Letters in Drug Design & Discovery - Volume 5, Issue 6, 2008

A number of Mannich bases were synthesized by a reaction between 6-(4-chlorocinnamoyl)-2(3H)-benzoxazolone, formaldehyde and secondary amines. The structures of the compounds were confirmed by elemental analysis, IR and 1H-NMR spectra. The tested compounds exhibited concentration-dependent cytotoxic effects at low micromolar concentrations with IC50 values ranging between 1.4 and 30.9 μM.

The synthesis and stability assay of 4-methylumbelliferyl (1→3)-β-D-pentaglucoside 3 are described. The acid-solubilized (1→3)-β-D-oligoglucosides were prepared by partial acid hydrolysis of glucan. The peracetylated (1→3)-β-D-pentaglucoside 1 was obtained by isolation of peracetylated (1→3)-β-D-oligoglucoside mixture. The peracetylated 4-methylumbelliferyl (1→3)-β-D-pentaglucoside 2 was synthesized by treating compound 1 with the 4-methylumbelliferone and a Lewis acid (SnCl4) catalyst. NaOMe in dry methanol was used for the deacetylation of the blocked derivative, to give the target compound 3 in an overall yield of 35%. In the activity assays of fungal β-glucosidase, it indicates that compound 3 is much more stable than the corresponding pentasaccharide.

A series of some newer 2, 5-disubstituted-1, 3, 4-oxadiazole derivatives (5a-5j) were synthesized and evaluated for anticancer activity. Compound 5f showed excellent activity in majority of the cell lines.

PDK1 is pivotal in the development and progression of several cancers. A 3D pharmacophore was developed for pyrazole derivatives displaying anti-proliferative activity and PDK1 inhibition. The pharmacophore was utilized in the design of benzimidazole analogs. Our preliminary results indicate the pharmacophore should be useful in designing PDK1 inhibitors and anti-proliferative agents.

Comparative molecular field analysis (CoMFA) studies were conducted on a series of 100 isoniazid derivatives as anti-tuberculosis agents using two receptor-independent structural data set alignment strategies: (1) rigid-body fit, and (2) pharmacophore-based. Significant cross-validated correlation coefficients were obtained (CoMFA(1), q2 =0,75 and CoMFA(2), q2 = 0.74), indicating the potential of the models for untested compounds. The models were then used to predict the inhibitory potency of 20 test set compounds that were not included in the training set, and the predicted values were in good agreement with the experimental results.

A series of new 7-aminosteroid derivatives were evaluated for their in vitro antimicrobial properties against human pathogens such as Gram positive bacteria. All the compounds present excellent activities against Gram-positive bacteria exhibiting similar results against Staphylococcus aureus and Streptococcus faecalis with MICs varying from 1.56 to 12.5 μg/mL. Moreover, all these considered derivatives possess MICs against Gram-negative Escherichia Coli bacteria (MIC varying from 2.5 to 10 μg/mL) making them particularly suitable for topical antibacterial use.

Applicability of HPLC based models for calculating partition coefficient (logP) of steroids was investigated. Retention time was used to calculate retention factor (logK'), isocratic (CHIi) and gradient (CHIg) Chromatography Hydrophobicity Index. CHIi was shown to be an accurate logP predictor for selected steroids and as such offer an alternative to the shake flask method.

A number of urea derivatives were synthesized and screened for their urease and α-chymotrypsin inhibition effects, whereby one of the compounds, N-4-nitrophenyl-N’-4’-nitrophenylurea (3), showed strong urease inhibition (IC50 = 1.25μM). We found that the same compound is also an efficient α-chymotrypsin inhibitor having an IC50 value of 3.15μM.

The object of this work is to investigate physicochemical characteristics and inclusion behavior of binary systems based on cyclodextrin polymer (Poly-CD) or native cyclodextrins (CDs) with a poorly water-soluble, nonsteroidal anti-inflammatory drug, nimesulide (NIM) chemically, N-(4-nitro-2-phenoxyphenyl)methanesulfonamide. Our formulations were studied in solution and solid-state. Drug-cyclodextrin solid binary systems were prepared by the freezedrying method. Phase solubility study was used to evaluate the interaction in solution, between NIM/CDs and NIM/(Poly- CD). The stability constants of NIM/CDs and NIM/(Poly-CD) complexes were calculated using the phase solubility method. The apparent solubility of NIM was enhanced especially with Poly-α-CD (up to78-fold) in neutral aqueous solutions without any organic solvents or surfactants. Copmlexes formation was confirmed, in the solid state, by differential scanning calorimetry, infrared spectroscopy and DRX. Complexation spontaneity of drug with cyclodextrin polymers was highlighted using ΔG°values.

Time-resolved FRET (TR-FRET) assays offer advantages over fluorescence polarization (FP) assays including reduced optical interference from compound autofluorescence or precipitation, and a greater ability to resolve potencies of tight-binding ligands. Here, we demonstrate the facile conversion of FP assays to a TR-FRET format using nuclear receptor ligand binding assays as examples.

This is to notify that the article entitled “An Alternative Method for the Synthesis of Tetraketones and their Lipoxygenase Inhibiting and Antioxidant Properties” by K.M. Khan, G.M. Maharvi, S.A. Nawaz, S. Perveen and M.I. Choudhary, published in Letters in Drug Design & Discovery, June 2007, Vol. 4, No. 4, pp. 272-278, was found to be identical to the one published in Journal of Enzyme Inhibition and Medicinal Chemistry, February 2008, Vol. 23, No. 1, pp. 62-69, entitled “Mild and Efficient Synthesis of New Tetraketones as Lipoxygenase Inhibitors and Antioxidants”. The authors of the article have decided to withdrawn their submission from both the journals.