RESUMEN
Prenylation of peptides is widely observed in the secondary metabolites of diverse organisms, granting peptides unique chemical properties distinct from proteinogenic amino acids. Discovery of prenylated peptide agents has largely relied on isolation or genome mining of naturally occurring molecules. To devise a platform technology for de novo discovery of artificial prenylated peptides targeting a protein of choice, here we have integrated the thioether-macrocyclic peptide (teMP) library construction/selection technology, so-called RaPID (Random nonstandard Peptides Integrated Discovery) system, with a Trp-C3-prenyltransferase KgpF involved in the biosynthesis of a prenylated natural product. This unique enzyme exhibited remarkably broad substrate tolerance, capable of modifying various Trp-containing teMPs to install a prenylated residue with tricyclic constrained structure. We constructed a vast library of prenylated teMPs and subjected it to in vitro selection against a phosphoglycerate mutase. This selection platform has led to the identification of a pseudo-natural prenylated teMP inhibiting the target enzyme with an IC50 of 30â nM. Importantly, the prenylation was essential for the inhibitory activity, enhanced serum stability, and cellular uptake of the peptide, highlighting the benefits of peptide prenylation. This work showcases the de novo discovery platform for pseudo-natural prenylated peptides, which is readily applicable to other drug targets.
Asunto(s)
Prenilación , Ligandos , Humanos , Péptidos Cíclicos/química , Péptidos Cíclicos/farmacología , Péptidos Cíclicos/metabolismo , Péptidos/química , Péptidos/metabolismo , Péptidos/farmacología , Compuestos Macrocíclicos/química , Compuestos Macrocíclicos/farmacología , Compuestos Macrocíclicos/metabolismo , Productos Biológicos/química , Productos Biológicos/farmacología , Productos Biológicos/metabolismo , Dimetilaliltranstransferasa/metabolismo , Dimetilaliltranstransferasa/química , Dimetilaliltranstransferasa/antagonistas & inhibidores , Prenilación de ProteínaRESUMEN
A series of 1H-1,2,3-triazole-4H-chromene-D-glucose hybrid compounds 7a-w were synthesized using click chemistry of 2-amino-7-propargyloxy-4H-chromene-3-carbonitriles 5a-w. CuNPs@montmorillonite was used as a catalyst in the presence of DIPEA as an additive for this chemistry. All synthesized 1H-1,2,3-triazoles were examined for in vitro inhibition against Mycobacterium tuberculosis protein tyrosine phosphatase B (MtbPtpB). Nine 1H-1,2,3-triazoles, including 7c-e, 7h, 7i, and 7r-t, displayed remarkable inhibitory activity against MtbPtpB with IC50 < 10 µM; compound 7t exhibited the most potent inhibition in vitro with an IC50 value of 0.61 µM. Kinetic studies of the three most active compounds, 7c,h,t, showed their competitive inhibition toward the MtbPtpB enzyme. Induced-fit docking and MM-GBSA studies on the enzyme (PDB: 2OZ5) revealed that the most active compound 7t was more effective against MtbPtpB. Residues Arg64, Arg136, Ash165, Arg166, and Arg63 in the binding pocket were identified as potential ligand-binding hot-spot residues for ligand 7t. The binding free energy calculation by the MM-GBSA approach for ligand 7t indicated that Coulomb, lipophilic, and van der Waals energy terms are major contributors to the inhibitor binding. Furthermore, the stability of the ligand-protein complex and the structural insights into the mode of binding were confirmed by 300-ns molecular dynamics simulation of 7t/2OZ5.
Asunto(s)
Mycobacterium tuberculosis , Glucosa , Relación Estructura-Actividad , Triazoles/farmacología , Triazoles/química , Benzopiranos/farmacología , Benzopiranos/química , Cinética , Ligandos , Proteínas Tirosina Fosfatasas/metabolismo , Proteínas Tirosina Fosfatasas/farmacología , Simulación del Acoplamiento MolecularRESUMEN
Coumarin-pyrimidine hybrid compounds were synthesized by condensation reaction of α,ß-unsaturated ketones of 6-acetyl-5-hydroxy-4-methylcoumarin with guanidine. The reaction yields were of 42-62%. The antidiabetic and anticancer activities of these compounds were examined. These compounds displayed low toxicity to two cancer cell lines (including KB and HepG2 ones), but exhibited remarkably active against α-amylase with IC50 values of 102.32 ± 1.15 µM to 249.52 ± 1.14 µM and against α-glucosidase with IC50 values of 52.16 ± 1.12 µM to 184.52 ± 1.15 µM. Amongst these compounds, 6c was the best inhibitory activity against α-amylase, and 6f had the highest activity against α-glucosidase. The kinetics of inhibitor 6f was competitive α-glucosidase inhibitor property. ADMET predictions showed that almost all synthesized compounds exhibited drug-like activity. IFD and MD simulations were carried out on enzymes 4W93 and 5NN8 to elucidate inhibitory potential of 6c and 6f against tested enzymes. The binding free energy calculation by MM-GBSA approach showed that Coulomb, lipophilic and van der Waals energy terms are major contributors for the inhibitor binding. Molecular dynamics simulations in water solvent system were carried out for the 6f/5NN8 complex to elucidate the variability of active interactions between ligand 6f and active pockets of this enzyme.
RESUMEN
In this study, the click chemistry between N-propargyl derivatives of substituted 4H-pyrano[2,3-d]pyrimidines and tetra-O-acetyl-α-d-glucopyranosyl azide carried out under catalytic conditions using catalyst CuI@Montmorillonite and additive N,N-diisopropylethylamine (DIPEA). The yields of obtained hybrid compounds having 4H-pyrano[2,3-d]pyrimidine connected to 1H-1,2,3-triazole rings were about 85-94 %. All these synthesized hybrid compounds were examined for inâ vitro α-amylase (with IC50 values in the range of 103.63±1.13â µM to 295.45±1.11â µM) and α-glucosidase (with IC50 values in the range of 45.63±1.14â µM to 184.52±1.15) inhibitory activity. Amongst this series, ethyl ester 8m showed the best inhibitory activity against α-amylase with IC50 of 103.63±1.13â µM, while ethyl ester 8t exhibited the highest activity against α-glucosidase with IC50 of 45.63±1.14â µM. The kinetics of the inhibition of compound 8t showed the competitive α-glucosidase inhibitor property of this compound. Furthermore, the most potent compounds had any cytotoxicity against human normal cells. Induced fit docking and molecular dynamics simulation calculations indicated that the inhibition potential compounds 8m and 8t had the active interactions with the residues in receptors of corresponding tested enzymes. The calculated binding free energy from MM-GBSA approach showed that the major energy components contributed to the active binding of these studied inhibitors, including Coulomb, lipophilic and van der Waals energy. Further, 300â ns MD simulation showed that studied ligand-protein complexes were stable and indicated the structural observations into mode of binding in these complexes.
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Glucosa , alfa-Glucosidasas , Humanos , alfa-Glucosidasas/metabolismo , Glucosidasas/metabolismo , alfa-Amilasas/metabolismo , Relación Estructura-Actividad , Amilasas/metabolismo , Triazoles/química , Simulación del Acoplamiento Molecular , Inhibidores de Glicósido Hidrolasas/química , Pirimidinas/farmacología , Pirimidinas/química , Estructura MolecularRESUMEN
Some heterocycles, namely 2-amino-4H-pyran-3-carbonitriles, were synthesized in a three-component reaction from substituted benzaldehydes, malononitrile, and ethyl acetoacetate. These heterocycles have been converted subsequently into 4H-pyrano[2,3-d]pyrimidine ring by ring-closing reaction with acetic anhydride in the presence of the concentrated sulfuric acid as catalyst. The successive alkylation reaction of lactam NH bond on pyrimidine-4-one ring was carried out using propargylic bromide in dry acetone in the presence of anhydrous potassium carbonate. The click chemistry of 3-propargyl-4H-pyrano[2,3-d]pyrimidine compounds has been accomplished by reaction with tetra-O-acetyl-α-d-glucopyranosyl azide using the metal-organic framework Cu@MOF-5 as a catalyst in absolute ethanol. All the synthesized 1H-1,2,3-triazoles 8a-y were screened for their in vitro Mycobacterium tuberculosis protein tyrosine phosphatase B (MtbPtpB) inhibition. Kinetic studies of the most active compounds 8v, 8x, and 8y showed their competitive inhibition toward the MtbPtpB enzyme. The detailed structure-activity relationship (SAR) in vitro and in silico studies suggested that the interaction of Arg63 amino acids with anion type of para-hydroxyl group via a salt bridge of iminium cation was essential for strong inhibitory activity against MtbPtpB.
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Antibacterianos/farmacología , Inhibidores Enzimáticos/farmacología , Mycobacterium tuberculosis/efectos de los fármacos , Proteínas Tirosina Fosfatasas/antagonistas & inhibidores , Pirimidinas/farmacología , Triazoles/farmacología , Antibacterianos/síntesis química , Antibacterianos/química , Relación Dosis-Respuesta a Droga , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/química , Pruebas de Sensibilidad Microbiana , Estructura Molecular , Mycobacterium tuberculosis/metabolismo , Proteínas Tirosina Fosfatasas/metabolismo , Pirimidinas/química , Relación Estructura-Actividad , Triazoles/síntesis química , Triazoles/químicaRESUMEN
A series of synthesized sulfonyl thiourea derivatives (7a-o) of substituted 2-amino-4,6-diarylpyrimidines (4a-o) exhibited the remarkable inhibitory activity against some the human carbonic anhydrases (hCAs), including hCA I, II, IX, and XII isoforms. The inhibitory efficacy of synthesized sulfonyl thiourea derivatives were experimentally validated by in vitro enzymatic assays. 7a (KI = 46.14 nM), 7j (KI = 48.92 nM), and 7m (KI = 62.59 nM) (for isoform hCA I); 7f (KI = 42.72 nM), 7i (KI = 40.98 nM), and 7j (KI = 33.40 nM) (for isoform hCA II); 7j (KI = 228.5 nM), 7m (KI = 195.4 nM), and 7n (KI = 210.1 nM) (for isoform hCA IX); 7l (KI = 116.9 nM), 7m (KI = 118.8 nM), and 7n (KI = 147.2 nM) (for isoform hCA XII) in comparison with KI values of 452.1, 327.3, 437.2, and 338.9 nM, respectively, of the standard drug AAZ. These compounds also had significantly more potent inhibitory action against cytosolic isoform hCA I and tumor-associated isoforms hCA IX and hCA XII. Furthermore, the potential inhibitory compounds were subjected to in silico screening for molecular docking and molecular dynamics simulations. The results of in vitro and in silico studies revealed that compounds 7a, 7j, and 7m were the most promising derivatives in this series due to their significant effects on studied hCA I, II, IX, and XII isoforms, respectively. The results showed that the sulfonyl thiourea moiety was accommodated deeply in the active site and interacted with the zinc ion in the receptors.
Asunto(s)
Anhidrasa Carbónica I , Inhibidores de Anhidrasa Carbónica , Humanos , Anhidrasa Carbónica I/metabolismo , Inhibidores de Anhidrasa Carbónica/farmacología , Inhibidores de Anhidrasa Carbónica/química , Isoenzimas/metabolismo , Simulación del Acoplamiento Molecular , Estructura Molecular , Relación Estructura-Actividad , Pirimidinas/química , Pirimidinas/farmacologíaRESUMEN
In Vietnam, erectile dysfunction (ED) is prevalent and recognized to be associated with mental disorders; however, societal taboos impede a comprehensive understanding of this connection. Our study aims to investigate the factors related to higher levels of anxiety and/or depression (HAD) in individuals with ED. Between November 2022 and March 2023, a face-to-face survey was conducted at the Center for Andrology of Viet Duc University Hospital, involving 390 patients diagnosed with ED. The survey included 51 questions covering general patient information, the International Index of Erectile Function-15 (IIEF-15), the Patient Health Questionnaire-9 (PHQ-9), and the Generalized Anxiety Disorder-7 (GAD-7). The stepwise Akaike Information Criterion (AIC) method was used to identify factors associated with HAD. The study revealed an average age of 37.63 (11.84) years among participants, with a HAD prevalence of 17.69%. Several factors were associated with a higher likelihood of belonging to the HAD group in ED patients. These factors included non-office workers (OR: 1.11; 95% CI: [1.01, 1.21], p = .025), medium and high levels of work-related stress (OR: 1.23; [1.06, 1.44], p = .008; OR: 1.22; [1.04, 1.45], p = .018), multiple shameful experiences related to ED (OR: 1.16; [1.08, 1.25], p < .001), moderate and severe ED (OR: 1.17; [1.03, 1.32], p = .013; OR: 1.31; [1.14, 1.51], p < .001), and dissatisfaction with intercourse skills (OR: 1.09; [1.01, 1.17], p = .028). Our findings suggest a 16% higher likelihood of HAD status in individuals with multiple shameful experiences related to ED, while moderate and severe ED are associated with respective increases of 17% and 31% in the likelihood. These findings emphasize the importance of considering mental health in the care of individuals with ED.
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Disfunción Eréctil , Masculino , Humanos , Adulto , Estudios Transversales , Depresión/psicología , Ansiedad/epidemiología , Trastornos de Ansiedad , Prevalencia , Factores de RiesgoRESUMEN
Some substituted glucose-conjugated thioureas containing 1,3-thiazole ring, 4a-h, were synthesized by the reaction of the corresponding substituted 2-amino-4-phenyl-1,3-thiazoles 2a-h with 2,3,4,6-tetra-O-acetyl-ß-d-glucopyranosyl isocyanate. The antibacterial and antifungal activities of these thiazole-containing thioureas were estimated using a minimum inhibitory concentration protocol. Among these compounds, 4c, 4g, and 4h were better inhibitors with MIC = 0.78-3.125 µg mL-1. These three compounds were also tested for their ability to inhibit S. aureus enzymes, including DNA gyrase, DNA topoisomerase IV (Topo IV), and dihydrofolate reductase, and compound 4h was found to be a strong inhibitor with IC50 = 1.25 ± 0.12, 67.28 ± 1.21, and 0.13 ± 0.05 µM, respectively. Induced-fit docking and MM-GBSA calculations were performed to observe the binding efficiencies and steric interactions of these compounds. The obtained results showed that compound 4h is compatible with the active site of S. aureus DNA gyrase 2XCS with four H-bond interactions with residues Ala1118, Met1121, and F:DC11 and also three interactions with F:DG10 (two interactions) and F:DC11 (one interaction). Molecular dynamics simulation in a water solvent system showed that ligand 4h had active interactions with enzyme 2XCS through residues Ala1083, Glu1088, Ala1118, Gly1117, and Met1121.
RESUMEN
AIMS: This study aims are the synthesis of 3-(2-amino-6-arylpyrimidin-4-yl)-4-hydroxy-1- methylquinolin-2(1H)-ones and estimation their anticancer activities on HepG2 and KB cancer lines. BACKGROUND: Many derivatives of quinoline-2-on have been interested to synthesize and evaluate their biological properties by organic chemists due to their various biological effects, including antibacterial, antioxidant, anti-inflammatory, anticancer activities. Quinoline-pyrimidine hybrid compounds exhibited various biological activities, such as antituberculosis, antibacterial, anticancer, antifungal, etc. The connection of 4-hydroxyquinoline-2-one with 2-amino-pyrimidine could initiate the new activities. OBJECTIVE: α,ß-Unsaturated ketones of 3-acetyl-4-hydroxy-N-methylquinolin-2-one were prepared. Novel 2-amino-6-aryl-4-(4'-hydroxy-N-methylquinolin-2'-on-3'-yl)pyrimidines have been synthesized by reaction of these corresponding α,ß-unsaturated ketones with guanidine hydrochloride. Human hepatocellular carcinoma HepG2 and squamous cell carcinoma KB cancer lines were used for screening their cytotoxicity. METHODS: 3-Acetyl-4-hydroxy-N-methylquinolin-2-one was prepared from N-methylaniline and diethyl malonate. Reaction of (un)substituted benzaldehydes with this 4-hydroxyquinoline-2-one produced corresponding substituted α,ß-unsaturated ketones in the presence of piperidine as catalyst. 2- Amino-6-aryl-4-(4'-hydroxy-N-methylquinolin-2'-on-3'-yl)pyrimidines have been synthesized from these α,ß-unsaturated ketones of 3-acetyl-4-hydroxy-N-methylquinolin-2-one by reaction of corresponding α,ß-unsaturated ketones with guanidine hydrochloride. All obtained pyrimidines were screened for anticancer activity using MTT bio-assay method. RESULTS: Seven substituted (E)-4-hydroxy-3-(3-(aryl)acryloyl)-1-methylquinolin-2(1H)-ones were prepared and converted to corresponding substituted 2-amino-6-aryl-4-(4'-hydroxy-N-methylquinolin- 2'-on-3'-yl)pyrimidines with yields of 58-74%. All the synthesized pyrimidines were screened for their in vitro anticancer activity against human hepatocellular carcinoma HepG2 and squamous cell carcinoma KB cancer lines. Compounds 6b and 6e had the best activity in the series, with IC50 values equal to 1.32 and 1.33 µM, respectively. ADMET properties showed that compounds 6b, 6e, and 6f possessed the drug-likeness behavior. Cross-docking results indicated that residues GLN778(A), DT8(C), DT9(D), DA12(F), and DG13(F) in the binding pocket as potential ligand binding hot-spot residues for compounds 6b, 6e, and 6f. CONCLUSION: New substituted 2-amino-6-aryl-4-(4'-hydroxy-N-methylquinolin-2'-on-3'-yl)pyrimidines were obtained and displayed significant inhibition against human hepatocellular carcinoma HepG2 and squamous cell carcinoma KB cancer lines.
Asunto(s)
Antineoplásicos , Quinolinas , Antineoplásicos/farmacología , Línea Celular Tumoral , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Simulación del Acoplamiento Molecular , Estructura Molecular , Pirimidinas/farmacología , Quinolinas/farmacología , Relación Estructura-ActividadRESUMEN
BACKGROUND: Reaction of α,ß-unsaturated ketones with o-phenylenediamine afforded corresponding 2,3-dihydro-1H-1,5-benzodiazepines. OBJECTIVE: α,ß-Unsaturated ketones of 6-acetyl-5-hydroxy-4-methylcoumarin are precursors for synthesis of 2,3-dihydro-1H-1,5-benzodiazepines by a reaction with o-phenylenediamine. METHODS: Enones of 6-acetyl-5-hydroxy-4-methylcoumarin were prepared from this ketone and (un)substituted benzaldehydes in the presence of piperidine, triethylamine, or pyridine as a catalyst in absolute ethanol with 1:1 molar ratios, respectively. 2',3'-Dihydro-1H-1',5'-benzodiazepines were synthesized by using the reaction of these enones with o-phenylenediamine in absolute ethanol in the presence of glacial acetic acid as a catalyst. Their biological activities were evaluated using the disk diffusion method. RESULTS: Seven new 2',3'-dihydro-1H-1',5'-benzodiazepines were obtained and their structures were confirmed by thin-layer chromatography, IR, NMR and MS spectra. Some synthesized benzodiazepines showed antibacterial and antifungal activities against Escherichia coli (Gram-(-) bacterium), Staphylococus epidermidis (Gram-(+) bacterium). Candida albicans (fungus). CONCLUSION: The formation of enones from 6-acetyl-5-hydroxy-4-methylcoumarin and (un)substituted benzaldehydes could be catalyzed by piperidine, triethylamine, pyridine to afford similar yields. 2',3'-dihydro-1H- 1',5'-benzodiazepines have been synthesized from the aforementioned enones and o-phenylenediamine.
RESUMEN
The series of 2-amino-7-propargyloxy-4H-chromene-3-carbonitriles 5a-t were synthesized from corresponding 2-amino-7-phydroxy-4H-chromene-3-carbonitriles 4a-t and propargyl bromide. Two procedures were used in these syntheses: K2CO3/acetone and NaH/DMF procedures with yields of 65-89% and 80-96%, respectively. 1H-1,2,3-Triazole-tethered 4H-chromene-d-glucose conjugates 7a-t were synthesized using click chemistry of propargyl ethers 5a-t and tetra-O-acetyl-ß-d-glucopyranosyl azide. Cu@MOF-5 was the optimal catalyst for this chemistry. The yields of 1H-1,2,3-triazoles were 80-97.8%. All triazoles 7a-t were evaluated in vitro for anti-microorganism activities. Among tested compounds with MIC values of 1.56-6.25⯵M, there were four compounds against B. subtilis, four compounds against S. aureus, and four compounds against S. epidermidis; five compounds against E. coli, four compounds against K. pneumoniae, five compounds against P. aeruginosa, and six compounds against S. typhimurium. Compounds 7c,7d,7f,7h, and 7r had MIC values of 1.56-6.25⯵M for three clinical MRSA isolates. Some compounds had inhibitory activities against four fungi, including A. niger, A. flavus, C. albicans, and S. cerevisiae, with MIC values of 1.56-6.25⯵M. Some 1H-1,2,3-triazoles had comparatively low toxicity against RAW 264.7â¯cells.
Asunto(s)
Antibacterianos/síntesis química , Antifúngicos/síntesis química , Benzopiranos/química , Química Clic/métodos , Triazoles/química , Animales , Antibacterianos/farmacología , Antifúngicos/farmacología , Bacterias/efectos de los fármacos , Benzopiranos/farmacología , Diseño de Fármacos , Hongos/efectos de los fármacos , Glucosa , Staphylococcus aureus Resistente a Meticilina/efectos de los fármacos , Ratones , Pruebas de Sensibilidad Microbiana , Células RAW 264.7 , Triazoles/farmacologíaRESUMEN
Some new isatin N-(2,3,4,6-tetra-O-acetyl-ß-d-glucopyranosyl)thiosemicarbazones 4a-t with different substituents at 1-, 5- and 7-positions of isatin ring have been synthesized by reaction of N-(2,3,4,6-tetra-O-acetyl-ß-d-glucopyranosyl)thiosemicarbazide 2 with corresponding isatins 3a-t. Compounds 4a-t were evaluated in vivo for antioxidant activity and in vitro for anti-microorganism activities. The MIC values were found for Gram positive bacteria (MIC = 1.56-6.25 µM), for Gram negative bacteria (MIC = 12.5 µM), and for fungi Aspergillus niger (MIC = 3.12-12.5 µM), Fusarium oxysporum (MIC = 6.25-12.5 µM) and Saccharomyces cerevisiae (MIC = 6.25-12.5 µM). Regarding the antioxidant activity, the SOD, GHS-Px and catalase activities of 4c-i and 4m-r were MIC = 10.57-10.85, 0.27-0.93 and 345.45-399.75 unit/mg protein, respectively. Compounds 4e-h had MIC values of 0.78, 1.56, and 3.12 µM for three clinical MRSA isolates. Compound 4e showed the selective cytotoxic effects against some cancer (LU-1, HepG2, MCF7, P338, SW480, KB) cell lines and normal fibroblast cell line NIH/3T3.
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Isatina/síntesis química , Isatina/farmacología , Staphylococcus aureus Resistente a Meticilina/efectos de los fármacos , Tiosemicarbazonas/química , Animales , Antibacterianos/síntesis química , Antibacterianos/química , Antibacterianos/farmacología , Antibacterianos/toxicidad , Antifúngicos/síntesis química , Antifúngicos/química , Antifúngicos/farmacología , Antifúngicos/toxicidad , Antioxidantes/síntesis química , Antioxidantes/química , Antioxidantes/farmacología , Antioxidantes/toxicidad , Línea Celular Tumoral , Técnicas de Química Sintética , Evaluación Preclínica de Medicamentos , Isatina/química , Isatina/toxicidad , Ratones , Pruebas de Sensibilidad Microbiana , Ratas , Ratas Wistar , Relación Estructura-ActividadRESUMEN
BACKGROUND: Sydnone is a heterocycle that exhibits remarkable pharmacological activities, including antimicrobial, anti-inflammatory, analgesic, antipyretic and antioxidant activities. Thiosemicarbazones are of compounds that contain the -NHCSNHN=C< linkage group and are considerable interest because they exhibit important chemical properties and potentially beneficial biological activities. Similarly, thiosemicarbazones having carbohydrate moieties also exhibit various significant biological activities. RESULTS: The compounds of 3-formyl-4-phenylsydnones were obtained by Vilsmeyer-Haack's formylation reaction and were transformed into thiosemicarbazones by condensation reaction with N-(2,3,4,6-tetra-O-acetyl-ß-d-glucopyranosyl)thiosemicarbazide. Reaction were performed in the presence glacial acetic acid as catalyst using microwave-assisted heating method. Reaction yields were 43â85 %. The antimicrobial activities of these thiosemicarbazones were screened in vitro by using agar well diffusion and MIC methods. Among these thiosemicarbazones, compounds 4k, 4l, 4m and 4n were more active against all tested bacterial strains, especially against S. epidermidis, B. subtilis and E. coli. The MIC values in these cases are 0.156, 0.156 and 0.313 µg/mL, respectively. All compounds showed weak to moderate antifungal activity against C. albicans and A. niger than nystatin (MIC = 0.156â0.625 µg/mL vs. MIC = 0.078 µg/mL of nystatin), and thiosemicarbazones 4l, 4m and 4n exhibited significant activity with MIC = 0.156 µg/mL. These compounds also had good antifungal activity against F. oxysporum similarly to nystatin (MIC = 0.156 µg/mL). Among the tested compounds having halogen group 4k, 4l, 4m and 4n showed highest activity against three strains of fungal organisms. CONCLUSIONS: In summary, we have developed a clean and efficient methodology for the synthesis of novel thiosemicarbazone derivatives bearing sydnone ring and d-glucose moiety; the heterocyclic and monosaccharide system being connected via âNHâC(=S)NHâN=C< linker using molecular modification approach. The methodology could be further extended and used for the synthesis of other thiosemicarbazones of biological importance. 4-Formyl-3-arylsydnone N-(2,3,4,6-tetra-O-acetyl-ß-d-glucopyranosyl)thiosemicarbazones have been synthesized under microwave-assisted heating conditions. Almost all obtained compounds showed remarkable activities against the tested microorganisms. Among the tested compounds having halogen group 4k, 4l, 4m and 4n showed highest activity against all tested strains of bacterial and fungal organisms. Graphical abstract:Synthesis and antibacterial and antifungal activities of N-(tetra-O-acetyl-ß-D-glucopyranosyl)thiosemicarbazones of substituted 4-formylsydnones.
RESUMEN
Some 2-amino-4,6-diarylpyrimidines 2 have been prepared from substituted benzylideneacetophenones and guanidine hydrochloride in the presence of alkali by conventional heating in alcoholic medium and microwave heating in solvent-free conditions. N-(2,3,4,6-Tetra-O-acetyl-beta-D-glucopyranosyl)-N'-(4',6'-diarylpyrimidin-2'-yl)thioureas 4 have been synthesized by reaction of per-O-acetylated glucopyranosyl isothiocyanate 1 and substituted 2-amino-4,6-diarylpyrimidines 2. Two different methods have been used, namely, refluxing in anhydrous dioxane and solvent-free microwave-assisted coupling. The second procedure afforded higher yields in much shorter reaction times. The compounds 2 and 4 were tested for their antibacterial and antifungal activities in vitro against Staphylococcus epidermidis, Enterobacter aerogenes and Candida albicans by disc diffusion method.