Abstracts


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Synthesis and Urease Inhibitory Properties of Some New N⁴-Substituted 5-Nitroisatin-3-thiosemicarbazones
H. Pervez, N. Manzoor, M. Yaqub, A. Khan, K.M. Khan, Faiz-ul-Hassan Nasim and M.I. Choudhary

A series of seventeen N⁴-substituted 5-nitroisatin-3-thiosemicarbazones 2a-2q has been synthesized and screened for in vitro urease inhibitory activities. Compounds 2a-2d, 2g, 2i, 2j and 2q were found to be potent inhibitors of the enzyme. Of these, 2c exhibited a potent inhibitory activity with IC₅₀ value 16.4 µM and may act as a lead molecule for further studies. Structure-activity relationship studies revealed that electronic effects of the substituents play an important role in the urease inhibitory potential of the synthetic compounds.


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Exploring 3D-QSAR for Ketolide Derivatives as Antibacterial Agents Using CoMFA and CoMSIA
Q.-L. Song, P.-H. Sun and W.-M. Chen

Comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) were performed on a series of ketolide derivatives as antibacterial agents. The 3D-QSAR models resulted from 42 molecules gave r²_cv values of 0.699 and 0.630, r² values of 0.945 and 0.925. The predictive ability of CoMFA and CoMSIA, determined using a test set of 10 compounds, gave predictive correlation coefficients of 0.849 and 0.786, respectively. The results provided insight for predictive and diagnostic aspects of ketolide derivatives for better antibacterial activity.


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DPPH Scavenging Assay of Novel 1,3-disubstituted-1H-pyrazol-5-ols and their in silico Studies on Some Proteins Involved in Alzheimer’s Disease Signaling Cascade
B.K. Sarojini, M. Vidyagayatri, C.G. Darshanraj, B.R. Bharath and H. Manjunatha

A series of new 1,3-disubstituted-1H-pyrazol-5-ols (3) which are the analogues of known radical scavenger ‘edaravone’ are synthesized, characterized and evaluated for DPPH scavenging capacity. The docking studies are carried out for these compounds in the enol form and also in the respective keto form against the proteins and peptides involved in Alzhemier disease signal cascade. Some of them showed good radical scavenging capacity and molecular binding.


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Synthesis of Coumarin linked Naphthalimide Conjugates as Potential Anticancer and Antimicrobial Agents
A. Kamal, S.F. Adil, J.R. Tamboli, B. Siddardha and U.S.N. Murthy

A series of new coumarin linked naphthalimides (16a-g; 18a-g) was synthesised and evaluated for their in vitro anticancer activity against six cancer cell lines. Most of the compounds investigated have shown good to moderate anticancer activity against colon, breast and lung cancer cell lines. Thermal denaturation studies indicated that some compounds exhibited DNA binding ability. They were also found to be active against gram-positive and gram-negative bacterial strains as well as a few fungal strains.


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QSAR Analysis of Isosteviol Derivatives as α-Glucosidase Inhibitors with Element Count and Other Descriptors
N.S.H.N. Moorthy, M.J. Ramos and P.A. Fernandes

A QSAR analysis of 25 isosteviol derivatives was carried out to interpret the relationship between structural properties and α-glucosidase inhibitory activity. The selected significant models have good predictive ability, which was validated by LOO cross validation techniques (Q²>0.6) and which gives significant Cook´s distances (< 1) and other statistical parameters. The selected significant models suggest that the nitrogen count amongst those that contribute most to α-glucosidase inhibitory activity is positively accounted for activity. Besides nitrogen count, the XlogP (by Kellog method) and the SlogP (by Audry method) mosthydrophobichydrophilic distance descriptors also contribute positively and the Quadrupole2, Avg+P and SAMH parameters are negatively contributed for the activity while a triple bonded atom connected with another triple bonded atom by four or seven bonds distance is important for the activity. In conclusion, the presence of nitrogen atom along with the hydrophobic-hydrophilic distance in the molecule is important for the α-glucosidase inhibitory activity.


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Novel 3-(1-acetyl-5-(substituted-phenyl)-4,5-dihydro-1H-pyrazol -3-yl)-7-fluoro-2H chromen-2-one Derivatives: Synthesis and Anticancer Activity
Z.-Y. Cai, Y. Yang, X.-H. Liu and X.-B. Qi

A series of novel coumarin derivatives containing 4,5-dihydropyrazole moiety as potential telomerase inhibitors were synthesized. The bioassay tests showed that compound 3b exhibited potentially high activity against human gastric cancer cell SGC-7901 with IC₅₀ value was 2.98±0.16. Docking simulation was performed to position compound 3b into the telomerase (3DU6) active site to determine the probable binding model. The result shows that some coumarin containing 4,5-dihydropyrazole moiety can combine well with the telomerase active site and may have use as potential telomerase inhibitors.


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Chemometric Evaluation of the Significance of Molecular Structural Descriptors on Binding of Acridinone Derivatives to DNA
M. Koba and T. Baczek

The acridinones represented by imidazo- and triazoloacridinones are a group of potential antitumor agents. The most active derivative, the antitumor imidazoacridone C-1311 expected to be used as a topoisomerase II poison, has been recently selected for extended preclinical and clinical trials. In the current study, one of the chemometric techniques, namely factor analysis was performed to model the relationships between several molecular structural descriptors and the ability of the selected acridinone derivatives to the noncovalent binding to DNA. The noncovalent binding to DNA was measured and expressed as DNA-duplexes stabilization. Factor analysis led to extract four main factors with eigenvalues higher than 1 and the total variance explanation was on the level of 84.5% (by the first three principal component). Among the molecular structural descriptors studied, the most significant influence was recognized for lipophilicity parameters, quantum-chemical parameters and electron affinity specifying parameters. Importantly, distribution of individual compounds on the plane determined by two principal components produced patterns in good agreement with their ability to noncovalent binding to DNA as well as with their chemical structures. Finally, the proposed FA-based strategy enabled to classify the tested acridinone derivatives in view of their ability to noncovalent interaction with DNA.


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Application of Molecular Topology to the Search of Novel NSAIDs: Experimental Validation of Activity
M. M. Galvez-Llompart, R.M. Giner, M.C. Recio, S. Candelettiand R. Garcia-Domenech

A topological-mathematical model obtained by linear discriminant analysis has been used to the search of new nonsteroidal antinflammatory drugs (NSAIDs). After carrying out an in silico screening based on such a model, on the Aldrich database, new structures potentially active were selected. Among these structures stand fourteen compounds, from which only one had been previously recorded as NSAID in the literature. The experimental tests performed on the remaining substances demonstrated that several compounds showed either in vitro or in vivo or both activity. Moreover, four compounds, namely 1,3-bis(benzyloxycarbonyl)-2-methyl-2-thiopseudourea, 4,6-dichloro-2-methylthio-5-phenylpyrimi-dine, 2-chloro-2',6'-acetoxylidide and trans-1,3-diphenyl-2-propen-1-ol, showed a significant in vivo antinflammatory activity as compared to the reference drug (indomethacin). These results reinforce the role of Molecular Topology as a useful tool for drug discovery.


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Self-Organizing Molecular Field Analysis on Pyridazine Analogues as Protein Tyrosine Phosphatase 1B (PTP 1B) Inhibitors
S. Thareja, S. Aggarwal, T. R. Bhardwaj and M. Kumar

A 3D-QSAR study has been performed using Self-organizing molecular field analysis (SOMFA) on a novel class of pyridazine analogues as non-competitive and reversible inhibitors of PTP 1B. SOMFA is a novel 3D-QSAR methodology, similar to both comparative molecular field analysis (CoMFA) and molecular similarity studies. SOMFA studies have been performed to correlate chemical structures of pyridazine analogues with their observed PTP 1B inhibitory activity. The master grid obtained for the various SOMFA models indicates electrostatic and shape potential contributions. These can be mapped back onto the structural features relating to trends in activities of the molecules. On the basis of the spatial arrangement of the various shape and electrostatic potential contributions, new inhibitors of PTP 1B can be designed with improved spectrum of activity for the management of type 2 diabetes.


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The Cytotoxicity of Titanocene Y Against CAKI-1 Cells: An In Vitro Formulation Study
M. Hogan, B. Gleeson and M. Tacke

Various formulations containing titanocene Y (bis-[(p-methoxybenzyl)cyclopentadienyl] titanium (IV) dichloride) were prepared and tested in vitro on CAKI-1 cells in order to compare the cytotoxic behaviour of the compound with different formulation reagents. Formulations were prepared with non-ionic surfactants like Cremophor EL and Tween 80, pegylated reagents PEG-400 and Solutol HS 15, and the co-solvent Soluphor P (pyrrolidone-2). All formulations were tested with and without the presence of dimethylsulfoxide. When the lipophilic derivative titanocene Y was formulated with Soluphor P and tested in vitro, an IC50 value of 10 (+/- 1) µM was observed, which is a 3-fold increase in cytotoxicity when compared to the DMSO formulation. In order to compare to a more hydrophilic titanocene this Soluphor P formulation method was extended to the water-soluble titanocene G, which is a dihydrochloride derivative of bis-[(1-methyl- 3-dimethylaminomethylindol-2-yl)cyclopentadienyl] titanium (IV) dichloride). When titanocene G was tested in vitro in the presence of Soluphor P, it resulted in a 10-fold increase in cytotoxicity with an IC50 value of 0.71 (+/- 0.24) µM against CAKI-1 cells.