Search Results (302)

A series of eleven new N-alkyl 3-(3-benzyloxyquinoxalin-2-yl) propanamides were prepared based on the azide coupling of 3-(3-benzyloxyquinoxalin-2-yl) propanhydrazide with a variety of primary and secondary amines and the consequent conjunction of a broad spectrum of lipophile and hydrophile characters to a quinoxaline ring system. 3-(3-benzyloxyquinoxalin-2-yl) propanhydrazide was produced in a two-step reaction of methyl 3-(3-oxo-3,4-dihydroquinoxalin-2-yl) propanoate with benzyl chloride followed by the hydrazinolysis of the corresponding ester. The antiproliferative activity of the compounds was tested in various cancer cell lines, including PC-3, Hela, HCT-116, and MCF-7; they showed a wide spectrum of activity for most of the tested compounds. Compound 6k exhibited the highest activity, which was comparable to that of doxorubicin, with IC₅₀ (µM) values of 12.17 ± 0.9, 9.46 ± 0.7, 10.88 ± 0.8, and 6.93 ± 0.4 µM compared to 8.87 ± 0.6, 5.57 ± 0.4, 5.23 ± 0.3, and 4.17 ± 0.2 µM for doxorubicin against Hela, HCT-116, and MCF-7, respectively. The in silico mechanistic study revealed the inhibition of HDAC-6 through the binding of the unique zinc finger ubiquitin-binding domain (HDAC6 Zf-UBD). The docking results showed a specific binding pattern that emphasized the crucial role of the quinoxaline ring and its substituents. The newly developed derivatives were evaluated for antitumor effects against four cancer cell lines PC-3, HeLa, HCT-116, and MCF-7. This research led to the identification of a quinoxaline-based scaffold exhibiting broad-spectrum antiproliferative activity and a distinct mechanism involving binding to HDAC6 Zf-UBD. The findings highlight its potential for further optimization and preclinical studies to support future anticancer drug development. Full article

The synthesis of cannabigerol—a cannabinoid with significant pharmaceutical potential—is described. The synthesis involves four stages. In the first step, (E)-non-3-en-2-one reacts with dimethyl malonate to yield a cyclic enone, which is subsequently oxidized with bromine to produce the olivetol ester. This ester then undergoes an alumina-catalyzed coupling reaction with geraniol, followed by ester hydrolysis to obtain cannabigerol. By modifying the chain length of the enone in the initial step and employing allylic alcohols other than geraniol, a range of cannabigerol derivatives can be synthesized, including the natural product cannabigerovarin. Full article

The recent global coronavirus pandemic highlighted the ever-present threat of respiratory virus outbreaks and the consequent need for ongoing research into antiviral therapy. To this end, structural analogues of the guanidinium-based drug camostat mesylate have been synthesised to probe their potential inhibition of Transmembrane Serine Protease 2 (TMPRSS2), a human protease that is essential for infection by many respiratory viruses, including Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2). Our in vitro fluorescence-based protease assays and supporting computational docking studies suggest that C-terminal camostat analogues retain TMPRSS2 inhibition potencies (IC₅₀ = 1–3 nM, BE = −6.6 to −7.0 kcal/mol) that match or exceed that of the parent drug. Analogues 1c and 1d emerge as lead candidates in this regard, thereby validating the rationale behind C-terminal structural modifications and highlighting these derivatives as promising scaffolds for the future development of targeted antiviral therapeutics. Replacement of camostat’s ester functionality with peptide linkages largely preserves non-covalent binding but disrupts in vitro protease inhibition, findings consistent with the parent drug’s known role as an acylating suicide inhibitor. Docking studies confirm that the replacement of aromatic residues with flexible, equivalent-length alkyl chains is detrimental to drug binding. These function and binding data offer new directions for the synthesis of further analogues of camostat and of other guanidinium-based protease inhibitors that have yet to be refined via structure–activity relationship studies. Further investigation will support tailoring this class of drugs for repurposing in antiviral therapy. Full article

Background: Betulinic acid (BA) and some derivatives are well-known antiproliferative compounds. Literature precedents suggest that incorporating triphenylphosphonium (TPP⁺) salts on this triterpenoid scaffold enhances its biological activity. In the present study, we carried out a simple synthesis of C-28 ester derivatives of this triterpenoid conjugated with TPP⁺ bromide salts through 4- to 6-carbon chains via nucleophilic substitution of the corresponding ω-TPP⁺bromoalkanes. Tests for antiproliferative activity in nine cancer cell lines and normal human fibroblasts showed that TPP⁺ incorporation enhanced the potency of BA by more than an order of magnitude, up to 100-fold. BA-C₄-TPP⁺Br⁻, with a four-carbon chain separating the TPP⁺ moiety from the BA, showed remarkable antiproliferative effects, sometimes more potent than the reference drug (Etoposide). This compound exhibited the strongest mitochondrial uncoupling effect in human cancer cells. No significant LDH release was noted in colorectal carcinoma cells at low micromolar concentrations of BA-C₄-TPP⁺Br⁻, and sub-micromolar concentrations were sufficient for inducing apoptosis. The in silico prediction of pharmacokinetic properties suggested high oral absorption (88%), as well as a non-inhibitor and non-substrate profile vs. cytochrome isoenzymes. These results point to this compound as a promising lead for the development of novel anticancer drugs. Full article

Cyanohydrin synthesis, as the simplest preparative method for introducing a carboxyl group into a piperidine molecule, has been used to obtain potentially biologically active piperidinecarboxylic acids, which have alkyl and arylalkyl radicals at the nitrogen atom of the piperidine ring. Hydrochlorides of cyclopropanecarboxylic acid esters based on piperidinecarboxylic acids, as well as hydrochlorides of fluorobenzoic acid esters of N-substituted piperidines, have been synthesized. The purpose of this study was to search for antiviral drugs among new piperidine derivatives. The structure of the synthesized compounds was studied by NMR methods, including COSY (¹H-¹H), HMQC (¹H-¹³C) and HMBC (¹H-¹³C) techniques. The values of chemical shifts, multiplicities, and integrated intensities of ¹H and ¹³C signals in one-dimensional NMR spectra were determined. The results of COSY (¹H-¹H), HMQC (¹H-¹³C), and HMBC (¹H-¹³C) revealed homo- and heteronuclear interactions, confirming the structure of the studied compounds. The antiviral and cytotoxic activities of the synthesized compounds were studied. The antiviral activity in vitro was determined according to the therapeutic regimen against the influenza A/Swine/Iowa/30 (H1N1) virus on the MDCK cell model. The cytotoxicity of the studied substances in vitro was assessed using the MTT test. Based on the results of the antiviral activity against the influenza A virus, it can be concluded that all substances are effective against the influenza A/H1N1 virus compared to the commercial preparations Tamiflu and Rimantadine. Full article

A traditional dairy product from northern Colombia is suero costeño (SC), typically handmade through artisanal processes involving the natural fermentation of raw cow’s milk (RM); it is characterized by a creamy texture and a distinctive sensory profile, with a sour/salty taste and rancid odor. This study aimed to determine the chemical identity (using GC-FID/MSD) of SC and RM samples (from eight locations in the department of Córdoba-Colombia) by analyzing volatile components (trapped by HS-SPME and SDE) and fatty acid content. Consequently, the most notable results were as follows: (a) myristic (7–12%), stearic (12–17%), oleic (13–23%), and palmitic (21–29%) acids were the most abundant constituents [without significant differences among them (p > 0.05)] in both RM and SC fats; these were also expressed as polyunsaturated (2–5%), monounsaturated (26–36%), saturated (59–69%), omega-9 (19–30%), omega-6 (0.5–1.6%), and omega-3 (0.2–1.2%) fatty acids; (b) differences in the composition (p < 0.05) of the volatile fractions were distinguished between RM and SC samples; likewise, the SC samples differed (from each other) in their volatile composition due to the preparation processes applied (processes with raw milk and natural fermentation had less variability); nonetheless, it was possible to determine the volatilome for the artisanal product; and (c) the major components responsible for the chemical identity of SC were ethyl esters (of linear saturated and unsaturated acids, short/medium chains), aliphatic alcohols (linear/branched, short/long chains), aliphatic aldehydes (long chains, >C₁₄), alkyl methyl ketones (long chains, >C₁₁), sesquiterpenes (caryophyllane/humulane types), monoterpenes (mono/bi-cyclics), short-chain fatty acids, and aromatic alcohol/acid, among others. Full article

The development of alternative energies has become a concern for all countries to ensure domestic energy supply and provide environmental friendliness. One of the providential alternative energies is biodiesel. Biodiesel, commonly stated as fatty acid alkyl ester (FAAE), is a liquid fuel intended to substitute petroleum diesel. Nevertheless, implementation of pure biodiesel is not recommended for conventional diesel engines. It holds poor values of cold flow properties, as the effect of high saturated FAAE content contributes to this constraint. Several processes have been proposed to enhance cold flow properties of biodiesel, but this work focuses on the skeletal isomerization process. This process rearranges the skeletal carbon chain of straight-chain FAAE into branched isomeric products to lower the melting point, related to the good cold flow behavior. This method specifically requires an acid catalyst to elevate the isomerization reaction rate. And then, sulfated tin(IV) oxide emerged as a solid superacid catalyst due to its superiority in acidity. The results of biodiesel isomerization over this catalyst and its modification with iron had not satisfied the expectation of high isomerization yield and significant CFP improvement. However, they emphasized that the skeletal isomers demonstrated minimum impact on biodiesel oxidation stability. They also affirmed the role of an acid catalyst in the reaction mechanism in terms of protonation, isomerization, and deprotonation. Furthermore, the metal promotion was theoretically necessary to boost the catalytic activity of this material. It initiated the dehydrogenation of linear hydrocarbon before protonation and terminated the isomerization by hydrogenating the branched carbon chain after deprotonation. Finally, the overall findings indicated promising prospects for further enhancement of catalyst performance and reusability. Full article

Accurately identifying local interactions such as hydrophilicity and hydrophobicity is of critical importance in regulating the functions of amphiphilic biomolecules, but in situ identification methods for such interactions are still lacking. This study proposes a probe based on carbonyl (C=O) stretching vibration to study the hydrophilic and hydrophobic interactions in amphiphilic alcohol–water systems. A combination of theoretical calculations and Raman spectroscopy experiments is employed to investigate the molecular interactions of ethyl acetate C=O in an ethanol aqueous solution, as well as the reasons behind the splitting of spectral peaks. The results indicate that the spectral peak splitting of the C=O stretching vibration is attributed to ethyl acetate existing in different hydrophilic and hydrophobic environments. Specifically, the two low-wavenumber components arise from the formation of double and single hydrogen bonds between C=O and water or ethanol, respectively, while the high-wavenumber component is attributed to the interaction between C=O and the hydrophobic alkyl group. These findings suggest that the C=O stretching vibration of esters is sensitive to the surrounding hydrophilic and hydrophobic environments, thereby indicating its potential as a useful probe for identifying hydrophilic and hydrophobic interactions. Full article

This paper describes the first detailed NMR analysis of the borylated intermediates and target compounds for a small library of pyrrolidine iminosugars of l-gulose absolute stereochemical configuration. The iminosugars were functionalised via N-alkylation to bear a boronate ester or boronic acid groups. The addition of the organic boron pharmacophore allows to further explore the chemical space around and in the active sites, where the boron atom has the capability to make reversible covalent bonds with enzyme nucleophiles and other nucleophiles. We discuss the concurrent complex equilibrium processes of mutarotation and borarotation as studied by NMR. Full article

Choline-based ionic liquids (ILs) have gained attention as antimicrobial and antibiofilm agents due to their biocompatibility and tuneable antimicrobial properties. However, a significant drawback of amphiphilic choline-based ILs is their decreasing biodegradability as the alkyl chain length increases. To address this issue and enhance the ecotoxicological profile of these compounds, a labile ester functionality was incorporated into the alkyl side chain. This strategic modification aims to improve biodegradation rates while maintaining the desirable antimicrobial properties of the ILs. A series of ester-functionalized choline-based ionic liquids (CnECholBr) with alkyl chains containing from 10 to 14 carbon atoms were synthesized, and their self-aggregation behaviour in aqueous solutions was studied. Their antimicrobial properties were then tested against clinically significant bacteria and yeasts, as well as their effectiveness in eliminating MRSA and C. albicans biofilms. Furthermore, the ecotoxicological properties of these compounds were investigated by assessing their aerobic biodegradability and aquatic toxicity using luminescent bacteria. The results indicated that CnECholBr exhibit higher surface activity and biodegradation rates than non-functionalized choline-based ILs. Conversely, their antimicrobial and antibiofilm activity was found to be lower to that of non-functionalized choline-based ILs. Among the compounds evaluated, the C₁₂ECholBr was identified as the most effective antimicrobial and antibiofilm agent. Full article

Quorum quenchers are emerging as an alternative to conventional antimicrobials, since they hinder the development of virulence or resistance mechanisms but without killing the microorganisms, thus, reducing the risk of antimicrobial resistance. Many quorum quenchers are analogs of the natural quorum-sensing signaling molecules or autoinducers. Thus, different analogs of natural N-acylhomoserine lactones (AHLs) have been reported for controlling virulence or reducing the production of biofilms in Gram-negative pathogens. Herein we report the preparation of AHL analogs with a variety of N-substituents in just two steps from readily available N-substituted hydroxyproline esters. The substrates underwent an oxidative radical scission of the pyrrolidine ring. The resulting N-substituted β-aminoaldehyde underwent reduction and in situ cyclization to give a variety of homoserine lactones, with N- and N,N-substituted amino derivatives and with high optical purity. The libraries were screened for the inhibition of violacein production in Chromobacterium violaceum, a Gram-negative pathogen. For the first time, N,N-disubstituted AHL analogs were studied. Several N-sulfonyl derivatives, one carbamoyl, and one N-alkyl-N-sulfonyl homoserine lactone displayed a promising inhibitory activity. Moreover, they did not display microbicide action against S. aureus, C. jejuni, S. enterica, P. aeruginosa, and C. albicans, confirming a pure QQ activity. The determination of structure–activity relationships and in silico ADME studies are also reported, which are valuable for the design of next generations QQ agents. Full article

Background: Fatty acids (FAs) represent a ubiquitous class of nonpolar alkyl carboxylate metabolites with diverse biological functions. Nutrition, metabolism, and endogenous and exogenous stress influence the overall FA metabolic status and transport via the bloodstream. FAs esterified in lipids are of particular interest, as they represent promising biomarkers of pathological diseases and nutritional status. Methods: Here, we report a validated gas chromatographic-mass spectrometric (GC-MS) method for the quantitative analysis of 32 FAs exclusively bound in esterified lipids. The developed sample preparation protocol comprises three steps using only 5 µL of human serum for Folch extraction, sodium methoxide-catalyzed transesterification in tert-butyl methyl ether, and re-extraction in isooctane prior to a quantitative GC-MS analysis with positive ion chemical ionization (PICI) and selected ion monitoring (SIM). Results: The base-catalyzed transmethylation step was studied for 14 lipid classes and was found to be efficient under mild conditions for all major esterified lipids but not for free FAs, lipid amides, or sphingolipids. To minimize matrix effects and instrument bias, internal fatty acid trideuteromethyl esters (D3-FAME) standards were prepared through isotope-coded derivatization with D3-labeled methylchloroformate/methanol medium mixed with each transmethylated serum extract for the assay. The method was validated according to FDA guidelines and evaluated by analyzing NIST SRM 2378 Serum 1 and sera from three healthy donors. Conclusions: The measured quantitative FA values are consistent with the reference data of SRM 2378, and they demonstrate the application potential of the described method for general FA analysis in esterified lipids as a novel complementary tool for lipidomics, as well as for the analysis of membrane FAs in dry blood spots and red blood cells. Full article

The crystal structures of rod-like molecules with nitro-biphenyl or nitro-phenyl end groups and attached n-alkyl units with terminal acid or ester groups are determined by single crystal analysis and their arrangements are compared. The molecules are linked by head-to-tail arrangements and form strings. They point in a single or two different directions and are placed side by side to create the crystal structure. Some of the space groups of the structures can only be determined by a statistical routine because strongly disordered structures prevent the use of extinction methods, since many extinction violations occur for monoclinic and orthorhombic unit cells. An agreement between experimental and calculated X-ray reflection intensities serves as proof of the correctness of the method as well as a test of the existence of an inversion center. The single crystals are grown in solution with ethanol, isopropanol, DMAc, and toluene as solvents. Cocrystals are formed in DMAc solutions by the dissolved acid compounds. The two-molecule asymmetric unit of the acid compound is reduced to a one-molecule asymmetric unit with one DMAc included which forms a hydrogen bond with the acid group of the biphenyl molecule. These changes alter the hydrogen bonding scheme along a string. Some structural similarities as the head-to-tail arrangement in the strings are maintained between the terminal acid and ester compounds despite disordered ester groups in the compounds and the ester molecules themselves at ambient temperature. Full article

The utilization of the homogeneous (S)-2-pyrrolidine-tetrazole organocatalyst (Ley catalyst) in the self-condensation of ethyl pyruvate and cross-aldol reactions of ethyl pyruvate donor with non-enolizable pyruvate acceptors, namely the sterically hindered ethyl 3-methyl-2-oxobutyrate or the highly electrophilic methyl 3,3,3-trifluoropyruvate, is described as the key enantioselective step toward the synthesis of the corresponding biologically relevant isotetronic acids featuring a quaternary carbon functionalized with ester and alkyl groups. The transition from homogeneous to heterogeneous flow conditions is also investigated, detailing the fabrication and operation of packed-bed reactors filled with a silica-supported version of the pyrrolidine-tetrazole catalyst (SBA-15 as the matrix). Full article

The presented work discusses the highly efficient esterification of poly (γ-glutamic acid) (γ-PGA) with alkyl halides at room temperature. The esterification reaction was completed within 3 h, and the prepared γ-PGA esters were obtained with excellent yields (98.6%) when 1,1,3,3-tetramethylguanidine (TMG) was used as a promoter. The influence of the amount of TMG, solvent, reaction conditions, and alkyl halides on the esterification reaction was examined. It was found that polar aprotic solvents, such as N-Methylpyrrolidone (NMP) and 1,3-Dimethyl-2-imidazolidinone (DMI), were favorable for the esterification. Non-polar or weakly polar solvents (i.e., dichloroethane, acetonitrile) were not favorable for the esterification. Water as a solvent had a negative effect on esterification. The reactivity of bromine halogenated compounds was higher than that of chlorine halogenated compounds but lower than that of iodine halogenated compounds. The structures of the prepared γ-PGA ester were confirmed by ¹H NMR and FT-IR spectroscopy. Thermal stability and hydrophobic properties of the resulting product were tested. The results showed that the prepared γ-PGA propyl ester had high thermal stability (up to 267 °C) and showed good hydrophobicity (contact angle 118.7°). Full article