SIMPLE AND RAPID HPLC METHOD DETERMINATION OF CSR1 AND CSR2, NEW HETEROCYCLIC THIAZOLIDINEDIONE DERIVATIVES, IN RAT PLASMA

Objective: This study aimed at developing a simple and rapid high-performance liquid chromatography (HPLC) method for determination of two thiazolidinedione derivatives, which were developed as anti-proliferative moieties (CSR1 and CSR2) in rat plasma. In addition, their oral pharmacokinetics were studied.Methods: Drugs were recovered from plasma using acetonitrile and analyzed on a Kromasil C8 column (250 mm × 4.6 mm; 4 μm). HPLC running conditions (0.01M phosphate buffer [pH = 3.0]; flow rate, 0.9 ml/min; at 210 nm; run time, 17 min) were optimized and further used for the determination of pharmacokinetic parameters.Results: At the described chromatographic conditions, CSR1, CSR2 and internal standard (metformin) eluted at 10.44, 9.41, and 3.15 min, respectively. The calibration curves were linear over the range of 0.25–20 µg/ml, with a correlation coefficient>0.999. The quantification limit was 0.25 µg/ml. Within- and between-day precision values were less than 15%. The developed HPLC method was successfully used to study the pharmacokinetics of CSR1 and CSR2 in rats. The developed method was successfully used to study the pharmacokinetics of CSR1 and CSR2. Cmax, AUC0-12, Tmax, t1/2 for CSR1 were 12.2±1.9 µg/ml, 65.34±0.12 µg h/ml, 4.07±0.23 h, t1/2= 4.54±0.12 h, respectively, and those for CSR2 were 10.6±2.2 µg/ml, 62.45±0.31 µg h/ml, 3.56±0.23 h, 3.86±0.09 h, respectively.Conclusion: A specific, linear, and reproducible method was successfully developed and implemented to determine pharmacokinetic activity for two thiazolidinedione derivatives (CSR1 and CSR2), which have been shown to have significant anti-proliferative activity.Â

QUANTITATIVE STRUCTURE-ACTIVITY RELATIONSHIP ANALYSIS OF NOVEL PYRAZOLINE DERIVATIVES USING K NEAREST NEIGHBOUR MOLECULAR FIELD ANALYSIS METHOD

Objective: Malonyl CoA decarboxylase (MCD) enzyme plays important role in fatty acid and glucose oxidation. Inhibition of MCD might turn to a novel approach to treat ischemia. The main objective of this research article was to develop a novel pharmacophore for enhanced activity.Methods: Three-dimensional quantitative structure-activity relationships (3D-QSAR) was performed for pyrazoline derivatives as MCD inhibitors using VLife MDS 4.6 software. The QSAR model was developed using the stepwise 3D-QSAR kNN-MFA method.Results: The statistical results generated from kNN-MFA method indicated the significance and requirements for better MCD inhibitory activity. The information rendered by 3D-QSAR model may render to better understanding and designing of novel MCD inhibitors.Conclusion: 3D-QSAR is an important tool in understanding the structural requirements for the design of novel and potent MCD inhibitors. It can be employed to design new drug discovery

Computer-assisted design of novel leukotriene C4 receptor antagonists

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Ester prodrugs of flurbiprofen: Synthesis, plasma hydrolysis and gastrointestinal toxicity

1164-1168Nine alkyl ester prodrugs of flurbiprofen have been synthesized with an aim to reduce it’s gastrointestinal side-effects. The synthesized prodrugs have been subjected to plasma hydrolysis and gastrointestinal toxicity studies. The chemical structures of the prodrugs have been varied in terms of lipophilicity and reactivity towards hydrolysis. The plasma hydrolysis studies indicate that methyl and propyl prodrugs of flurbiprofen undergo faster hydrolysis as compared to the remaining ester prodrugs. Reduction of ulcer index in rats indicate that n-propyl, iso-propyl, benzyl and cyclopentyl prodrugs of flurbiprofen are significantly (p< 0.05) less irritating to the gastric mucosa as compared to the parent drug, i.e., flurbiprofen

Synthesis and anti-inflammatory activity of fluorinated propanedione derivatives

364-367A new series of five 1-(2′,4′-difluorophenyl)-3-(substituted phenyl)-1,3 propanediones from 2′,4′-difluorinated chalcones have been synthesized. All the compounds (20 mg/kg po) possess anti-inflammatory activity, as reflected by their ability to provide protection (70.00 - 93.00%) against carrageenan induced edema in rat paw. Standard indomethacin provided 79.00% protection at the same dose. The safety of these substituted propanediones are reflected by toxicity studies

Synthesis and anti-inflammatory activity of fluorinated chalcone derivatives

2064-2067A series of twelve 2',4'-difluorinated chalcones have been synthesized by Claisen-Schmidt condensation of 2',4'-difluoroacetophenone with appropriately substituted benzaldehydes. These compounds have then been subjected to preliminary anti-inflammatory screening using the carrageenan induced rat paw oedema model. Compounds 1, 7, 10 and 11 have activity comparable to indomethacin at 20 mg kg⁻¹ by oral route

Retrometabolism based drug targeting- Soft drug approach

721-733Despite considerable progress in medicinal chemistry in the last century, rational drug design that allows the development of effective pharmaceutical agents with minimal side effects is still an elusive goal. The primary causes for side effects are the generalized effect of drug on receptors present throughout the body and uncontrolled drug metabolism. Thus, it has become evident that targeting and metabolism considerations should be an integral part of any drug design process and that the focus should be on increasing activity as well as therapeutic index of the potential drug candidate. Various ideas have been suggested over the years to come up with an ideal approach to drug design. In this review, we shall be dealing with one such approach, that is, the soft drug approach. A soft drug is pharmacologically active as such, and it undergoes a predictable and controllable metabolism to nontoxic and inactive metabolites. The main concept of soft drug design is to avoid oxidative metabolism as much as possible and to use hydrolytic enzymes to achieve predictable and controllable drug metabolism. The discussion shall present an overview on the need for the development of soft drugs, associated terminologies and the different classes of soft drugs

Current status and future prospects of molecular hybrids with thiazolidinedione (TZD) scaffold in anticancer drug discovery

Thiazolidinedione (TZD) containing derivatives have been proved to be promising anticancer agents in preclinical and clinical evaluation phases. Hybrid molecules not just offer the benefits such as enhanced therapeutic effects and improved specificity, but in addition could beat drug resistance, so hybridization of thiazolidinedione scaffold with other anticancer pharmacophoric scaffolds may constitute a hopeful strategy to develop newer and more efficacious anticancer agents. Based on this approach, in past decade, several such hybrids containing TZD scaffold have been reported and evaluated for their antitumor activity, and some of them revealed excellent in vitro potency, indicating their potential as presumed anticancer drugs. This review summarizes the recent advances of TZD hybrids as potential anticancer agents, highlighting their antitumor activity and possible mechanism of action. Structure‐activity relationship (SAR) studies will also be discussed to direct the rational molecular hybridization of TZD scaffolds to design more effective candidates

Mechanistic Insights into Binding of Ligands with Thiazolidinedione Warhead to Human Histone Deacetylase 4

Recently, we have reported that non-hydroxamate thiazolidinedione (TZD) analogs are capable of inhibiting human deacetylase 4 (HDAC4). This study aims at the dissection of the molecular determinants and kinetics of the molecular recognition of TZD ligands by HDAC4. For this purpose, a structure activity relationship analysis of 225 analogs was combined with a comprehensive study of the enzyme and binding kinetics of a variety of HDAC4 mutant variants. The experimental data were rationalized by docking to the two major conformations of HDAC4. TZD ligands are competitive inhibitors and bind via a two-step mechanism involving principal molecular recognition and induced fit. The residence time of 24 g is (34 ± 3) min and thus much larger than that of the canonical pan-HDAC inhibitor SAHA ((5 ± 2) min). Importantly, the binding kinetics can be tuned by varying the structure of the CAP group