Letters in Drug Design & Discovery - Volume 6, Issue 5, 2009

In addition to Rhodamine 123, a progress in genetic engineering allowed the microscopic observation of mitochondria with GFP (mtGFP). Here we evaluated these labeling procedures for their ability to analyze mitochondrial morphology quantitatively. Expression of mtGFP was the optimal procedure to monitor mitochondrial morphology quantitatively, because of photo-stability and precise localization.

The scaled-up preparation of 1H-pyrazole, 1-phenylpyrazole and isoxazole via sonocatalysis is reported. The products were isolated in good yields in short time reaction. These compounds had been assayed for antioxidant activity by ORAC and DPPH methodologies. The results showed that only 1-phenylpyrazole presented good antioxidant activity compared with Trolox^®.

Virtual screening (VS) approaches have been constantly increasing their applications into hit discovery process. In the last few years, we have performed an intensive screening campaign using different in silico strategies and combining them with a biochemistry validation. In the present work, using a consensus docking approach, we have identified a small family of novel protein kinase A (PKA) inhibitors. In particular, an anthraquinone derivative (compound 11) has shown an interesting inhibitory activity versus PKA with an IC50 value of 27 μM.

It has been shown that prostate cancer is associated with elevated androgen biosynthesis; therefore, inhibiting the activity of Cytochrome P450 17 (CYP17) may prevent progression of prostate cancer. In this study we identified, using in silico and experimental methods, two novel steroidal and non-steroidal lead compounds that inhibit the activity CYP17.

To design and synthesize disodium phosphate of novel norcanthridin analogues. All analogues have been screened for their antiproliferative activity in vitro against a panel of tumour cell lines: SMMC-7721, SGC7901, ECA109, A549 and MCF-7 producing IC50 values from 0.15 μM to >50 μM. Compounds 6 and 17 showed potency for the treatment of mammary adenocarcinoma, with IC50 value to MCF-7 cell line comparable to that of cantharidin, which proves that the phosphorylation of norcantharidin analogues is an effective way to increase the activity and solubility.

The synthesis of 6-[3-(3,4,5-trimethoxyphenyl)-2-propenoyl]-2(3H)-benzoxazolone, N-alkyl derivatives and their cytotoxic activity in vitro against the human cell line BV-173 (chronic myeloid leukemia in lymphoblast crisis) are described. 3-Methyl-6-[3-oxo-3-(3,4,5-trimethoxyphenyl)-1-propenyl]-2(3H)-benzoxazolone as a constitutional isomer of 3-methyl-6-[3-(3,4,5-trimethoxyphenyl)-2-propenyl]-2(3H)-benzoxazolone is synthesized and its influence on cytotoxic activity is investigated.

Schiff bases of isatin 1-20 were synthesized and tested for their antiglycation potential. Compound 6 showed 77% inhibition with an IC50= 177.2 ± 0.4 μM, which is an excellent antiglycation activity, if compared with standard aminoguanidine having 85.69% inhibition with an IC50 value 268.7 ± 12.4 μM. Compound 3 showed 71.3% inhibition with an IC50 = 675 ± 0.12 μ/M, which is moderately active antiglycation agent. Although compounds 1, 2, 5, 7-15, and 17- 19 demonstrated over 50% inhibition in preliminary screening, but found inactive when further evaluated for their IC50 values. However, compounds 4, 16, 20, and parent isatin showed less than 50% inhibition and considered to be completely inactive. The structures of all the synthesized compounds were determined by spectroscopic analysis, including UV, IR, mass and 1H-NMR spectrometry. All compounds gave satisfactory elemental analysis.

3-Formylchromone (1), 3-methyl-7-hydroxychromone (2) and Schiff Bases of 3-formylchromone 3-25 have been synthesized and their antibacterial, antifungal and phytotoxic potentials have been evaluated. Thirteen compounds 1- 7, 14, 17-20 and 22 were screened for their antibacterial effects against fourteen Gram positive and sixteen Gram negative bacterial strains using ampicilline as standard drug. Twelve compounds 1-7, 16-18, 21 and 22 were evaluated against fourteen fungal strains. Eighteen compounds 1-4, 6-13, 15, 17, and 23-25 were screened for their phytotoxic potential and showed varying degree of activity. The structures of the synthesized compounds were determined by using spectroscopic techniques including 1H NMR, EIMS, IR and UV. Elemental analysis results were found to be satisfactory.

A number of benzimidazole compounds namely, N-(4-(1H-benzimidazol-2-yl)phenyl)-4-(1H-benzimidazol-2- yl)-benzamide derivatives (8-10) and N-(3- or 4-(1H-benzimidazol-2-yl)phenyl)-2-phenyl-1H-benzimidazole-5- carboxamide derivatives (18-21) were synthesized and antibacterial and antioxidant activities were evaluated. Antibacterial activities of 9, 10, 18, and 20 against MRSA-isolate are equal to ampicillin. Compounds 18, 19, and 21 displayed better antifungal activities against Candida albicans. Antioxidant properties were evaluated by several methods, such as inhibition of lipid peroxidation, superoxide anion production, and DPPH stable free radical, and also their effects on hepatic cytochrome P450 (CYP) dependent ethoxyresorufin O-deethylase (EROD) enzyme were determined in rats in vitro. Compounds 18 and 20 had strong scavenger effect on superoxide anion (90%, and 99%, respectively) at 10-3 M concentration. Compound 19 showed significant inhibition on EROD activity with 98%, which is better than that of caffeine being a specific inhibitor of EROD activity (85%).

The purpose of this study was to evaluate the efficacy of newly synthesized bibenzoimidazolyl derivatives 2(ai) as antimicrobials. These molecules are obtained by the reaction of different pharmaceutically important bioactive aralkyl halides with 1, 7'-dimethyl-2'-propyl-1H, 3'H-[2, 5']bibenzoimidazole in presence of powdered potassium carbonate in DMF solvent under both conventional and microwave methods. The microwave method offers the products 2(a-i) in higher yields compared to conventional method. All the synthesized compounds were characterized by IR, 1H NMR and elemental analysis and evaluated their efficacy as antimicrobials. We observed the significant differences between the antimicrobial activities of the newly synthesized compounds based on their various substituents present at N1 position. Compounds 2h, 2a, 2c, 2e and 2f showed potent antimicrobial activity compared to standard drugs.

A series of chiral compounds were designed and synthesized as novel multidrug resistance (MDR) modulators on the basis of tetrahydroisoquinolines to reverse cancerous MDR on K562 cells and K562/DOX cells by using the MTT assay. The treatment of K562/DOX cells with 9e, 10a and 10e led to increased intracellular accumulation and decreased efflux of doxorubicin. The pharmacological effects of these tetrahydroisoquinolines on P-glycoprotein (P-gp) mediated MDR were much stronger than that of positive control drug verapamil.

Two hydrolytically activated anthraquinone-diclofenac prodrugs have been designed and synthesized. Both prodrugs show significant binding capability to hydroxyapative (HAP), the major component of bone, and hydrolytically activity in simulation physiological conditions in vitro.

As an important part of traditional Chinese medicine (TCM), Chinese Herbal Compound (CHC) is paid more and more attention nowadays. The elucidation of CHC action mechanisms becomes the key problem of how to further develop the TCM and find new novel drugs. Compound prescription is a complex system originating in China that accumulated enormous effective experiences in the thousands of years of its practice. It is very difficult to explain the effectiveness of CHC just using traditional pharmacological methods due to its extremely complex composition, uncertain action mechanism, and too many acting targets. The rapid development of molecular biology and genetics makes it possible to study the mechanism of TCM compounds at the cellular and molecular level. In the past, research of CHC on the organism level has achieved remarkable results. This paper reviews some progresses on the relevant action mechanisms of CHC at molecular level. Recent studies have shown that CHC may play an important role on interfering cell signal transduction pathways, such as apoptosis in tumor cells and regulating the expression of disease-related genes. Further studies should be conducted on its active components by detecting the disease-related genes and drug responsive genes through biochip technology.