Quality control methods for fruit extracts of Kigelia africana using high performance thin layer chromatography.

Kigelia africana is a tree native to Africa but also found in eastern and southern parts of India with reported anti-bacterial, anti-inflammatory, and immunomodulatory activities. Verbascoside, caffeic acid and ferulic acid are important markers for the quality control of the plant. Two different HPTLC methods were developed and validated; method - 1 for estimation of verbascoside and caffeic acid while method - 2 for estimation of caffeic acid and ferulic acid. Developed methods were applied to the methanolic fruit extract to determine the quantities of markers. Both methods were found to be linear, specific, precise, accurate, sensitive and robust. Results indicated that both methods can be used for quantitative determination of verbascoside, caffeic acid and ferulic acid in fruit extract. The developed methods may be utilised as a part of the quality control and standardisation for the raw material and extracts of Kigelia africana and can also aid to chromatographic fingerprinting of the plant.

Glycogen synthase kinase-3: A potential target for diabetes.

Elevated circulating glucose level due to ß-cell dysfunction has been a key marker of Type-II diabetes. Glycogen synthase kinase-3 (GSK-3) has been recognized as an enzyme involved in the control of glycogen metabolism. Consequently, inhibitors of GSK-3 have been explored for anti-diabetic effects in vitro and in animal models. Further, the mechanisms governing the regulation of this enzyme have been elucidated by means of a combination of structural and cellular biological investigations. This review article examines the structural analysis of GSK-3 as well as molecular modeling reports from numerous researchers in the context of the design and development of GSK-3 inhibitors. This article centers on the signaling pathway of GSK-3 relevant to its potential as a target for diabetes and discusses advancements till date on different molecular modification approaches used by researchers in the development of novel GSK-3 inhibitors as potential therapeutics for the treatment of Type II diabetes.

Structure-based De Novo Design and Docking Studies of 5(S)-Methyl-L-Proline Containing Peptidomimetic Compounds as Dipeptidyl Peptidase-4 Inhibitors.

BACKGROUND: Diabetes affects millions of people worldwide, with predicted numbers of about 700 million adults affected by 2045. Among the several anti-diabetic drug therapies available in the market, Dipeptidyl Peptidase-4 (DPP-4) inhibitors have emerged as a promising therapeutic approach with scope for exploration in the segment of peptidomimetics. OBJECTIVE: Series of proline-containing peptidomimetic compounds were designed and investigated for their drug-likeness through Lipinski's rule of five, lead-likeness through the rule of three, predictive pharmacokinetic studies (absorption, distribution, metabolism, and excretion), and toxicity properties through in-silico approaches. The designed compounds were evaluated for their interactions with binding sites of the enzyme DPP-4 using an extra precision docking approach. METHODS: Proline-containing peptidomimetic compounds were designed rationally. Drug-likeness and lead-likeness properties were calculated using Schrödinger Maestro v11.2 software. ADME and toxicity properties were predicted using PreADMET version 2.0. Docking study was performed using Schrödinger Maestro v11.2 software, and ligands for the study were designed using MarvinSketch software. RESULTS: 5(S)-methyl-L-proline containing 17 ligands were designed. All of them were found to obey Lipinski's rule of five. Compounds were found to have good ADME profile and low toxicity predictions. CONCLUSION: Four compounds were found to have good interactions with DPP-4 binding sites and hence created the scope to develop DPP-4 inhibitors containing 5(S)-methyl-L-proline moiety.

CoMFA, CoMSIA and HQSAR Analysis of 3-aryl-3-ethoxypropanoic Acid Derivatives as GPR40 Modulators.

BACKGROUND: Human GPR40 receptor, also known as free fatty-acid receptor 1, is a Gprotein- coupled receptor that binds long chain free fatty acids to enhance glucose-dependent insulin secretion. In order to improve the resistance and efficacy, computational tools were applied to a series of 3-aryl-3-ethoxypropanoic acid derivatives. A relationship between the structure and biological activity of these compounds, was derived using a three-dimensional quantitative structure-activity relationship (3D-QSAR) study using CoMFA, CoMSIA and two-dimensional QSAR study using HQSAR methods. METHODS: Building the 3D-QSAR models, CoMFA, CoMSIA and HQSAR were performed using Sybyl-X software. The ratio of training to test set was kept 70:30. For the generation of 3D-QSAR model three different alignments were used namely, distill, pharmacophore and docking based alignments. Molecular docking studies were carried out on designed molecules using the same software. RESULTS: Among all the three methods used, Distill alignment was found to be reliable and predictive with good statistical results. The results obtained from CoMFA analysis q2, r2cv and r2 pred were 0.693, 0.69 and 0.992 respectively and in CoMSIA analysis q2, r2cv and r2pred were 0.668, 0.648 and 0.990. Contour maps of CoMFA (lipophilic and electrostatic), CoMSIA (lipophilic, electrostatic, hydrophobic, and donor) and HQSAR (positive & negative contribution) provided significant insights i.e. favoured and disfavoured regions or positive & negative contributing fragments with R1 and R2 substitutions, which gave hints for the modifications required to design new molecules with improved biological activity. CONCLUSION: 3D-QSAR techniques were applied for the first time on the series 3-aryl-3- ethoxypropanoic acids. All the models (CoMFA, CoMSIA and HQSAR) were found to be satisfactory according to the statistical parameters. Therefore such a methodology, whereby maximum structural information (from ligand and biological target) is explored, gives maximum insights into the plausible protein-ligand interactions and is more likely to provide potential lead candidates has been exemplified from this study.

Combiphore (Structure and Ligand Based Pharmacophore) - Approach for the Design of GPR40 Modulators in the Management of Diabetes.

BACKGROUND: Pharmacophore mapping and molecular docking can be synergistically integrated to improve the drug design and discovery process. A rational strategy, combiphore approach, derived from the combined study of Structure and Ligand based pharmacophore has been described to identify novel GPR40 modulators. METHODS: DISCOtech module from Discovery studio was used for the generation of the Structure and Ligand based pharmacophore models which gave hydrophobic aromatic, ring aromatic and negative ionizable as essential pharmacophoric features. The generated models were validated by screening active and inactive datasets, GH scoring and ROC curve analysis. The best model was exposed as a 3D query to screen the hits from databases like GLASS (GPCR-Ligand Association), GPCR SARfari and Mini-Maybridge. Various filters were applied to retrieve the hit molecules having good drug-like properties. A known protein structure of hGPR40 (pdb: 4PHU) having TAK-875 as ligand complex was used to perform the molecular docking studies; using SYBYL-X 1.2 software. RESULTS AND CONCLUSION: Clustering both the models gave RMSD of 0.89. Therefore, the present approach explored the maximum features by combining both ligand and structure based pharmacophore models. A common structural motif as identified in combiphore for GPR40 modulation consists of the para-substituted phenyl propionic acid scaffold. Therefore, the combiphore approach, whereby maximum structural information (from both ligand and biological protein) is explored, gives maximum insights into the plausible protein-ligand interactions and provides potential lead candidates as exemplified in this study.

Drug solubility: importance and enhancement techniques.

Solubility, the phenomenon of dissolution of solute in solvent to give a homogenous system, is one of the important parameters to achieve desired concentration of drug in systemic circulation for desired (anticipated) pharmacological response. Low aqueous solubility is the major problem encountered with formulation development of new chemical entities as well as for the generic development. More than 40% NCEs (new chemical entities) developed in pharmaceutical industry are practically insoluble in water. Solubility is a major challenge for formulation scientist. Any drug to be absorbed must be present in the form of solution at the site of absorption. Various techniques are used for the enhancement of the solubility of poorly soluble drugs which include physical and chemical modifications of drug and other methods like particle size reduction, crystal engineering, salt formation, solid dispersion, use of surfactant, complexation, and so forth. Selection of solubility improving method depends on drug property, site of absorption, and required dosage form characteristics.

Isolation and structure elucidation of major alkaline degradant of ezetimibe.

This work presents the isolation and characterization of the alkaline degradant of Ezetimibe. Ezetimibe, a selective inhibitor of intestinal cholesterol absorption, was subjected to alkaline degradation. Ezetimibe was reacted with 0.1M methanolic sodium hydroxide solution for 10min at 80°C to yield alkaline degradant to an extent of 90% of initial amount of the drug taken. This degradant was detected by high performance liquid chromatography (HPLC) at relative retention time (RRT) of 1.48 with respect to Ezetimibe. HPLC method involved an isocratic elution on a Waters Symmetry C(8) 150mm×4.6mm, 5µm column using ammonium acetate buffer (pH 4.5, 50mM) - acetonitrile (50:50, v/v) as the mobile phase at a flow rate of 1.0mL/min and UV detection at 242nm. The degradant was isolated by preparative HPLC. Purity of the isolated solid was found to be more than 99%. Structure of alkaline degradant was confirmed by LC-MS, (1)H and (13)C NMR and IR spectroscopy. On the basis of spectral data, the structure of the degradant was confirmed as 5-(4-fluorophenyl)-2-[(4-fluorophenyl amino)-(4-hydroxyphenyl)methyl]-pent-4-enoic acid. The route for the formation of this degradant is also proposed. Determining the structures of degradation products arouse during stress testing can be useful for preclinical discovery efforts.

Pharmaceutical importance and synthetic strategies for imidazolidine-2-thione and imidazole-2-thione derivatives.

Imidazole heterocycles containing oxygen or sulfur heteroatoms are of considerable pharmaceutical interest. Many synthetic strategies for imidazolidine-2-thione and imidazole-2-thione derivatives were developed in the past years. They have been well documented by a steadily increasing number of publications and patents. Substituted imidazolidine-2-thiones and imidazole-2-thiones display remarkable biological activities. For instance, imidazole-2-thione has been reported to exhibit antimicrobial, antifungal, antithyroid, antioxidant, cardiotonic, antihypertensive, Dopamine beta-Hydroxylase (DBH) inhibitory and anti-HIV properties. Imidazolidine-2-thione derivatives have been reported to exhibit antimicrobial activity, anti-HIV activity, antifungal activity and so forth. The main purpose of this review is to present a survey of the literature on the different methods of synthesis and reactions involving imidazolidine-2-thione and imidazole-2-thione during the last few decades. This article summarizes an efficient, microwave-assisted method for the liquid-phase combinatorial synthesis of 3,5-disubstituted-thiohydantoin, also reported previously. Synthesis of metal complexes of imidazolidine-2-thione and its derivatives were reported as antimicrobial agents also discussed in the article. Some of the chiral imidazolidine-2-thione N-and C-nucleoside were reported as precursors for the synthesis of azidonucleosides and fluoronucleosides known for their anti-AIDS activity. Metal complexes of heterocyclic thione ligands were reported to possess antifungal activity. Imidazolidine-2-thione and imidazole-2-thione derivatives have found applications in diverse therapeutic areas. Imidazolidine-2-thiones are also used as a chiral auxiliary and ligand for asymmetric catalysis.

Pharmacological Review on Centella asiatica: A Potential Herbal Cure-all.

In recent times, focus on plant research has increased all over the world. Centella asiatica is an important medicinal herb that is widely used in the orient and is becoming popular in the West. Triterpenoid, saponins, the primary constituents of Centella asiatica are manly believed to be responsible for its wide therapeutic actions. Apart from wound healing, the herb is recommended for the treatment of various skin conditions such as leprosy, lupus, varicose ulcers, eczema, psoriasis, diarrhoea, fever, amenorrhea, diseases of the female genitourinary tract and also for relieving anxiety and improving cognition. The present review attempts to provide comprehensive information on pharmacology, mechanisms of action, various preclinical and clinical studies, safety precautions and current research prospects of the herb. At the same time, studies to evaluate the likelihood of interactions with drugs and herbs on simultaneous use, which is imperative for optimal and safe utilization of the herb, are discussed.