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Hyperactivity of the urease enzyme induces the pathogenesis of peptic ulcers and gastritis. The identification of new urease inhibitors can reduce the activity of urease. Therefore, in the current study, we have evaluated 28 analogues of triazolothiadiazole and triazolothiadiazine heteroaromatics for their in vitro urease inhibitory efficacy. All the tested compounds displayed a remarkable inhibitory potential ranging from 3.33 to 46.83 µM. Among them, compounds 5k and 5e emerged as lead inhibitors with IC50 values of 3.33 ± 0.11 and 3.51 ± 0.49 µM, respectively. The potent inhibitory potential of these compounds was â¼6.5-fold higher than that of the marketed drug thiourea (IC50 = 22.45 ± 0.30 µM). The mechanistic insights from kinetics experiments of the highest potent inhibitors (4g, 5e, and 5k) revealed a competitive type of inhibition with ki values 2.25 ± 0.0028, 3.11 ± 0.0031, and 3.62 ± 0.0034 µM, respectively. In silico modeling was performed to investigate the binding interactions of potent inhibitors with the enzyme active site residues, which strongly supported our experimental results. Furthermore, ADME analysis also showed good druglikeness properties demonstrating the potential of these compounds to be developed as lead antiurease agents.
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The current studies mainly demonstrate the coumarin based azomethine-clubbed thiazoles synthesis and their in-vitro evaluation for the first time against α-glucosidase. Due to the catalytic role of α-glucosidase, it has become a precise target for the treatment of type diabetes mellitus (T2DM). The high rate of prevalence of diabetes and its associated health related problems led us to scrutinize the anti-diabetic capability of the synthesized thiazole derivatives (6a-6k). The anticipated structures of prepared compounds were confirmed through FT-IR and NMR spectroscopic methods. All the compounds showed several times potent activity than the standard drug, acarbose (IC50 = 873.34 ± 1.67 µM) against α-glucosidase with IC50 values in range of 0.87 ± 0.02-322.61 ± 1.14 µM. The compound 6k displayed the highest anti-diabetic activity (IC50 = 1.88 ± 0.03 µM). Kinetic study revealed that these are competitive inhibitors for α-glucosidase. The mode of binding of the synthesized molecules were further evaluated by molecular docking, which reflects the importance of azomethine group in protein-ligand interaction. The docking scores are complementary with the IC50 values of compounds while the interaction pattern of the compounds clearly demonstrates their structure-activity relationship. Current study reported medicinal importance of thiazole derivative as future drug candidates for the management of Type 2 Diabetes Mellitus (T2DM).
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Diabetes Mellitus Tipo 2 , Inhibidores de Glicósido Hidrolasas , Humanos , Inhibidores de Glicósido Hidrolasas/química , Simulación del Acoplamiento Molecular , Estructura Molecular , Diabetes Mellitus Tipo 2/tratamiento farmacológico , alfa-Glucosidasas/metabolismo , Espectroscopía Infrarroja por Transformada de Fourier , Relación Estructura-Actividad , Cinética , Tiazoles/químicaRESUMEN
Cardiovascular diseases (CVDs) are a major cause of premature adult death. Various factors contribute to the development of CVDs, such as atherosclerosis leading to myocardial infarction (MI), and compromised cardiac function after MI leads to chronic heart failure with systemic health complications and a high mortality rate. Microtubule detyrosination has rapidly evolved as an essential mechanism to regulate cardiomyocyte contractility. Microtubule affinity regulating kinase 4 (MARK4) regulates cardiomyocyte contractility in a way that it promotes phosphorylation of microtubule-associated protein 4, thereby facilitating the access of vasohibin 2-a tubulin carboxypeptidase-to microtubules for the detyrosination of α-tubulin. Lisinopril, a drug belonging to the class of angiotensin-converting enzyme inhibitors, is used to treat high blood pressure. This is also used to treat heart failure, which plays a vital role in improving the survival rate post-heart attack. In this study, we will evaluate the MARK4 inhibitory potential of lisinopril employing molecular docking and molecular dynamics (MD) simulation approaches. Molecular docking analysis suggested that lisinopril binds to MARK4 with a significant binding affinity forming interactions with functionally essential residues of MARK4. Additionally, MD simulation deciphered the structural dynamics and stability of the MARK4-lisinopril complex. The findings of MD studies established that minimal structural deviations are observed during simulation, affirming the stability of the MARK4-lisinopril complex. Altogether, this study demonstrates lisinopril's crucial role in the therapeutic management of CVD by targeting MARK4.Communicated by Ramaswamy H. Sarma.
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Oral cancer has a high mortality rate, which is mostly determined by the stage of the disease at the time of admission. Around half of all patients with oral cancer report with advanced illness. Hitherto, chemotherapy is preferred to treat oral cancer, but the emergence of resistance to anti-cancer drugs is likely to occur after a sequence of treatments. Curcumin is renowned for its anticancer potential but its marred water solubility and poor bioavailability limit its use in treating multidrug-resistant cancers. As part of this investigation, we prepared and characterized Curcumin nanomicelles (CUR-NMs) using DSPE-PEG-2000 and evaluated the anticancer properties of cisplatin-resistant cancer cell lines. The prepared CUR-NMs were sphere-shaped and unilamellar in structure, with a size of 32.60 ± 4.2 nm. CUR-NMs exhibited high entrapment efficiency (82.2%), entrapment content (147.96 µg/mL), and a mean zeta potential of -17.5ζ which is considered moderately stable. The cellular uptake and cytotoxicity studies revealed that CUR-NMs had significantly higher cytotoxicity and cellular uptake in cisplatin drug-resistant oral cancer cell lines and parental oral cancer cells compared to plain curcumin (CUR). The DAPI and FACS analysis corroborated a high percentage of apoptotic cells with CUR-NMs (31.14%) compared to neat CUR (19.72%) treatment. Conclusively, CUR-NMs can potentially be used as an alternative carrier system to improve the therapeutic effects of curcumin in the treatment of cisplatin-resistant human oral cancer.
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The present work highlights the suitability of an oil-based nanocarrier to deliver quercetin (Q) and curcumin (C) through the intravenous route for treatment of breast cancer. The nanoemulsion prepared by the modified emulsification-solvent evaporation method resulted in particle size (<30 nm), polydispersity index (<0.2), zeta potential (<10 mV), optimum viscosity, high encapsulation efficiency and drug loading for both drugs. The pH and osmolarity of the nanoemulsion were about 7.0 and 280 mOsm, respectively, demonstrated its suitability for intravenous administration. In-vitro release of drugs from all the formulations demonstrated initial fast release followed by sustained release for a period of 48 h. The fabricated single and dual drug−loaded nanoemulsion (QNE, CNE, QC-NE) exhibited moderate hemolysis at a concentration of 50 µg/mL. The % hemolysis caused by all the formulations was similar to their individual components (p Ë 0.05) and demonstrated the biocompatibility of the nanoemulsion with human blood. In vitro cytotoxic potential of single and dual drug−loaded nanoemulsions were determined against breast cancer cells (MF-7). The IC50 value for QNE and CNE were found to be 40.2 ± 2.34 µM and 28.12 ± 2.07 µM, respectively. The IC50 value for QC-NE was 21.23 ± 2.16 µM and demonstrated the synergistic effect of both the drugs. The internalization of the drug inside MF-7 cells was detected by cellular uptake study. The cellular uptake of QNE and CNE was approximately 3.9-fold higher than free quercetin and curcumin (p < 0.0001). This strategically designed nanoemulsion appears to be a promising drug delivery system for the proficient primary preclinical development of quercetin and curcumin as therapeutic modalities for the treatment of breast cancer.
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AIMS: The study aims to synthesize hybrid molecules containing pyrazole and aryldiazenyl/arylhydrazono fragments with promising anticancer activity. BACKGROUND: The clinical effectiveness of anticancer drugs is limited by their adverse side effects and patient resistance. Therefore, the development of safer classes of drugs through rational drug design is imperative. OBJECTIVE: Considering the anticancer potential of the pyrazole moiety, the study was carried out with the objective of synthesizing some hybrid pyrazole derivatives with anticancer potential. METHODS: The anticancer potential of these pyrazolyl analogues were evaluated by sulforhodamine B assay using three cancer cell lines MCF-7, HepG2, and HCT-116. RESULTS: HCT-116 was the most sensitive cell line against these pyrazolyl analogues. Among these newly synthesised derivatives, 1-(4-((4-bromophenyl)diazenyl)-3,5-dimethyl-1H-pyrazol-1-yl)-2-(naphthalen-2-yloxy)ethan-1-one (5e) emerged as a promising anticancer agent (IC50 3.6-24.6 µM), having a xanthine oxidase inhibitory effect (IC50 10.87 µM). To obtain further insights into the binding interactions of these molecules, molecular docking studies were also carried out. CONCLUSION: In summary, our findings suggest that these hybrid pyrazolyl derivatives can be considered as potential lead molecules for anticancer agents.
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Antineoplásicos , Xantina Oxidasa , Antineoplásicos/química , Línea Celular Tumoral , Proliferación Celular , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Simulación del Acoplamiento Molecular , Estructura Molecular , Pirazoles/química , Pirazoles/farmacología , Relación Estructura-Actividad , Xantina Oxidasa/farmacologíaRESUMEN
Angiotensin converting enzyme (ACE) plays a crucial role in regulating blood pressure in the human body. Identification of potential ACE inhibitors from medicinal plants supported the idea of repurposing these medicinal plants against hypertension. A method based on ultra-performance liquid chromatography (UPLC) coupled with a diode array detector (DAD) was used for the rapid screening of plant extracts and purified compounds to determine their ACE inhibitory activity. Hippuryl-histidiyl-leucine (HHL) was used as a substrate, which is converted into hippuric acid (HA) by the action of ACE. A calibration curve of the substrate HHL was developed with the linear regression 0.999. The limits of detection and quantification of this method were found to be 0.134 and 0.4061 mM, respectively. Different parameters of ACE inhibitory assay were optimized, including concentration, incubation time and temperature. The ACE inhibition potential of Adhatoda vasica (methanolic-aqueous extract) and its isolated pyrroquinazoline alkaloids, vasicinol (1), vasicine (2) and vasicinone (3) was evaluated. Compounds 1-3 were characterized by various spectroscopic techniques. The IC50 values of vasicinol (1), vasicine (2) and vasicinone (3) were found to be 6.45, 2.60 and 13.49 mM, respectively. Molecular docking studies of compounds 1-3 were also performed. Among these compounds, vasicinol (1) binds as effectively as captopril, a standard drug of ACE inhibition.
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Alcaloides/farmacología , Inhibidores de la Enzima Convertidora de Angiotensina/farmacología , Género Justicia/química , Extractos Vegetales/farmacología , Quinazolinas/farmacología , Alcaloides/química , Inhibidores de la Enzima Convertidora de Angiotensina/química , Cromatografía Líquida de Alta Presión , Descubrimiento de Drogas , Evaluación Preclínica de Medicamentos , Humanos , Simulación del Acoplamiento Molecular , Extractos Vegetales/química , Quinazolinas/químicaRESUMEN
Diabetes is a major health problem that is associated with high risk of various complications. Medicinal plants hold great promise against diabetes. The traditional use of Cleome droserifolia as an antidiabetic agent was correlated to its flavonol glycosides content. In the current study, five major flavonol glycosides appeared on the RP-HPLC chromatogram of the aqueous extract namely; quercetin-3-O-ß-d-glucosyl-7-O-α-rhamnoside (1), isorhamnetin-7-O-ß-neohesperidoside (2), isorhamnetin-3-O-ß-d-glucoside (3) kaempferol-4'-methoxy-3,7-O-α-dirhamnoside (4), and isorhamnetin-3-O-α-(4â³-acetylrhamnoside)-7-O-α-rhamnoside (5). The inhibitory activities of these compounds were tested in vitro against several enzymes involved in diabetes management. Only the relatively less polar methoxylated flavonol glycosides (4, 5) showed mild to moderate α-amylase and α-glucosidase inhibitory activities. Compounds 1-4 displayed remarkable inhibition of dipeptidyl peptidase IV (DPPIV) enzyme (IC50 0.194 ± 0.06, 0.573 ± 0.03, 0.345 ± 0.02 and 0.281 ± 0.05 µg/mL, respectively) comparable to vildagliptin (IC50 0.154 ± 0.02 µg/mL). Moreover, these compounds showed high potential in preventing diabetes complications through inhibiting aldose reductase enzyme and combating oxidative stress. Both isorhamnetin glycoside derivatives (2, 3) exhibited the highest activities in aldose reductase inhibition and compound 2 (IC50 5.45 ± 0.26 µg/mL) was even more potent than standard quercetin (IC50 7.77 ± 0.43 µg/mL). Additionally, these flavonols exerted excellent antioxidant capacities through 2, 2-diphenyl-1-picrylhydrazil (DPPH) and ferric reducing antioxidant (FRAP) assays.
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Dipeptidil Peptidasa 4/química , Inhibidores de la Dipeptidil-Peptidasa IV/química , Glicósidos/farmacología , Aldehído Reductasa/química , Aldehído Reductasa/metabolismo , Antioxidantes/química , Compuestos de Bifenilo/química , Química Farmacéutica/métodos , Cromatografía Líquida de Alta Presión , Cleome , Diseño de Fármacos , Depuradores de Radicales Libres , Humanos , Hipoglucemiantes , Técnicas In Vitro , Concentración 50 Inhibidora , Espectroscopía de Resonancia Magnética , Modelos Químicos , Estrés Oxidativo , Picratos/química , Vildagliptina/farmacología , alfa-Amilasas/química , alfa-Glucosidasas/metabolismoRESUMEN
Kleinia pendula (Forssk.) DC. is a prostrate or pendent dark green succulent herb found in the southwestern mountain regions of Saudi Arabia. The literature survey of the plant reveals a lack of phytochemical and pharmacological studies, although traditional uses have been noted. The objective of the present work was to assess the in vivo analgesic and anti-inflammatory activities, as well as, the in vitro cytotoxic potential of the fractions of Kleinia pendula, and correlate these activities to the plant metabolites. The methanolic extract of Kleinia pendula was subjected to fractionation with n-hexane, ethyl acetate, chloroform, n-butanol, and water. The fractions were screened for their analgesic and anti-inflammatory activities, as well as cytotoxic activity against breast, liver, and colon cancer cell lines. The n-hexane and chloroform fractions of Kleinia pendula showed significant cytotoxic activity against all three cancer cell lines tested. The ethyl acetate and chloroform fractions showed significant analgesic and anti-inflammatory activities. The metabolites in these three active fractions were determined using UPLC-PDA-ESI-MS. Thus, the analgesic and anti-inflammatory activities of the plant were attributed to its phenolic acids (caffeoylquinic acid derivatives, protocatechuic, and chlorogenic acids). While fatty acids and triterpenoids such as (tormentic acid) in the hexane fraction are responsible for the cytotoxic activity; thus, these fractions of Kleinia pendula may be a novel source for the development of new plant-based analgesic, anti-inflammatory, and anticancer drugs.
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Analgésicos/farmacología , Antiinflamatorios/farmacología , Antineoplásicos Fitogénicos/farmacología , Fabaceae/química , Fitoquímicos/farmacología , Analgésicos/química , Antiinflamatorios/química , Antineoplásicos Fitogénicos/química , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Cromatografía Líquida de Alta Presión , Células HCT116 , Células Hep G2 , Humanos , Células MCF-7 , Espectrometría de Masas , Fitoquímicos/química , Extractos Vegetales/química , Arabia Saudita , SenecioRESUMEN
BACKGROUND: Viral and microbial infections constitute one of the most important life-threatening problems. The emergence of new viral and bacterial infectious diseases increases the demand for new therapeutic drugs. PURPOSE: The objective of this study was to use the aqueous and hexane extracts of Lampranthus coccineus and Malephora lutea F. Aizoaceae for the synthesis of silver nanoparticles, and to investigate its possible antiviral activity. In addition to the investigation of the phytochemical composition of the crude methanolic extracts of the two plants through UPLC-MS metabolomic profiling, and it was followed by molecular docking in order to explore the chemical compounds that might contribute to the antiviral potential. METHODS: The formation of SNPs was further confirmed using a transmission electron microscope (TEM), UV-Visible spectroscopy and Fourier transform infrared spectroscopy. The antiviral activity of the synthesized nanoparticles was evaluated using MTT assay against HSV-1, HAV-10 virus and Coxsackie B4 virus. Metabolomics profiling was performed using UPLC-MS and molecular docking was performed via Autodock4 and visualization was done using the Discovery studio. RESULTS: The early signs of SNPs synthesis were detected by a color change from yellow to reddish brown color. The TEM analysis of SNPs showed spherical nanoparticles with mean size ranges between 10.12 nm to 27.89 nm, and 8.91 nm 14.48 nm for Lampranthus coccineus and Malephora lutea aqueous and hexane extracts respectively. The UV-Visible spectrophotometric analysis showed an absorption peak at λmax of 417 nm.The green synthesized SNPs of L. coccineus and M. lutea showed remarkable antiviral activity against HSV-1, HAV-10, and CoxB4 virus. Metabolomics profiling of the methanolic extract of L. coccineus and M. lutea resulted in identifying 12 compounds. The docking study predicted the patterns of interactions between the compounds of L. coccineus and M. lutea with herpes simplex thymidine kinase, hepatitis A 3c proteinase, and Coxsackievirus B4 3c protease, which was similar to those of the co-crystal inhibitors and this can provide a supposed explanation for the antiviral activity of the aqueous and nano extracts of L. coccineus and M. lutea. CONCLUSION: These results highlight that SNPs of L. coccineus and M. lutea could have antiviral activity against HSV-1, HAV-10, and CoxB4 virus.
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Aizoaceae/química , Antivirales/farmacología , Tecnología Química Verde , Nanopartículas del Metal/química , Plata/farmacología , Animales , Antivirales/química , Muerte Celular/efectos de los fármacos , Chlorocebus aethiops , Ligandos , Metabolómica , Nanopartículas del Metal/ultraestructura , Simulación del Acoplamiento Molecular , Extractos Vegetales/química , Plata/química , Espectrofotometría Ultravioleta , Espectroscopía Infrarroja por Transformada de Fourier , Células VeroRESUMEN
Twelve new Schiff base derivatives have been prepared by the condensation reaction of different amino substituted compounds (aniline, pyridin-2-amine, o-toluidine, 2-nitrobenzenamine, 4-aminophenol, and 3-aminopropanol) and substituted aldehydes such as nicotinaldehyde, o,m,p-nitrobenzaldehyde, and picolinaldehyde in ethanol using acetic acid as a catalyst. The envisaged structures of the all the synthesized ligands have been confirmed on the basis of their spectral analysis FT-IR, mass spectroscopy, 1H- and 13C-NMR. In vitro screening of their antibacterial and antifungal potential against Escherichia coli bacterium and Fusarium oxysporum f.sp albedinis (F.o.a) fungus, respectively, revealed that all the ligands showed no significant antibacterial activity, whereas most of them displayed good antifungal activity. Homology modeling and docking analysis were performed to explain the antifungal effect of the most and least active compound against two F.o.a fungus proteins.
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Antibacterianos/química , Complejos de Coordinación/química , Escherichia coli/efectos de los fármacos , Fusarium/efectos de los fármacos , Aminofenoles/química , Compuestos de Anilina/química , Antibacterianos/farmacología , Antifúngicos/química , Antifúngicos/farmacología , Escherichia coli/patogenicidad , Fusarium/patogenicidad , Humanos , Ligandos , Pruebas de Sensibilidad Microbiana , Simulación del Acoplamiento Molecular , Estructura Molecular , Bases de Schiff/químicaRESUMEN
In the present study, LC-HRESIMS-assisted dereplication along with bioactivity-guided isolation led to targeting two brominated oxindole alkaloids (compounds 1 and 2) which probably play a key role in the previously reported antibacterial, antibiofilm, and cytotoxicity of Callyspongia siphonella crude extracts. Both metabolites showed potent antibacterial activity against Gram-positive bacteria, Staphylococcus aureus (minimum inhibitory concentration (MIC) = 8 and 4 µg/mL) and Bacillus subtilis (MIC = 16 and 4 µg/mL), respectively. Furthermore, they displayed moderate biofilm inhibitory activity in Pseudomonas aeruginosa (49.32% and 41.76% inhibition, respectively), and moderate in vitro antitrypanosomal activity (13.47 and 10.27 µM, respectively). In addition, they revealed a strong cytotoxic effect toward different human cancer cell lines, supposedly through induction of necrosis. This study sheds light on the possible role of these metabolites (compounds 1 and 2) in keeping fouling organisms away from the sponge outer surface, and the possible applications of these defensive molecules in the development of new anti-infective agents.
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Alcaloides/farmacología , Callyspongia/química , Oxindoles/farmacología , Animales , Antiinfecciosos/farmacología , Antiprotozoarios/farmacología , Bacterias/efectos de los fármacos , Biopelículas/efectos de los fármacos , Línea Celular Tumoral , Células HT29 , Halogenación , Humanos , Océano Índico , Pruebas de Sensibilidad Microbiana/métodosRESUMEN
BACKGROUND: 4-Thiazolidinone ring is reported to have almost all types of biological activities. Also, it present in many marketed drugs. RESULTS: Ethyl acetoacetate reacted with phenyl isothiocyanate and ethyl chloroacetate in presence of K2CO3 and DMF to afford the thiazolidinone derivative 5. Thiazolidinone 5 reacted with dimethylformamide-dimethylacetal to afford (Z)-ethyl 2-((Z)-5-((dimethylamino) methylene)-4-oxo-3-phenylthiazolidin-2-ylidene)acetate (6). The structure of thiazolidinone 6 was elucidated from its spectral analysis and X-ray crystallography and was optimized using B3LYP/6-31G(d,p) method. The geometric parameters and NMR spectra were discussed both experimentally and theoretically. Also, the natural charges at the different atomic sites were predicted. The synthesized compounds had moderate cytotoxic activity. CONCLUSIONS: An unexpected synthesis of (Z)-ethyl 2-((Z)-5-((dimethylamino)methylene)-4-oxo-3-phenylthiazolidin-2-ylidene)acetate via deacetylation mechanism. The structure was established using X-ray and spectral analysis. The geometric parameters, and NMR spectra were discussed. The synthesized compounds showed moderate anticancer activity.
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The combination of liquid chromatography coupled to high resolution mass spectrometry (LC-HRESMS)-based dereplication and antiproliferative activity-guided fractionation was applied on the Red Sea-derived soft coral Sarcophyton sp. This approach facilitated the isolation of five new cembrane-type diterpenoids (1-5), along with two known analogs (6 and 7), as well as the identification of 19 further, known compounds. The chemical structures of the new compounds were elucidated while using comprehensive spectroscopic analyses, including one-dimensional (1D) and two-dimensional (2D) NMR and HRMS. All of the isolated cembranoids (1-7) showed moderate in vitro antiproliferative activity against a human breast cancer cell line (MCF-7), with IC50 ranging from 22.39-27.12 µg/mL. This class of compounds could thus serve as scaffold for the future design of anticancer leads.
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Antozoos/química , Antineoplásicos/farmacología , Diterpenos/farmacología , Animales , Antineoplásicos/química , Antineoplásicos/aislamiento & purificación , Proliferación Celular/efectos de los fármacos , Diterpenos/química , Diterpenos/aislamiento & purificación , Diseño de Fármacos , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Océano Índico , Concentración 50 Inhibidora , Células MCF-7 , Estructura MolecularRESUMEN
A series of new thiazoline derivatives were synthesized. Structure analyses were accomplished employing 1H-NMR, 13C-NMR, X-ray and MS techniques. The in vitro antitumor activities were assessed against human hepatocellular carcinoma (HepG-2) and colorectal carcinoma (HCT-116) cell lines. The results revealed that the thiazolines 5b and 2c exhibited significant activity against the two cell lines. The in vitro antimicrobial screening showed that the thiazolines 2c, 5b and 5d showed promising inhibition activity against Salmonella sp. Additionally, the inhibition activity of thiazolines 2e and 5b against Escherichia coli was comparable to that of the reference compound gentamycin.