Thiazole-Chalcone Hybrids as Prospective Antitubercular and Antiproliferative Agents: Design, Synthesis, Biological, Molecular Docking Studies and In Silico ADME Evaluation.

Compounds bearing thiazole and chalcone pharmacophores have been reported to possess excellent antitubercular and anticancer activities. In view of this, we designed, synthesized and characterized a novel series of thiazole-chalcone hybrids (1-20) and further evaluated them for antitubercular and antiproliferative activities by employing standard protocols. Among the twenty compounds, chalcones 12 and 7, containing 2,4-difluorophenyl and 2,4-dichlorophenyl groups, showed potential antitubercular activity higher than the standard pyrazinamide (MIC = 25.34 µM) with MICs of 2.43 and 4.41 µM, respectively. Chalcone 20 containing heteroaryl 2-thiazolyl moiety exhibited promising antiproliferative activity against the prostate cancer cell line (DU-145), higher than the standard methotrexate (IC50 = 11 ± 1 µM) with an IC50 value of 6.86 ± 1 µM. Furthermore, cytotoxicity studies of these compounds against normal human liver cell lines (L02) revealed that the target molecules were comparatively less selective against L02. Additional computational studies using AutoDock predicted the key binding interactions responsible for the activity and the SwissADME tool computed the in silico drug likeliness properties. The lead compounds generated through this study, create a way for the optimization and development of novel drugs against tuberculosis infections and prostate cancer.

Development and validation of Lenalidomide in human plasma by LC-MS/MS.

A highly sensitive and ultra-fast high performance liquid chromatography- tandem mass spectrometry (LC-MS/MS) assay is developed and validated for the quantification of Lenalidomide in human plasma. Lenalidomide is extracted from human plasma by Liquid- Liquid Extraction by Ethyl Acetate and analyzed using a reversed phase isocratic elution on a XTerra RP18, (4.6 × 50 mM, 5 µm) column. A 0.1% Formic acid: Methanol (10:90% v/v), is used as mobile phase and detection was performed by Triple quadrupole mass spectrometry LC-MS/MS using electrospray ionization in positive mode. Fluconazole is used as the internal standard. The lower limit of quantification is 9.999 ng/mL for Lenalidomide. The calibration curves are consistently accurate and precise over the concentration range of 9.999 to 1010.011 ng/mL in plasma for Lenalidomide. This novel LC-MS/MS method competes with all the regulatory requirements and shows satisfactory accuracy and precision and is sufficiently sensitive for the performance of pharmacokinetic and bioequivalence studies in humans.

Computational Modeling of Polymeric Physicochemical Properties for Formulation Development of a Drug Containing Basic Functionality.

In the present research, predictive models were developed by correlating polymeric properties with characteristics of a formulation containing a drug with basic heterocycle (glipizide). Glipizide tablets containing different polymers from 3 categories (immediate, moderate, and extended release) were prepared and evaluated. Dissolution kinetics indicated Korsmeyer-Peppas as the best-fit model, whereas transportability was influenced by release rate and hydrophobicity of the drug. Calculated polymeric descriptors were correlated with formulation properties for the development of predictive quantitative structure-property relationship models. Regression coefficients and subsequent validation of developed models indicated potential predictability of the model for formulation properties containing any drug with basic heterocycle. Such models could also help to decide the formulation composition for desired characteristics with saving of time and formulation cost.

Experimental and chemoinformatics evaluation of some physicochemical properties of excipients influencing release kinetics of the acidic drug ibuprofen.

In the present study, ibuprofen, a nonsteroidal anti-inflammatory drug was used in the formulation of tablets using three polymers representing different categories (immediate, moderate and extended release). Prepared tablets were evaluated for different post-compression parameters including dissolution and transportability studies. In vitro dissolution studies indicated Korsmeyer-Peppas as a best fit model, however, the transport of the drug was found to be influenced by its rate of release. A total of 118 molecular descriptors representing physicochemical and topological properties of polymeric structure was calculated and correlated with formulation characteristics for model generation. Further, predictive quantitative-structure property relationship models were developed for correlating polymeric descriptors with formulation properties containing acidic drug (ibuprofen). Developed models exhibited good predictability for formulation characteristics as indicated by squared correlation coefficients (>0.9). Such models could have an ability to predict the formulation properties as well as composition for desired characteristics with saving of time, material and cost.

Guggulipid of Commiphora mukul, with antiallodynic and antihyperalgesic activities in both sciatic nerve and spinal nerve ligation models of neuropathic pain.

CONTEXT: Guggulipid is a neutral fraction of ethyl acetate extract of gum resin of the tree Commiphora mukul Engl. (Burseraceae) and used in Ayurvedic medicine for treatment of neurological disorders. OBJECTIVES: The present study was undertaken to assess the antiallodynic and antihyperalgesic activities of guggulipid in rats. MATERIALS AND METHODS: The screening study included the CCI and L5-L6 SNL models of neuropathic pain. Guggulipid (100 and 50 mg/kg) or saline was administered intraperitoneally in a blinded, randomized manner from postoperative day (POD) 7 to 13. Paw withdrawal duration (PWD) to spontaneous pain, chemical allodynia and mechanical hyperalgesia and paw withdrawal latency (PWL) to mechanical allodynia and thermal hyperalgesia were tested before surgery, before and after guggulipid or saline administration (from POD7 to 13) and after the withdrawal of treatment (from POD14 to 20). RESULTS: The activity profiles of the different doses of guggulipid were found to vary with time. In CCI rats, guggulipid (100 and 50 mg/kg) significantly (p < 0.05) reduced the spontaneous pain, mechanical allodynia and mechanical and thermal hyperalgesia responses and the LD50 of guggulipid was 1600 mg/kg. In SNL rats, both doses of guggulipid were found to be ineffective in reversing the spontaneous pain but showing antiallodynic and antihyperalgesic activity. DISCUSSION AND CONCLUSION: The results demonstrated that guggulipid produce antinociception in the peripheral nerve injury (CCI and SNL) models of neuropathic pain. The underlying mechanisms are expected to be modulating microglial activation occurring due to peripheral nerve injury.