RESUMEN
Sortase A (SrtA) is an attractive target for developing new anti-infective drugs that aim to interfere with essential virulence mechanisms, such as adhesion to host cells and biofilm formation. Herein, twenty hydroxy, nitro, bromo, fluoro, and methoxy substituted chalcone compounds were synthesized, antimicrobial activities and molecular modeling strategies against the SrtA enzyme were investigated. The most active compounds were found to be T2, T4, and T19 against Streptococcus mutans (S. mutans) with MIC values of 1.93, 3.8, 3.94â µg/mL, and docking scores of -6.46, -6.63, -6.73â kcal/mol, respectively. Also, these three active compounds showed better activity than the chlorohexidine (CHX) (MIC value: 4.88â µg/mL, docking score: -6.29â kcal/mol) in both inâ vitro and in silico. Structural stability and binding free energy analysis of S.mutans SrtA with active compounds were measured by molecular dynamic (MD) simulations throughout 100 nanoseconds (ns) time. It was observed that the stability of the critical interactions between these compounds and the target enzyme was preserved. To prove further, inâ vivo biological evaluation studies could be conducted for the most promising precursor compounds T2, T4, and T19, and it might open new avenues to the discovery of more potent SrtA inhibitors.
Asunto(s)
Aminoaciltransferasas , Proteínas Bacterianas , Cisteína Endopeptidasas , Pruebas de Sensibilidad Microbiana , Streptococcus mutans , Aminoaciltransferasas/antagonistas & inhibidores , Aminoaciltransferasas/metabolismo , Cisteína Endopeptidasas/metabolismo , Cisteína Endopeptidasas/química , Proteínas Bacterianas/antagonistas & inhibidores , Proteínas Bacterianas/metabolismo , Proteínas Bacterianas/química , Streptococcus mutans/efectos de los fármacos , Streptococcus mutans/enzimología , Antibacterianos/farmacología , Antibacterianos/síntesis química , Antibacterianos/química , Relación Estructura-Actividad , Simulación de Dinámica Molecular , Simulación del Acoplamiento Molecular , Estructura Molecular , Modelos Moleculares , Chalcona/química , Chalcona/farmacología , Chalcona/síntesis química , Relación Dosis-Respuesta a DrogaRESUMEN
Five new phenyl dihydroisocoumarin glycosides (1-5) and two known compounds (6-7) were identified from the butanol fraction of Scorzonera longiana. The structures of 1-7 were elucidated based on spectroscopic methods. Antimicrobial, antitubercular, and antifungal evaluation of compounds 1-7 were carried out using the microdilution method against nine microorganisms. Compound 1 was active only against Mycobacterium smegmatis (Ms) with a MIC value of 14.84â µg/mL. All tested compounds (1-7) were active against Ms but only compounds 3-7 were active against fungi (C. albicans, S. cerevisiae) with MIC values of 25.0-125â µg/mL. In addition, molecular docking studies were conducted against Ms DprE1 (PDB ID: 4F4Q), Mycobacterium tuberculosis (Mbt) DprE1 (PDB ID: 6HEZ), and arabinosyltransferase C (EmbC, PDB ID: 7BVE) enzymes. Compounds 2, 5, and 7 are the most effective Ms 4F4Q inhibitors. Compound 4 was the most promising inhibitory activity on Mbt DprE with the lowest binding energy of -9,9â kcal/mol.
Asunto(s)
Antiinfecciosos , Glicósidos , Isocumarinas , Mycobacterium tuberculosis , Scorzonera , Antiinfecciosos/farmacología , Antiinfecciosos/química , Antituberculosos/farmacología , Antituberculosos/química , Pruebas de Sensibilidad Microbiana , Simulación del Acoplamiento Molecular , Estructura Molecular , Saccharomyces cerevisiae , Scorzonera/química , Isocumarinas/química , Isocumarinas/farmacología , Glicósidos/química , Glicósidos/farmacología , Antifúngicos/química , Antifúngicos/farmacologíaRESUMEN
A violacein-producing bacterium was isolated from a mud sample collected near a hot spring on Kümbet Plateau in Giresun Province and named the GK strain. According to the phylogenetic tree constructed using 16S rRNA gene sequence analysis, the GK strain was identified and named Janthinobacterium sp. GK. The crude violacein pigments were separated into three different bands on a TLC sheet. Then violacein and deoxyviolacein were purified by vacuum liquid column chromatography and identified by NMR spectroscopy. According to the inhibition studies, the HIV-1 RT inhibition rate of 1 mM violacein from the GK strain was 94.28% and the CoV-2 spike RBD:ACE2 inhibition rate of 2 mM violacein was 53%. In silico studies were conducted to investigate the possible interactions between violacein and deoxyviolacein and three reference molecules with the target proteins: angiotensin-converting enzyme 2 (ACE2), HIV-1 reverse transcriptase, and SARS-CoV-2 spike receptor binding domain. Ligand violacein binds strongly to the receptor ACE2, HIV-1 reverse transcriptase, and SARS-CoV-2 spike receptor binding domain with a binding energy of -9.94 kcal/mol, -9.32 kcal/mol, and -8.27 kcal/mol, respectively. Deoxyviolacein strongly binds to the ACE2, HIV-1 reverse transcriptase, and SARS-CoV-2 spike receptor binding domain with a binding energy of -10.38 kcal/mol, -9.50 kcal/mol, and -8.06 kcal/mol, respectively. According to these data, violacein and deoxyviolacein bind to all the receptors quite effectively. SARS-CoV-2 spike protein and HIV-1-RT inhibition studies with violacein and deoxyviolacein were performed for the first time in the literature.
Asunto(s)
Enzima Convertidora de Angiotensina 2 , COVID-19 , VIH-1 , Indoles , Glicoproteína de la Espiga del Coronavirus , COVID-19/metabolismo , COVID-19/virología , VIH-1/metabolismo , Indoles/metabolismo , Indoles/farmacología , Peptidil-Dipeptidasa A/química , Peptidil-Dipeptidasa A/metabolismo , Filogenia , Unión Proteica , ARN Ribosómico 16S , SARS-CoV-2 , Glicoproteína de la Espiga del Coronavirus/metabolismoRESUMEN
The essential oil (EO) of Cota tinctoria var. tinctoria was analyzed using GC-FID / MS. A total of 51 compounds were determined from this taxon, accounting for 99.79% in hydrodistillation. Monoterpenes were the primary chemical class for the volatile organic compounds in the EO (36.1%, 13 compounds). Borneol (18.1%), camphor (14.9%), and ß-pinene (11.3%) were the major components in the EO of C. tinctoria var. tinctoria. The antimicrobial activities of EO and n-hexane, acetonitrile, methanol, and water solvent extracts of the taxon were screened in vitro against ten microorganisms. The EO yielded the best activity (15 mm, 372.5 MIC, 59600 µg/µL) against Mycobacterium smegmatis. The acetonitrile extract was the most active against the Staphylococcus aureus and Bacillus cereus with 274 µg/mL MIC value. IC50 values for the lipase enzyme inhibitory activity of EO and solvent extracts (n-hexane, acetonitrile, methanol, and water) were found to be 59.80 ± 4.3285 µg/mL 68.28 ± 3.1215 µg/mL, 52.60 ± 3.7526 µg/mL, 48.73 ± 2.8265 µg/mL, and 99.50 ± 5.5678 µg/mL, respectively.