STRUCTURAL EXPLORATION AND PHARMACOPHORIC INVESTIGATION OF PYRAZOLE BASED ANALOGS AS NOVEL HISTONE DEACETYLASE 1 INHIBITOR USING COMBINATORIAL STUDIES

Objective: Histone deacetylase inhibitors (HDACi) have four essential pharmacophores as cap group, connecting unit, a linker moiety and zinc binding group for their anticancer and histone deacetylase (HDAC) inhibition activity. On the basis of this fact, the objective of this research was to evaluate the exact role of pyrazole nucleus as connecting unit and its role in the development of newer HDACi.Methods: Ligand and structure-based computer-aided drug design strategies such as pharmacophore and atom based 3D QSAR modelling, molecular docking and energetic based pharmacophore mapping have been frequently applied to design newer analogs in a precise manner. Herein, we have applied these combinatorial approaches to develop the structure-activity correlation among novel pyrazole-based derivatives.Results: the Pharmacophore-based 3D-QSAR model was developed employing Phase module and e-pharmacophore on compound 1. This 3D-QSAR model provides fruitful information regarding favourable and unfavourable substitution on pyrazole-based analogs for HDAC1 inhibition activity. Molecular docking studies indicated that all the pyrazole derivatives bind with HDAC1 proteins and showed critical hydrophobic interaction with 5ICN and 4BKX HDAC1 proteins.Conclusion: The outcome of the present research work clearly indicated that pyrazole nucleus added an essential hydrophobic feature in cap group and could be employed to design the ligand molecules more accurately

Exploration of anticancer potential of hydroxamate derivatives as selective HDAC8 inhibitors using integrated structure and ligand based molecular modeling approach

136-147Recently, histone deacetylase inhibitors are evolving as an exhilarating new class of promising antitumor agents for the treatment of multiple malignancies. It may play a pivotal role as a therapeutic target for challenging the globally wide spread disease, cancer. At the same time, the prediction of biological activity of novel compounds, which was once a major challenge in drug design, is also pacing up its speed. This computational study has been performed in Schrodinger suite packages such as sitemap generation, grid formation, Glide for docking, Quikprop for ADME analysis, e-pharmacophore post docking script and Phase for 3D QSAR models designing, that all are available in Maestro version 9.3. Docking not only helps in predicting the preferred orientation of ligand with its target receptor, but also the binding affinity between the ligand and receptor. The application of Phase and e-pharmacophore script predicts some computational models of the provided ligands using 3D QSAR method. This decreases the cost and time of biological experiments. Glide XP reveals that compound 21 with the highest score value as the best compound from the dataset. Also, it shows good R2=0.9834, Q2= 0.7753, stability = 0.5407 and low standard of deviation SD=0.1085 for hypothesis ADDRR.1601, for the PLS factor 5. The outcome of these studies suggests compound 21 as a potential drug molecule for HDAC targets

Exploration of anticancer potential of hydroxamate derivatives as selective HDAC8 inhibitors using integrated structure and ligand based molecular modeling approach

Recently, histone deacetylase inhibitors are evolving as an exhilarating new class of promising antitumor agents for the treatment of multiple malignancies. It may play a pivotal role as a therapeutic target for challenging the globally wide spread disease, cancer. At the same time, the prediction of biological activity of novel compounds, which was once a major challenge in drug design, is also pacing up its speed. This computational study has been performed in Schrodinger suite packages such as sitemap generation, grid formation, Glide for docking, Quikprop for ADME analysis, e-pharmacophore post docking script and Phase for 3D QSAR models designing, that all are available in Maestro version 9.3. Docking not only helps in predicting the preferred orientation of ligand with its target receptor, but also the binding affinity between the ligand and receptor. The application of Phase and e-pharmacophore script predicts some computational models of the provided ligands using 3D QSAR method. This decreases the cost and time of biological experiments. Glide XP reveals that compound 21 with the highest score value as the best compound from the dataset. Also, it shows good R2=0.9834, Q2= 0.7753, stability = 0.5407 and low standard of deviation SD=0.1085 for hypothesis ADDRR.1601, for the PLS factor 5. The outcome of these studies suggests compound 21 as a potential drug molecule for HDAC targets

IN VIVO ANTICANCER EVALUATION OF (2-AMINO-3,4,5-TRIMETHOXYPHENYL) (6-METHOXY-1H-INDOL-3-YL) METHANONE

Objective: The design and development of Combretastatin A-4 analogues as anticancer agent has always attracted the attention of scientific community involved in anticancer research. The aim of the present work was to investigate the in-vivo cytotoxic activity of a novel CA-4 analogues i.e., (2-amino-3,4,5-trimethoxyphenyl)(6-methoxy-1H-indol-3-yl)methanone.Method: The in-vivo cytotoxic activity of test compound was examined using Human Tumor Xenograft model on MCF-7 cancer cell line in Balb/c mice.Result: The test compound exhibited excellent cytotoxic activity against MCF-7 (0.013 µM), and colon HT-29 (0.143 µM), slightly higher than CA-4 activity. Relative Tumor Volume (RTV) value was found to increase rapidly in control group A during the period of 1 to 18 days indicating the higher growth rates of tumor. On the other hand group B and C showed slower growth rate of tumor as a result of treatment with CA-4 and test compound, respectively. The group B treated with CA-4 (5 mg/kg) showed significant inhibition in tumor growth during day 5 to 18 with %TGI in range of 47.24%-62.31% as compared to control group. The group C treated with test compound  (5mg/kg) caused significant inhibition in tumor growth during day 5 to 18 with %TGI in range of 55.66%-75.93% as compared to control group. The % survival value was found 100% indicating that CA-4 and test compound were nontoxic at the dose of 5mg/kg under experimental conditions.Conclusion: The parameters of In-vivo anticancer evaluation i.e., relative tumour volume and % tumor growth inhibition showed better anticancer potential of test compound. It was further supported by non-toxic nature of test compound as indicated by 100% survival value determined at the dose of 5 mg/kg during in-vivo studies

Synthesis and characterization of N-Mannich based prodrugs of ciprofloxacin and norfloxacin: In vitro anthelmintic and cytotoxic evaluation

Prodrugs, the inert derivatives of existing drugs have successfully contributed to the modification of their physicochemical properties. The improved antimicrobial potential due to enhanced lipophilicity of some of the synthesized prodrugs of antibacterial agents by various schemes has already been reported. In the current study, synthesis, characterization, and biological evaluation of some more lipid based prodrugs/compounds of ciprofloxacin and norfloxacin has been carried out. The synthesized prodrugs/compounds have been screened for anthelmintic activity using Indian earthworms and cytotoxic activity against human lung cancer cell lines A-549 employing sulforhodamine B (SRB) assay method. The prodrugs FQF1, 6b, 6c, and 6k were found to possess promising anthelmintic activity due to improved partition coefficient. Growth of selected cells lines was found to decrease with increase in concentration of prodrugs as compared to parent drug. Prodrug, 6k having GI50 value 28.8, has been proved to be the most active among all the synthesized prodrugs. Results of present investigation reveal that some of the synthesized prodrugs/compounds were found to possess promising biological activity

Ebola virus disease: past, present and future

Ebola virus disease is one of the most deadly ailments known to mankind due to its high mortality rate (up to 90%) accompanying with the disease. Ebola haemorrhagic fever (EHF) is an infectious disease of animal that can be transmitted to both human and non-human primates. The first epidemic of EHF occurred in 1976 in the Democratic Republic of the Congo. The incubation period of ebola is less than 21 days. Ebola virus infections are depicted by immune suppression and a systemic inflammatory response that leads to damage of the vascular, coagulation and immune systems, causing multi-organ failure and shock. Five genetically distinct members of the Filoviridae family responsible for EHF are as follows: Zaire ebolavirus, Sudan ebolavirus, Côte d’Ivoire ebolavirus, Bundibugyo ebolavirus and Reston ebolavirus. The ongoing 2014 West Africa ebola epidemic has been considered as the most serious panic in the medical field with respect to both the number of human cases and death toll. The natural host for ebola virus is unknown, thus it is not possible to carry out programs to regulate or abolish virus from transmission to people. The ebola virus infection provides little chance to develop acquired immunity causing rapid progression of the disease. It is pertinent to mention that at present, there is no antiviral therapy or vaccine that is helpful against ebola virus infection in humans. The impediment of EHF necessitates much better understanding of the epidemiology of the disease, particularly the role of wildlife, as well as bats, in the spread of ebola virus to humans

Novel UV spectrophotometer methods for quantitative estimation of metronidazole and furazolidone using mixed hydrotropy solubilization

Two simple, accurate, novel, safe and precise methods were developed for the simultaneous estimation of poorly water-soluble drugs Metronidazole (MTR) and Furazolidone (FZ) in a tablet dosage form using 2 M sodium acetate and 8 M urea solution (50:50%V/V) as a mixed hydrotropic solution. MTR and FZ show maximum absorbances at 319 and 364 nm, respectively. Sodium acetate and urea solution did not show any absorbance above 240 nm and thus no interference in the estimation of drugs was seen. MTR and FZ follow Beer’s law in the concentration range of 10–50 μg/ml and 5–25 μg/ml (r2 = 0.9992 and 0.9996). Method-A employs the simultaneous equation method using 319 and 364 nm as two analytical wavelengths, method-B employs the absorption ratio method, which uses 339.2 and 364 nm as two analytical wavelengths for estimation of MTR and FZ. The mean percent label claims of tablet dosage were found to be 98.715 ± 1.012 and 98.74 ± 0.912 in method A, 98.99 ± 0.872 and 97.89 ± 0.903 in method B for MTR and FZ, respectively. The developed methods were validated according to ICH guidelines and values of accuracy, precision and other statistical analysis were found to be in good accordance with the prescribed values therefore both methods can be used for routine monitoring of MTR and FZ in industry in the assay of bulk drug and tablets

Combretastatin A-4 based thiophene derivatives as antitumor agent: Development of structure activity correlation model using 3D-QSAR, pharmacophore and docking studies

The structure and ligand based synergistic approach is being applied to design ligands more correctly. The present report discloses the combination of structure and ligand based tactics i.e., molecular docking, energetic based pharmacophore, pharmacophore and atom based 3D-QSAR modeling for the analysis of thiophene derivatives as anticancer agent. The main purpose of using structure and ligand based synergistic approach is to ascertain a correlation between structure and its biological activity. Thiophene derivatives have been found to possess cytotoxic activity in several cancer cell lines and its mechanism of action basically involves the binding to the colchicine site on β-tubulin. The structure based approach (molecular docking) was performed on a series of thiophene derivatives. All the structures were docked to colchicine binding site of β tubulin for examining the binding affinity of compounds for antitumor activity. The pharmacophore and atom based 3D-QSAR modeling was accomplished on a series of thiophene (32 compounds) analogues. Five-point common pharmacophore hypotheses (AAAAR.38) were selected for alignment of all compounds. The atom based 3D-QSAR models were developed by selection of 23 compounds as training set and 9 compounds as test set, demonstrated good partial least squares statistical results. The generated common pharmacophore hypothesis and 3D-QSAR models were validated further externally by measuring the activity of database compounds and assessing it with actual activity. The common pharmacophore hypothesis AAAAR.38 resulted in a 3D-QSAR model with excellent PLSs data for factor two characterized by the best predication coefficient Q2 (cross validated r2) (0.7213), regression R2 (0.8311), SD (0.3672), F (49.2), P (1.89E-08), RMSE (0.3864), Stability (0.8702), Pearson-r (0.8722). The results of these molecular modeling studies i.e., molecular docking, energetic based pharmacophore, pharmacophore and atom based 3D-QSAR modeling would be fruitful to improve the pharmacophore for design of novel combretastatin A-4 based thiophenes for anticancer activity