooxygenase 2 (COX-2) protein expressions, mRNA levels of pro-inflammatory cytokins of tumor necrosis factor-α (TNF-α), interleukin 6 (IL-6) and interleukin 1β (IL-1β). The underlying mechanism by which compound 3 exerted anti-neuroinflammatory effects was investigated by western blot and immunofluorescence assay, which suggested compound 3 inhibited LPS induced neuroinflammation via the suppression of toll-like receptor 4 (TLR4) dependent Signal Transducer and Activator of Transcription 3 (Stat3) and mitogen-activated protein kinase (MAPK) signaling pathways, and the activation of Heme Oxygenase-1 (HO-1) mediated signals.

An efficient synthesis of new 3,5‐bis(2‐arylthiazol‐4‐yl)‐1,2,4‐oxadiazole derivatives and their antimicrobial evaluation

AbstractA new series of 3,5‐bis(2‐arylthiazol‐4‐yl)‐1,2,4‐oxadiazole (8a–o) has been synthesized by modified reaction conditions. The reaction of ester 7a with N′‐hydroxy‐2‐phenylthiazole‐4‐carboximidamide 6a using NaOH in DMSO gave the formation of product 8a up to 40% yield. In the second method, the reaction with K2CO3 in toluene at reflux conditions gave a 50% yield. In the third method, the reaction condition was modified. The ester 7a was hydrolyzed to acid 9a. The reactions of acid 9a using N,N‐dimethyl amino pyridine (DMAP) in N,N‐dimethylformamide (DMF), followed by the addition of N‐(3‐dimethylaminopropyl)‐N′‐ethylcarbodiimide hydrochloride (EDC·HCl), and then N′‐hydroxy‐2‐phenylthiazole‐4‐carboximidamide 6a, furnished a 65% yield of 8a. The compounds 8b–o were synthesized using DMAP and EDC·HCl as coupling reagents and gave 60%–72% yields. The structure of newly synthesized compounds was confirmed by spectral analysis. The synthesized compounds were screened for in vitro antimicrobial activity against Escherichia coli (NCIM 2574), Proteus mirabilis (NCIM 2388), Bacillus subtilis (NCIM2063), Staphylococcus albus (NCIM 2178), Candida albicans (NCIM 3100), and Aspergillus niger (ATCC 504). Among the 8a–o derivatives, eight compounds 8c, 8e, 8f, 8g, 8i, 8j, 8k, and 8l showed good activity S. albus with a MIC 31.25–62.5 μg/mL.

Synthesis and evaluation of NHC derivatives and 4'-fluorouridine prodrugs.

β-D-N4-Hydroxycytidine (NHC) derivatives with structural modifications at the C4', O4' or C6 position and 4'-fluorouridine prodrugs were synthesized and evaluated for their antiviral activities against respiratory syncytial virus (RSV) or influenza virus (IFV) in vitro. The NHC derivatives were found inactive, but 4'-fluorouridine and its prodrugs had potent anti-RSV and anti-IFV activities. 4'-Fluorouridine was proved to be a nucleoside with poor stability, but the tri-ester prodrugs exhibited enhanced stability, especially tri-isobutyrate ester 1a. This prodrug also showed excellent oral pharmacokinetic properties in rats, with potential to be an oral antiviral candidate.

Copper-Catalyzed Ligand-Controlled Selective Borocarbonylation of α-Substituted Styrenes Toward β-Boryl Aldehydes and Cyclopropyl Boronate Esters

Copper-Catalyzed Ligand-Controlled Selective Borocarbonylation of α-Substituted Styrenes Toward β-Boryl Aldehydes and Cyclopropyl Boronate Esters

Simple Method for the Conversion of Light Cracked Naphtha into Efficient Lubricity Improvers for Ultra-Low Sulfur Diesel.

Light cracked naphtha (LCN) is one of the olefin streams obtained from oil refinery in the petrochemical fluidized catalytic cracking unit. In this communication, we report a new method for the conversion of LCN into lubricity improvers for ultra-low sulfur diesel (ULSD) through a feasible two-step synthetic procedure. In the first step, olefins of LCN were subjected to the hydroboration reaction using BH3 to get the hydroxy LCN derivative which was then subjected to the esterification reaction with different organic acids to get the final LCN esters (6a–j). The lubricating property of the LCN esters was studied at two blending concentrations (300 and 150 ppm, wt/vol) with ULSD. Interestingly, ester (6a) derived from stearic acid showed the tiniest wear scar diameter in both dosage levels. The mechanism of lubricity action of LCN esters on metallic surfaces was studied by analyzing the worn surfaces using scanning electron microscopy and energy-dispersive X-ray spectroscopy techniques. The studies reveal that the lubricity additives derived from cracked naphtha through a simple chemical reaction strategy are promising precursors in enhancing the lubricity of ULSD.

Efficient synthesis and biological evaluation of some new series of pyridine derivatives: Promising and potent new class of anticancer agents

AbstractIn an attempt to develop potent anticancer agents, we have synthesized some substituted pyridine derivatives. Alkylation of the pyridine‐3‐carbonitrile 1a by chloroacetonitrile or methyl iodide and ethyl iodide produced the O‐alkylated nicotinonitrile derivatives (2–4), respectively. The reaction of nicotinonitrile 1a with acetic anhydride furnished the N‐acetyl derivative 5. In addition, the reaction of 1a with concentrated sulfuric acid yielded compound 6 whereas its reaction with chloroacetone gave the corresponding 2‐alkoxy‐pyridine derivative 7 which then refluxed with sodium methoxide to give compound 8. Furthermore, alkylation of 1a‐c with methyl bromoacetate and ethyl bromoacetate produced the corresponding methyl, ethyl ester derivatives 9, 10a–c, respectively. The reaction of ethyl ester 10c with a solution of sodium hydroxide in ethanol afforded the corresponding acid derivative 11. Hydrazinolysis was carried out by the reaction of ethyl ester 10a,c with hydrazine hydrate to afford the desired acetohydrazide derivative 12a,c which was used as a key intermediate for the synthesis of substituted pyridine derivatives 13–19. Chlorination of 1a with phosphorus oxychloride afforded the 2‐chloro derivative 20 which react with excess of hydrazine hydrate to yield compound 21. All synthesized compounds were characterized using IR, NMR, mass spectra, and elemental analysis. Their cytotoxic activity was evaluated against three different cancer cell lines, including breast (MCF‐7), colon (HCT‐116), and ovarian (SKOV3) cancers as well as human normal cells EA.hy 926 (human endothelial somatic cell hybrid). In general, compounds 3, 4, 5, 9, 12a, 12b, 13, 14, 15, 16, 18, 19, 21 exhibited high cytotoxicity against cancer cell lines. Besides that, the large number of synthesized compounds exhibited moderate anticancer activities.

Chiral Bicyclic Imidazole-Catalyzed Direct Enantioselective C -Acetylation of Indolones

Chiral Bicyclic Imidazole-Catalyzed Direct Enantioselective <i>C</i> -Acetylation of Indolones

Synthesis of 4-((4-(4-nitrophenoxy)phenyl)diazenyl)benzene-1,3-benzoate:Experimental, DFT and, DNA binding investigation through spectral and molecular docking studies

Pharmacists and other researchers have always been fascinated by the DNA sensing evaluation. This piece of work emphasizes on the synthesis, characterization and DNA sensing of a novel azo ester (N = N, -COO) molecule. The product (1A) was synthesized employing a typical esterification reaction between previously reported resorcinol coupled azo dye and Benzoyl chloride. The structural interpretation of the synthesized ester was done by FT-IR (Fourier transform infrared), NMR (Nuclear magnetic resonance), UV/VIS (ultraviolet–visible spectroscopy), and single crystal X-ray diffraction studies. XRD analysis elucidated the Ester 1A to be in the Monoclinic system with P21/n space group. The DFT simulation experiments were also examined to investigate the structural implications of the resulting product. The higher softness (S), electrophilicity index (ω) and electronegativity (χ) values demonstrated greater polarizability and reactive nature of the compound. Further, wet and silico binding methods were employed to examine the DNA sensing ability of the synthesized molecule with SS-DNA. UV/VIS spectroscopy and hydrodynamic measurements (Viscosity) suggested Groove binding mode of interaction with a moderate value of binding constant, which was further confirmed by molecular docking techniques.

A relay catalysis strategy for enantioselective nickel-catalyzed migratory hydroarylation forming chiral α-aryl alkylboronates

A relay catalysis strategy for enantioselective nickel-catalyzed migratory hydroarylation forming chiral α-aryl alkylboronates

4,4-Nitrophenoxyaniline derived Azo ester: Structural elucidation, DFT simulation, and DNA interactional studies via wet and in silico methods

A new ester namely,1-((4-(4-nitrophenoxy)phenyl)diazenyl)biphenyl benzoate, has been synthesized by esterification reaction between reported nitro terminated azo alcohol and benzoyl chloride. Complete structural elucidation of the synthesized ester was done by different spectroscopic techniques including (FT-IR), (Proton and Carbon-13 NMR), (UV/VIS) spectroscopy, and single-crystal XRD analysis and cyclic voltammetry. XRD structural elucidation revealed the ester 1a to be in Triclinic crystal system with P-1 space groups, showing two-dimensional supramolecular structure, involving only one intermolecular interaction between O4-O9…H9. DFT simulations were also performed to illustrate structural ramification of synthesized ester.Further, Drug DNA interaction was used to determine the biological significance of the produced ester. UV–VIS spectroscopy, hydrodynamic measurement, and molecular docking were used to determine the preferred binding mode of interaction of the synthesized ester with Salmon Sperm (SS) DNA and found that molecule interacts in groove binding fashion with DNA molecule. 2021 Elsevier Ltd. All rights reserved.

Synthesis of novel indole-thiazolidinone hybrid structures as promising scaffold with anticancer potential

A series of novel indole-azolidinone hybrids has been synthesized via Knoevenagel reaction of 5-fluoro-3-formyl-1H-indole-2-carboxylic acid methyl ester and some azolidinones differing in heteroatoms in positions 1, 2 and 4. Their anticancer activity in vitro was screened towards MCF-7 (breast cancer), HCT116 (colon cancer), HepG2 (hepatoma), HeLa (cervical cancer), A549 (lung cancer), WM793 (melanoma) and THP-1 (leukemia) cell lines, and a highly active 5-fluoro-3-(4-oxo-2-thioxothiazolidin-5-ylidenemethyl)-1H-indole-2-carboxylic acid methyl ester (3a) was identified and subjected to in-depth investigation of cytotoxicity mechanisms. This compound was found to possess the highest cytotoxic action towards tumor cells comparing with the action of other derivatives (1, 3b, 3c, 3d, 3e). Compound 3a exhibited toxicity toward MCF-7, HCT116, and A549, HepG2 cancer cells, while the non-malignant cells (human keratinocytes of HaCaT line and murine embryonic fibroblasts of Balb/c 3T3 line) possessed moderate sensitivity to it. The compound 3a induced apoptosis in studied tumor cells via caspase 3-, PARP1-, and Bax-dependent mechanisms; however, it did not affect the G1/S transition in HepG2 cells. The compound 3a impaired nuclear DNA in HepG2, HCT116, and MCF-7 cells without intercalating this biomolecule, but much less DNA damage events were induced by 3a in normal Balb/c 3T3 fibroblasts compared with HepG2 carcinoma cells. Thus, 5-fluoro-3-(4-oxo-2-thioxothiazolidin-5-ylidenemethyl)-1H-indole-2-carboxylic acid methyl ester 3a was shown to trigger DNA damage and induce apoptosis of human tumor cells and it might be considered as an anticancer agent perspective for in-depth studies.