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Colorectal cancer (CRC) is the second most common cause of death worldwide, affecting approximately 1.9 million individuals in 2020. Therapeutics of the disease are not yet available and discovering a novel anticancer drug candidate against the disease is an urgent need. Thymidylate synthase (TS) is an important enzyme and prime precursor for DNA biosynthesis that catalyzes the methylation of deoxyuridine monophosphate (dUMP) to deoxythymidine monophosphate (dTMP) that has emerged as a novel drug target against the disease. Elevated expression of TS in proliferating cells promotes oncogenesis as well as CRC. Therefore, this study aimed to identify potential natural anticancer agents that can inhibit the activity of the TS protein, subsequently blocking the progression of colorectal cancer. Initially, molecular docking was implied on 63 natural compounds identified from Catharanthus roseus and Avicennia marina to evaluate their binding affinity to the desired protein. Subsequently, molecular dynamics (MD) simulation, ADME (Absorption, Distribution, Metabolism, and Excretion), toxicity, and quantum chemical-based DFT (density-functional theory) approaches were applied to evaluate the efficacy of the selected compounds. Molecular docking analysis initially identified four compounds (PubChem CID: 5281349, CID: 102004710, CID: 11969465, CID: 198912) that have better binding affinity to the target protein. The ADME and toxicity properties indicated good pharmacokinetics (PK) and toxicity ability of the selected compounds. Additionally, the quantum chemical calculation of the selected molecules found low chemical reactivity indicating the bioactivity of the drug candidate. The global descriptor and HOMO-LUMO energy gap values indicated a satisfactory and remarkable profile of the selected molecules. Furthermore, MD simulations of the compounds identified better binding stability of the compounds to the desired protein. To sum up, the phytoconstituents from two plants showed better anticancer activity against TS protein that can be further developed as an anti-CRC drug.
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Antineoplásicos , Avicennia , Catharanthus , Neoplasias Colorrectales , Antineoplásicos/química , Antineoplásicos/farmacología , Avicennia/metabolismo , Catharanthus/metabolismo , Neoplasias Colorrectales/tratamiento farmacológico , Humanos , Simulación del Acoplamiento Molecular , Timidilato Sintasa/metabolismoRESUMEN
In the current study, nitrofurazone- (NFZ) and lidocaine-loaded (LD) silica microspheres were fabricated to address pathological indications of skin infections. The microspheres were prepared by the sol-gel method applying the Box-Behnken design and evaluated for size distribution, morphology, zeta potential, physico-chemical compatibility, XRD, thermogravimetric analysis, antibacterial and cytotoxicity activities. The comparative in vitro drug release study of microspheres revealed a 30% release of NFZ and 33% of LD after 8 h. The microspheres showed 81% percentage yield (PY) and 71.9% entrapment efficiency. XRD patterns confirmed the entrapment of NFZ-LD in silica microspheres with a significant reduction in crystallinity of the drugs. Thermal and FTIR studies proved the absence of any profound interactions of the formulation ingredients. The smooth spherical microspheres had a -28 mV zeta potential and a 10-100 µm size distribution. In vitro antibacterial activities of the NFZ-LD microspheres showed an increased zone of inhibition compared to pure drug suspensions. The in vivo efficacy tested on rabbits showed a comparatively rapid wound healing with complete lack of skin irritation impact. The cytotoxicity studies revealed more acceptability of silica microspheres with negligible harm to cells. The study suggests that the NFZ- and LD-loaded silica microspheres would be an ideal system for accelerating and promoting rapid healing of various acute and chronic wounds.
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Nitrofurazona , Dióxido de Silicio , Animales , Antibacterianos/farmacología , Lidocaína/farmacología , Microesferas , Nitrofurazona/farmacología , Tamaño de la Partícula , Conejos , Cicatrización de HeridasRESUMEN
The occurrence of fungal infections has increased over the past two decades. It is observed that superficial fungal infections are treated by conventional dosage forms, which are incapable of treating deep infections due to the barrier activity possessed by the stratum corneum of the skin. This is why the need for a topical preparation with advanced penetration techniques has arisen. This research aimed to encapsulate fluconazole (FLZ) in a novasome in order to improve the topical delivery. The novasomes were prepared using the ethanol injection technique and characterized for percent entrapment efficiency (EE), particle size (PS), zeta potential (ZP), drug release, Fourier-transform infrared spectroscopy (FTIR), differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), scanning electron microscopy (SEM) and antifungal activity. The FN7 formulation with 94.45% EE, 110 nm PS and -24 ZP proved to be the best formulation. The FN7 formulation showed a 96% release of FLZ in 8 h. FTIR showed the compatibility of FLZ with excipients and DSC studies confirmed the thermal stability of FLZ in the developed formulation. The FN7 formulation showed superior inhibition of the growth of Candida albicans compared to the FLZ suspension using a resazurin reduction assay, suggesting high efficacy in inhibiting fungal growth.
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Fluconazol , Micosis , Antifúngicos/uso terapéutico , Candida albicans , Portadores de Fármacos/química , Sistemas de Liberación de Medicamentos/métodos , Fluconazol/química , Fluconazol/farmacología , Micosis/tratamiento farmacológico , Tamaño de la PartículaRESUMEN
Halogens have been reported to play a major role in the inhibition of monoamine oxidase (MAO), relating to diverse cognitive functions of the central nervous system. Pyrazoline/halogenated pyrazolines were investigated for their inhibitory activities against human monoamine oxidase-A and -B. Halogen substitutions on the phenyl ring located at the fifth position of pyrazoline showed potent MAO-B inhibition. Compound 3-(4-ethoxyphenyl)-5-(4-fluorophenyl)-4,5-dihydro-1H-pyrazole (EH7) showed the highest potency against MAO-B with an IC50 value of 0.063 µM. The potencies against MAO-B were increased in the order of -F (in EH7) > -Cl (EH6) > -Br (EH8) > -H (EH1). The residual activities of most compounds for MAO-A were > 50% at 10 µM, except for EH7 and EH8 (IC50 = 8.38 and 4.31 µM, respectively). EH7 showed the highest selectivity index (SI) value of 133.0 for MAO-B, followed by EH6 at > 55.8. EH7 was a reversible and competitive inhibitor of MAO-B in kinetic and reversibility experiments with a Ki value of 0.034 ± 0.0067 µM. The molecular dynamics study documented that EH7 had a good binding affinity and motional movement within the active site with high stability. It was observed by MM-PBSA that the chirality had little effect on the overall binding of EH7 to MAO-B. Thus, EH7 can be employed for the development of lead molecules for the treatment of various neurodegenerative disorders.
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Simulación de Dinámica Molecular , Inhibidores de la Monoaminooxidasa/química , Pirazoles/química , Barrera Hematoencefálica/efectos de los fármacos , Dominio Catalítico , Química Farmacéutica/métodos , Cognición/efectos de los fármacos , Diseño de Fármacos , Halógenos/química , Humanos , Concentración 50 Inhibidora , Cinética , Modelos Químicos , Simulación del Acoplamiento Molecular , Estructura Molecular , Monoaminooxidasa/metabolismo , Movimiento (Física) , Análisis de Componente Principal , Unión Proteica , Proteínas Recombinantes/química , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
A small series of nitro group-bearing enamides was designed, synthesized (NEA1-NEA5), and evaluated for their inhibitory profiles of monoamine oxidases (MAOs) and ß-site amyloid precursor protein cleaving enzyme 1 (ß-secretase, BACE1). Compounds NEA3 and NEA1 exhibited a more potent MAO-B inhibition (IC50 value = 0.0092 and 0.016 µM, respectively) than the standards (IC50 value = 0.11 and 0.14 µM, respectively, for lazabemide and pargyline). Moreover, NEA3 and NEA1 showed greater selectivity index (SI) values toward MAO-B over MAO-A (SI of >1652.2 and >2500.0, respectively). The inhibition and kinetics studies suggested that NEA3 and NEA1 are reversible and competitive inhibitors with Ki values of 0.013 ± 0.005 and 0.0049 ± 0.0002 µM, respectively, for MAO-B. In addition, both NEA3 and NEA1 showed efficient BACE1 inhibitions with IC50 values of 8.02 ± 0.13 and 8.21 ± 0.03 µM better than the standard quercetin value (13.40 ± 0.04 µM). The parallel artificial membrane permeability assay (PAMPA) method demonstrated that all the synthesized derivatives can cross the blood-brain barrier (BBB) successfully. Docking analyses were performed by employing an induced-fit docking approach in the GLIDE module of Schrodinger, and the results were in agreement with their in vitro inhibitory activities. The present study resulted in the discovery of potent dual inhibitors toward MAO-B and BACE1, and these lead compounds can be fruitfully explored for the generation of newer, clinically active agents for the treatment of neurodegenerative disorders.
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Amidas/química , Secretasas de la Proteína Precursora del Amiloide/antagonistas & inhibidores , Inhibidores de la Monoaminooxidasa/química , Monoaminooxidasa/química , Inhibidores de Proteasas/química , Amidas/síntesis química , Amidas/metabolismo , Barrera Hematoencefálica/metabolismo , Membranas Artificiales , Estructura Molecular , Inhibidores de la Monoaminooxidasa/metabolismo , Inhibidores de Proteasas/metabolismoRESUMEN
The elaboration of new small molecules that target phosphodiesterase enzymes (PDEs), especially those of type 5 (PDE5), is an interesting and emerging topic nowadays. A new series of heterocycle-based aminothiazoles were designed and synthesized from the key intermediate, 3-oxo-N-(thiazol-2-yl)butanamide (a PDE5 inhibitor that retains its amidic function), as an essential pharmacophoric moiety. The PDE5 inhibitors prevent the degradation of cyclic guanosine monophosphate, thereby causing severe hypotension as a marked side effect. Hence, an in vivo testing of the target compounds was conducted to verify its relation with arterial blood pressure. Utilizing sildenafil as the reference drug, Compounds 5, 10a, and 11b achieved 100% inhibitions of PDE5 without significantly lowering the mean arterial blood pressures (115.95 ± 2.91, 110.3 ± 2.84, and 78.3 ± 2.57, respectively). The molecular docking study revealed that the tested compounds exhibited docking poses that were similar to that of sildenafil (exploiting the amide functionality that interacted with GLN:817:A). The molecular shape and electrostatic similarity revealed a comparable physically achievable electrostatic potential with the reference drug, sildenafil. Therefore, these concomitant results revealed that the tested compounds exerted sildenafil-like inhibitory effects (although without its known drawbacks) on blood circulation, thus suggesting that the tested compounds might represent a cornerstone of beneficial drug candidates for the safe treatment for erectile dysfunction.
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GMP Cíclico/metabolismo , Fosfodiesterasas de Nucleótidos Cíclicos Tipo 5/química , Diseño de Fármacos , Inhibidores de Fosfodiesterasa 5/química , Inhibidores de Fosfodiesterasa 5/farmacología , Piridinas/química , Tiazoles/química , Humanos , Relación Estructura-ActividadRESUMEN
A general strategy towards total synthesis of (-)-codonopsinine, (-)-codonopsine and codonopsinine analogues has been developed from (D)-tartaric acid via the intermediate (3S,4R)-1-methyl-2-oxo-5-(2,2,2-trichloroacetamido)pyrrolidinediacetate (7). α-amidoalkylation studies of 7 with electron rich benzene derivative 8a-g as C-nucleophiles afforded (aryl derivatives) 9a-g. The target compounds 1, 2 and 13c-g were readily obtained from 10a-gvia Grignard addition to the homochiral lactam which was produced by deoxygenation using Lewis-acid followed by deacetylation. The synthesized compounds were loaded onto solid lipid nanoparticle formulations (SLNs) prepared by hot emulsification-ultrasonication technique using Compritol as solid lipid and Pluronic f68 as surfactant. SLNs were fully evaluated and the permeation of synthesized compound from SLNs was assayed against non-formulated compounds through dialysis membranes using Franz cell. The data indicated good physical characteristics of the prepared SLNs, sustaining of release profiles and significant improvement of permeation ability when compared to the non-formulated compounds. The antibacterial and antifungal activities of 1, 2 and 13c-g were determined by disc diffusion and microbroth dilution method to determine the minimum inhibitory concentrations (MIC) against seven microorganisms (Staphyloccus aureus, Escherichia coli, Klebsiella pneumoniae, Proteus mirabilis, Pseudomonas aeruginosa, Acinetobacter baumannii and Candida albicans). The most active compounds against the Gram positive S. aureus were 1, 13C, 13d, and 13g. Also, 13c, 13d, and 13e had antibacterial activity but not 13f against some Gram negative organisms (E. coli, and P. mirabilis). MIC concentrations against P. aeruginosa, and K. pneumoniae wereâ¯≥512⯵g/ml, while that against A. baumannii wasâ¯≥128⯵g/ml except for nanoformulae of 13e and 13f that were 16 and 64⯵g/ml, respectively. No antifungal activity against Candida albicans was recorded for all compounds and their nanoformulae (MICâ¯>â¯1024⯵g/ml). SLNs were found to decrease the MIC values for some of the compounds with no effect on the antifungal activity. In conclusion, we demonstrated a novel, straight-forward and economical procedure for the total synthesis of (-)-codonopsinine 1, (-)-codonopsine 2 and codonopsinine analogues 13c-g from simple and commercially available starting materials; d-tartaric acid; with antimicrobial activities against Gram positive and Gram-negative organisms that were improved by SLNs formulations.
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Antibacterianos/farmacología , Antifúngicos/farmacología , Lípidos/química , Nanopartículas/química , Pirrolidinas/farmacología , Alquilación , Antibacterianos/síntesis química , Antibacterianos/química , Antifúngicos/síntesis química , Antifúngicos/química , Bacterias/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Composición de Medicamentos , Diseño de Fármacos , Hongos/efectos de los fármacos , Humanos , Pruebas de Sensibilidad Microbiana , Estructura Molecular , Pirrolidinas/síntesis química , Pirrolidinas/química , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
OBJECTIVE: This investigation aimed to synthesize amphiphilic hexyl amidic derivative of alginate to be used in the preparation of glibenclamide-loaded release system of improved dissolution rate. MATERIALS AND METHODS: Hexyl amine was associated to the activated carboxylic acid moieties of alginate to synthesize alginate hexyl amide polymer (AHAP). This polymer in comparison to alginate was used in different concentrations for preparing beads containing glibenclamide by an ionic gelation using Ca(++) as gelling ion. The prepared beads were characterized by DSC, FTIR and scanning electron microscope. The swelling behavior, drug loading capacity and release behavior were studied. RESULTS AND DISCUSSION: The results showed that the prepared AHAP beads were smaller in size and more spherical. The surface was highly corrugated with much and wider pore size. The beads showed a high drug loading capacity and efficacy that was affected by the polymer concentration. The drug release rate from AHAP beads reached 100% after 4, 8 and 12 hours in comparison to 75.3%, 73.2% and 69.2% from alginate beads at 3%, 2% and 1% polymer concentrations, respectively. CONCLUSION: It can thus be concluded that the amphiphilic AHAP-based bead is a simple and efficient delivery system of promising industrial significance for the improvement of the dissolution rate.
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Alginatos/química , Amidas/química , Portadores de Fármacos/química , Gliburida/administración & dosificación , Hipoglucemiantes/administración & dosificación , Calcio/química , Cationes Bivalentes/química , Geles/química , Ácido Glucurónico/química , Gliburida/química , Ácidos Hexurónicos/química , Hipoglucemiantes/química , SolubilidadRESUMEN
BACKGROUND: The monotropic membrane protein monoamine oxidase B (MAO-B) has been shown to be a crucial drug target for the treatment of neurodegenerative diseases. The design of recent inhibitor therapeutic agents of MAO-B involves conjugation and modification of a chalcone scaffold comprising two aryl or heteroaryl rings connected via a short spacer unit with rotatable bonds. Supported by experimental data, these modifications often result in high potent inhibitor compounds. METHODS: In this study, we employ molecular dynamics simulations to unravel the impact of extended double bond conjugation in two novel compounds, F1 and MO10, toward the inhibition of the MAO-B protein. It was revealed that extended double bond conjugation induced a unidirectional orientation and motion of F1 and MO10, suggesting a stable binding pocket anchorage favouring high-affinity pocket interactions. RESULTS: Conformational analyses also revealed that the incorporated double bond extension impeded the motion of individual binding pocket residues, which subsequently disrupted the functionality of MAO-B. DISCUSSION: Real-time structural dynamics also revealed that the extended double bond conjugation mediated peculiar interactions with MAO-B binding pocket residues characterized by π-alkyl, π-π stacking, and π-sulphur interactions which buried both compounds into the hydrophobic core of MAO-B and ultimately induced higher binding affinities of both F1 and MO10. CONCLUSION: These insights present useful structural perspectives of the extended double bond conjugation associated with the experimentally reported enhanced inhibitory activity of F1 and MO10 against MAO-B.
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Chalcona , Chalconas , Chalcona/química , Chalcona/farmacología , Chalconas/química , Chalconas/farmacología , Proteínas de la Membrana , Simulación del Acoplamiento Molecular , Simulación de Dinámica Molecular , Monoaminooxidasa/metabolismo , Inhibidores de la Monoaminooxidasa/química , Inhibidores de la Monoaminooxidasa/farmacología , Relación Estructura-Actividad , AzufreRESUMEN
Background: Different parts of Taraxacum officinale (L.) were used in traditional medicine in various parts of the world for the treatment of health problems, and they possess significant biological activities. The present study aimed to estimate phytochemical and biological activities of T. officinale using different extraction solvents. Methods: Methanolic, acetone, and n-hexane extracts of selected species were prepared, and ten secondary metabolites were examined using standard protocols. The antioxidant activity was performed using three in vitro methods, namely, DPPH assay, total reducing power (TRP) assay, and total antioxidant capacity (TAC). Toxicological analysis was done using the brine shrimp cytotoxic assay and radish seed phytotoxic assay. Results: The T. officinale methanolic extract showed the highest phenolic (178.27 ± 17.17 mg/GAE/g) and flavonoid (18.50 ± 1.64 mg QE/g) contents. Similarly, the methanolic extract also revealed the highest DPPH activity (32.80 ± 9.66 IC50), reducing potential (0.53 ± 0.02 mg/g), and TAC (19.42 ± 0.97 mg/g) as compared to the acetone and n-hexane extracts. The Pearson correlation analysis confirmed a strong positive correlation (r > 0.9) between total phenolic content (TPC), total flavonoid content (TFC), and all antioxidant assays. Furthermore, a heat map displayed the methanolic extract (red color) as a valuable source of phytochemicals and antioxidant agents. Moreover, the T. officinale methanolic extract also showed the highest (7.12 ppm) cytotoxic potential whereas both methanolic and acetone extracts were revealed as moderate phytotoxic agents when compared with the standard. Conclusion: The T. officinale methanolic extract exhibited comparatively notable phytochemicals that are actively involved in antioxidant activities and possess toxicological properties. This upholds the folkloric use of T. officinale as a possible source to develop natural plant-based drugs. Further investigations to isolate bioactive compounds and elements and on their safety need to be conducted.
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Carvacrol is a major natural constituent and is significantly present as an essential oil in aromatic plants and is well known for its numerous biological activities. Therapeutic properties of carvacrol have been demonstrated as anti-oxidant, anticancer, diabetes prevention, cardioprotective, anti-obesity, hepatoprotective and reproductive role, antiaging, antimicrobial, and immunomodulatory properties. The carvacrol biosynthesis has been mediated through mevalonate pathway. Carvacrol has the anticancer ability against malignant cells via decreasing the expressions of matrix metalloprotease 2 and 9, inducing apoptosis, enhancing the expression of pro-apoptotic proteins, disrupting mitochondrial membrane, suppressing extracellular signal-regulated kinase 1/2 mitogen-activated protein kinase signal transduction, and also decreasing the phosphoinositide 3-kinase/protein kinase B. It also decreased the concentrations of alanine aminotransferase, alkaline phosphatase and aspartate aminotransferase, and gamma-glutamyl transpeptidase as well as also restored liver function, insulin level, and plasma glucose level. Carvacrol also has been found to exert antimicrobial activity against Staphylococcus aureus, Pseudomonas aeruginosa, Coagulase-negative staphylococcus, Salmonella spp., Enterococcus sp. Shigella, and Escherichia coli. The current review article summarizes the health-promoting perspectives of carvacrol through various pathways.
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The purpose of the study was to develop an SNEDDS to improve the solubility and bioavailability of pitavastatin. The solubility of pitavastatin in different oils, surfactants, and co-surfactants was determined and a pseudo-ternary phase diagram was constructed. The SNEDDS was characterized by zeta-sizer, zeta-potential, FTIR, DSC, and TGA. Release and permeation of pitavastatin from the SNEDDS was studied for 12 and 24 h, respectively. The lipolysis test, RBC lysis, effect on lipid profile, and pharmacokinetics were studied. The SPC3 formulation showed a 104 ± 1.50 nm particle size, a 0.198 polydispersity index (PDI), and a -29 zeta potential. FTIR, DSC, and TGA showed the chemical compatibility and thermal stability. The release and permeation of pitavastatin from SPC3 was 88.5 ± 2.5% and 96%, respectively. In the lipolysis test, the digestion of SPC3 yielded a high amount of pitavastatin and showed little RBC lysis. The lipid profile suggested that after 35 days of administration of the SNEDDS, there was a marked decrease in TC, LDL, and triglyceride levels. The SNEDDS of SPC3 showed an 86% viability of Caco-2 cells. Pharmacokinetics of SPC3 showed improved values of Cmax, Tmax, half-life, MRT, AUC, and AUMC compared to the reference formulation. Our study demonstrated that the SNEDDS effectively enhanced the solubility and bioavailability of a BCS class II drug.
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Poor solubility is the major challenge involved in the formulation development of new chemical entities (NCEs), as more than 40% of NCEs are practically insoluble in water. Solid dispersion (SD) is a promising technology for improving dissolution and, thereby, the bioavailability of poorly soluble drugs. This study investigates the influence of a pH-sensitive acrylate polymer, EPO, on the physicochemical properties of rosuvastatin calcium, an antihyperlipidemic drug. In silico docking was conducted with numerous polymers to predict drug polymer miscibility. The screened-out polymer was used to fabricate the binary SD of RoC in variable ratios using the co-grinding and solvent evaporation methods. The prepared formulations were assessed for physiochemical parameters such as saturation solubility, drug content and in vitro drug release. The optimized formulations were further ruled out using solid-state characterization (FTIR, DSC, XRD and SEM) and in vitro cytotoxicity. The results revealed that all SDs profoundly increased solubility as well as drug release. However, the formulation RSE-2, with a remarkable 71.88-fold increase in solubility, presented 92% of drug release in the initial 5 min. The molecular interaction studied using FTIR, XRD, DSC and SEM analysis evidenced the improvement of in vitro dissolution. The enhancement in solubility of RoC may be important for the modulation of the dyslipidemia response. Therefore, pharmacodynamic activity was conducted for optimized formulations. Our findings suggested an ameliorative effect of RSE-2 in dyslipidemia and its associated complications. Moreover, RSE-2 exhibited nonexistence of cytotoxicity against human liver cell lines. Convincingly, this study demonstrates that SD of RoC can be successfully fabricated by EPO, and have all the characteristics that are favourable for superior dissolution and better therapeutic response to the drug.
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Fifteen multiconjugated dienones (MK1-MK15) were synthesized and evaluated to determine their inhibitory activities against monoamine oxidases (MAOs) A and B. All derivatives were found to be potent and highly selective MAO-B inhibitors. Compound MK6, with an IC50 value of 2.82 nM, most effectively inhibited MAO-B, like MK12 (IC50 = 3.22 nM), followed by MK5, MK13, and MK14 (IC50 = 4.02, 4.24, and 4.89 nM, respectively). The selectivity index values of MK6 and MK12 for MAO-B over MAO-A were 7361.5 and 1780.5, respectively. Compounds MK6 and MK12 were competitive reversible inhibitors of MAO-B, with K i values of 1.10 ± 0.20 and 3.0 ± 0.27 nM, respectively. Cytotoxic studies showed that MK5, MK6, MK12, and MK14 exhibited low toxicities on Vero cells, with IC50 values of 218.4, 149.1, 99.96, and 162.3 µg/mL, respectively, which were much higher than those for their effective nanomolar-level concentrations. Also, MK5, MK6, MK12, and MK14 decreased cell damage in H2O2-induced cells via a significant scavenging effect of reactive oxygen species. Molecular modeling was performed to rationalize the potential inhibitory activities of MK5, MK6, MK12, and MK14 toward MAO-B and their possible binding mechanisms, showing high-affinity binding pocket interactions and conformation perturbations of the compounds with MAO-B, which were interpreted as the conformational dynamics of MAO-B. This study concluded that all the compounds tested were more potent MAO-B inhibitors than the reference drugs, and leading compounds could be further explored for their effectiveness in various kinds of neurodegenerative disorders.
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The objective of this study was to improve the dissolution and solubility of dexibuprofen (DEX) using hydroxypropyl beta cyclodextrin (HPßCD) inclusion complexes and also to evaluate the effect of presence of hydrophilic polymers on solubilization efficiency of HPßCD. Three different methods (physical trituration, kneading and solvent evaporation) were used to prepare binary inclusion complexes at various drug-to-cyclodextrin weight ratios. An increase in solubility and drug release was observed with the kneading (KN) method at a DEX/HPßCD (1:4) weight ratio. The addition of hydrophilic polymers poloxamer-188 (PXM-188) and poloxamer-407 (PXM-407) at 2.5, 5.0, 10.0 and 20% w/w enhanced the complexation efficiency and solubility of DEX/HPßCD significantly. Fourier-transform infrared (FTIR) analysis revealed that DEX was successfully incorporated into the cyclodextrin cavity. Differential scanning calorimetry (DSC) and X-ray diffractometry (XRD) revealed less crystallinity of the drug and its entrapment in the cyclodextrin molecular cage. The addition of PXM-188 or PXM-407 reduced the strength of the DEX endothermic peak. With the addition of hydrophilic polymers, sharp and intense peaks of DEX disappeared. Finally, it was concluded that PXM-188 at a weight ratio of 10.0% w/w was the best candidate for improving solubility, stability and release rate of DEX.
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Merkel cell carcinoma (MCC) is a rare form of aggressive skin cancer mainly caused by Merkel cell polyomavirus (MCPyV). Most MCC tumors express MCPyV large T (LT) antigens and play an important role in the growth-promoting activities of oncoproteins. Truncated LT promotes tumorigenicity as well as host cell proliferation by activating the viral replication machinery, and inhibition of this protein in humans drastically lowers cellular growth linked to the corresponding cancer. Our study was designed with the aim of identifying small molecular-like natural antiviral candidates that are able to inhibit the proliferation of malignant tumors, especially those that are aggressive, by blocking the activity of viral LT protein. To identify potential compounds against the target protein, a computational drug design including molecular docking, ADME (absorption, distribution, metabolism, and excretion), toxicity, molecular dynamics (MD) simulation, and molecular mechanics generalized Born surface area (MM-GBSA) approaches were applied in this study. Initially, a total of 2190 phytochemicals isolated from 104 medicinal plants were screened using the molecular docking simulation method, resulting in the identification of the top five compounds having the highest binding energy, ranging between -6.5 and -7.6 kcal/mol. The effectiveness and safety of the selected compounds were evaluated based on ADME and toxicity features. A 250 ns MD simulation confirmed the stability of the selected compounds bind to the active site (AS) of the target protein. Additionally, MM-GBSA analysis was used to determine the high values of binding free energy (ΔG bind) of the compounds binding to the target protein. The five compounds identified by computational approaches, Paulownin (CID: 3084131), Actaealactone (CID: 11537736), Epigallocatechin 3-O-cinnamate (CID: 21629801), Cirsilineol (CID: 162464), and Lycoricidine (CID: 73065), can be used in therapy as lead compounds to combat MCPyV-related cancer. However, further wet laboratory investigations are required to evaluate the activity of the drugs against the virus.
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Tolmetin sodium (TLM) is a non-steroidal anti-inflammatory drug (NSAIDs). TLM is used to treat inflammation, skeletal muscle injuries, and discomfort associated with bone disorders. Because of the delayed absorption from the gastro intestinal tract (GIT), the currently available TLM dosage forms have a rather protracted start to the effect, according to pharmacokinetic studies. The aim of this study was to create a combination for TLM fast dissolving tablets (TLM-FDT) that would boost the drug's bioavailability by increasing pre-gastric absorption. The TLM-FDTs were developed using a Box-Behnken experimental design with varied doses of crospovidone (CP), croscarmellose sodium (CCS) as super-disintegrants, and camphor as a sublimating agent. In addition, the current study used response surface approach to explore the influence of various formulation and process factors on tablet qualities in order to verify an optimized TLM-FDTs formulation. The optimized TLM-FDTs formula was subsequently evaluated for its in vivo anti-inflammatory activity. TLM-FDTs have good friability, disintegration time, drug release, and wetting time, as well as fast disintegration and dissolution behavior. Significant increase in drug bioavailability and reliable anti-inflammatory efficacy were also observed, as evidenced by considerable reductions in paw thickness in rats following carrageenan-induced rat paw edema. For optimizing and analyzing the effect of super-disintegrants and sublimating agents in the TLM-FDTs formula, the three-factor, three-level full factorial design is a suitable tool. TLM-FDTs are a possible drug delivery system for enhancing TLM bioavailability and could be used to treat rheumatoid arthritis.
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Nicergoline (NIC) is a semisynthetic ergot alkaloid derivative applied for treatment of dementia and other cerebrovascular disorders. The efficacy of sesame oil to slow and reverse the symptoms of neurodegenerative cognitive disorders has been proven. This work aimed to formulate and optimize sesame oil-based NIC-nanostructured lipid carriers (NIC-NLCs) for intranasal (IN) delivery with expected synergistic and augmented neuroprotective properties. The NIC-NLC were prepared using sesame oil as a liquid lipid. A three-level, three-factor Box-Behnken design was applied to statistically optimize the effect of sesame oil (%) of the total lipid, surfactant concentration, and sonication time on particle size, zeta potential, and entrapment efficacy as responses. Solid-state characterization, release profile, and ex vivo nasal permeation in comparison to NIC solution (NIC-SOL) was studied. In vivo bioavailability from optimized NIC-NLC and NIC-SOL following IN and IV administration was evaluated and compared. The optimized NIC-NLC formula showed an average particle size of 111.18 nm, zeta potential of -15.4 mV, 95.11% entrapment efficacy (%), and 4.6% loading capacity. The NIC-NLC formula showed a biphasic, extended-release profile (72% after 48 h). Permeation of the NIC-NLC formula showed a 2.3 enhancement ratio. Bioavailability studies showed a 1.67 and 4.57 fold increase in plasma and brain following IN administration. The results also indicated efficient direct nose-to-brain targeting properties with the brain-targeting efficiency (BTE%) and direct transport percentage (DTP%) of 187.3% and 56.6%, respectively, after IN administration. Thus, sesame oil-based NIC-NLC can be considered as a promising IN delivery system for direct and efficient brain targeting with improved bioavailability and expected augmented neuroprotective action for the treatment of dementia.
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The monoamine oxidase (MAO) enzyme class is a prevalent target for many neurodegenerative and depressive disorders. Even though scrutinization of many promising drugs for the treatment of MAO inhibition has been carried out in recent times, a conclusive structural requirement for potent activity needs to be developed. Numerous approaches have been examined for the identification of structural features for potent MAO inhibitors (MAOIs) that mainly involve an array of computational studies, synthetic approaches, and biological evaluation. In this paper, we have analyzed â¼2200 well-known MAOIs to expand perceptions in the chemical space of MAOIs. The physicochemical properties of the MAOIs disclosed a discernible hydrophobic feature making a bunch discrete from the central nervous system (CNS) acting drugs, as exposed using the principal component analysis (PCA). The Murcko scaffold structure study revealed unfavorable and favorable scaffold structures, in both data sets, with the highest biological activity shown by the 3-phenyl-2H-chromen-2-one scaffold. This scaffold showed a polypharmacological effect. R-group disintegration and automatic structure-activity relationship (SAR) study resulted in identification of substructures responsible for the inhibitory bioactivity of the MAO-A and MAO-B enzymes. Moreover, with activity cliff analysis, significant biological activity was detected by simple molecular conversion in the chemical compound structure. In addition, we used the machine learning tool to generate a hypothesis wherein pyrazole, benzene ring, and amide containing structural functionalities can exhibit potential biological activities. This hypothesis revealed that CNS target drugs, C4155, C13390, C21265, C43862, C31524, C24810, C37100, C42075, and C43644, could be repurposed as valuable candidates for the MAO-B enzyme. For researchers, this study will bring new perceptions in the discovery and development of MAOIs and direct lead and hit optimization for the progress of small molecules beneficial for MAO-targeting associated diseases.
RESUMEN
The aim of this research is to formulate a lecithin-chitosan based nanoparticulate system loaded with berberine (BER-LC-CTS-NPs) that could be integrated into a topically applied formulation and assessed for healing wounds in a diabetic animal model. In order to formulate BER-LC-CTS-NPs, soybean lecithin, isopropyl myristate, and berberine dispersed in ethanolic solution were added into an aqueous solution of chitosan dropwise with sonication. We assessed the influence of lecithin amount, chitosan amount, and isopropyl myristate concentration on particle diameter, zeta potential, and entrapment and employed a Box-Behnken statistical design. The resulting optimized BER-LC-CTS-NPs had a mean size of 168.4 nm, a surface charge of 33.1 mV, and entrapment of 82.3%. The optimized BER-LC-CTS-NPs showed a sustained in vitro release profile. Furthermore, the potential of the optimized BER-LC-CTS-NPs integrated into a topical gel formulation for wound healing in streptozocin-induced diabetic rats was assessed. Our findings show that combining chitosan and berberine in the nanoparticles produces a synergistic effect when it comes to wound healing. The optimized nanoparticulate system works by reducing inflammation, inducing blood vessels and fibroblast proliferation, and promoting mature collagen fibers deposition. Based on the experimental results, lecithin-chitosan nanoparticles loaded with berberine have evolved as a promising strategy for accelerating wound the healing process in diabetic patients. However, the clinical merits of the developed system need to be investigated in diabetic patients.