Letters in Drug Design & Discovery - Volume 9, Issue 8, 2012

[SnPh3(DMNI)] (1), (2,6-dimethoxynicotinic acid (DMNIH)) was prepared by the reaction of SnPh3Cl with DMNIH. Molecular structure of 1 was determined by X-ray diffraction studies. The cytotoxic activity of 1 was tested against tumour cell lines human cervical adenocarcinoma HeLa, human myelogenous leukemia K562, human malignant melanoma Fem-x and normal immunocompetent cells, non-stimulated peripheral blood mononuclear cells (PBMC-PHA) and with phytohemagglutinin stimulated peripheral blood mononuclear cells (PBMC+PHA) showing a very high antiproliferative activity against tumour cell lines with IC50 values (after 72 h of treatment) in the range of 46-65 nM. This toxicity becomes lower against normal immunocompetent cells (IC50 values in the range of 88-148 nM) indicating some degree of selectivity towards cancer cell lines.

Novel succinimide derivatives based on nimesulide were designed as potential anticancer agents and their synthesis was carried out using a straightforward and atom economic method. The key step of this methodology involved an Aza-Michael addition of several nitrogen nucleophiles to the corresponding N-aryl maleimide derivatives prepared efficiently from nimesulide via a two-step process. A number of compounds containing -NHX (X = Ar, NHCOR, NHAr etc) at the C-3 of the succinimide were prepared in good yields. A number of compounds synthesized were tested for their cytotoxicity in vitro against human colon cancer cell lines and some of them showed promising activities.

Glycosylation has been widely used to improve the efficacy and bioavailability of certain anticancer drugs. In the present work, artemisinin glucoside was synthesized through glycosylation, and its antimuor effect was investigated both in vivo and in vitro by detecting its effects on suppressing U14 xenograft tumor proliferation, on inducing Hela cell apoptosis, and on affecting p53, Bcl-2 and Bax expressions. In vivo, the tumor growth behaves as a time- and dosedependent inhibitory effect when treated with artemisinin glucoside, and in vitro the apoptosis of Hela cells is induced by adding up to 40 or even 20 μM artemisinin glucoside. Molecular mechanism and structural basis of artemisinin glucoside interactions with galectin were investigated in detail through molecular docking and structure analysis. All of these findings come together to suggest that artemisinin glucoside exhibits a potent antitumor activity through the activation of cytochrome c pathway and the induction of apoptosis.

Non-steroidal anti-inflammatory drugs (NSAIDs) are evolving as the prototypical chemopreventive agents against colon cancer, an opinion nowadays reinforced by a substantial form of epidemiological, animal, and basic science data. Apart from their preventive role in the prophylaxis and management of colon cancer, NSAIDs at lower doses are widely employed in permutation with conventional anticancer drugs in order to reduce the dose related cytotoxic effects and to impart additive or synergistic therapeutic effect. In vitro cell-based cytotoxicity assays are effective techniques for hit ranking and lead optimization at the early stage of drug discovery. The present study has been focused on in silico screening and prediction of in vitro cytotoxicity (or growth inhibitory activity, GI50) of heterogeneous group of NSAIDs having flexibility in structure and cytotoxicity activity against DLD-1 and SW-480 colon cancer cell lines using 3DQSAR (3-dimensional quantitative structural activity relationship) SOMFA (self-organizing molecular field analysis) studies. Analysis of 3D-QSAR models through electrostatic and shape grids provide useful information about the steric, electrostatic potential contributions along with the combination of log P, total dipole moment and molar refractivity (MR) on GI50. The results obtained provided an insight on NSAIDs with optimum in vitro cytotoxicity activity and improved therapeutic profile.

Type II diabetes Mellitus is one of the common diseases worldwide and often recognized as life style disease. The major symptom of this disease is an increase in blood glucose level resulting in polydypsia, polyuria and polyphagia. Molecular modeling was used to design the drug molecules. Docking results showed imidazolidine derivatives have good interaction with the DPP IV receptors. The compound IMA4 showed good orientation and score. This novel compound represents potential scaffold for the design of clinically useful DPP IV inhibitors.

2-Chloro-1,3-dioxo-2,3-dihydro-1H-inden-2-yl acetate (1) and N11,N11'-benzene-1“,2”-diamino-11H,11'H- [11,11'-biindeno[1,2-b]quinoxaline] (2) were synthesized and structures have been established on the basis of spectral analysis. The structure of (2) has also been confirmed by single crystal X-ray analysis. Both the synthesized compounds were screened for their anticancer, antimicrobial and cholinesterase enzymes inhibitory activities. Compound (2) showed good anticancer and antibacterial activities. Both 1 and 2 showed good anticandida activity comparable to that of clinically used antifungal agent, amphotericin B. These compounds were found to have contrasting cholinesterase enzymes inhibitory activities. Compound 1 showed highly selective inhibitory activity against butyrylcholinesterase enzyme whereas 2 was more selective inhibitor of acetylcholinesterase with moderate inhibitory activity against butyrylcholinesterase. Structural modification of 1 to 2 has major implication on their antimicrobial and cholinesterase enzymes inhibitory bioactivities.

Four Caudatin glycosides were synthesized from Caudatin by reaction with tetra-O-actyl-D-glycosyl bromide catalyzed by CdCO3 and tested in vitro for their antiproliferative activities against human lung cancer A549, human prostate cancer PC3, human liver cancer BEL-7402 and human gastric cancer SGC-7901 cells. The IC50 values indicated that the inhibitory effect of Caudatin-tetra-O-actyl-D-glycosides was superior or comparable to Caudatin against most of the tested cells, worthy of further investigation.

Nineteen novel 4-indolyl-5-phenyl(indolyl)-1,2-dihydropyrazol-3-ones were synthesized and evaluated for their GSK-3β inhibitory activity. Half of the tested compounds showed moderate GSK-3β inhibitory activity. Preliminary structure-activity relationships were discussed, which showed that the presence of 3,4,5-trimethoxy group on the benezene ring enhanced potency while the existence of an electron-withdrawing group at the 4-position of the benezene ring deceased activity. Compounds 11c and 14, the most potent compounds with IC50 values of 9.28 and 8.98 μM, respectively, would be promising candidates for further development of novel GSK-3β inhibitors.

Solid state structure information for (2E)-1-(5-bromothiophen-2-yl)-3-[4-(dimethylamino)phenyl]prop-2-en-1- one is revealed by using single crystal X-ray diffraction study. The conformation of the molecule in solid state is used to carry out the drug design studies like structure optimization by Density Functional Theory (DFT) and Induced Fit Docking (IFD) study on human aldose reductase. The asymmetric unit of (2E)-1-(5-bromothiophen-2-yl)-3-[4- (dimethylamino) phenyl]prop-2-en-1-one, C15H14Br N O S, contains just one molecule. The crystal structure displays intermolecular C11---H11...O3 & C17---H17...O3 hydrogen bonds. Docking experiments were conducted for the crystal structure conformation inside AR active site using Maestro 9.1v. from Schrodinger Suite 2009. GLIDE scoring function was used to calculate the dock score. The co-crystallized inhibitor (IDD594) in X-ray structure of AR-inhibitor complex (PDB id: 1USO) was taken as reference to correlate the results. In docking study the molecule has shown good binding capacity with a dock score of - 9.53891. The negative score for docking experiment signifies favorable positioning of ligand inside AR active site and the value is comparable to that of reference substrate (-10.6841). Results suggested that the molecule can be used as starting point for the development of human aldose reductase inhibitor in fragment based design.

A series of 3-substituted-thiochroman-4-one semicarbazone derivatives were designed based on the bioisosterism and combination principle in drug design. The target compounds were prepared from 3-substitutedthiochroman- 4-one (1) and 4-substituted-semicarbazides( 2), their structures were confirmed by MS and 1H NMR. The antifungal assay was carried out in vitro by twofold dilution. The result shows that all the compounds are of antifungal activities against the tested fungi at different levels.

Diverse polyfunctionalized tetrahydroquinolines, easily prepared using BF3 .OEt2-catalyzed three component imino Diels-Alder reaction, were tested in vitro against Trypanosoma cruzi and Leishmania chagasi parasites and also for cytotoxicity using Vero and THP-1 mammalian cell lines. These studies showed that the most active compound was 7h (IC50 5.77 ± 0.21; IC90 40.43 ± 1.58 μM for T. cruzi and IC50 0.27 ± 0.03; IC90 2.16± 0.37 μM for L. chagasi) has selective index (SI) values greater than the reference drugs (SI > 46 and SI > 1000 in epimastigotes form of T. cruzi and promastigotes form of L. chagasi parasites, respectively). Moreover, the comp. 7h did not show cytotoxicity against Vero or THP-1 cells (IC50 > 270 μM).

Recombinant HSV-2 glycoprotein B amino-proximal polypeptide, a new designed polypeptide with potential immunogenic effect in vivo, was engineered. It is composed of thioredoxin and HSV-2 glycoprotein B amino-proximal segment. The recombinant gene was then highly expressed in Escherichia coli. Furthermore, the expressed fusion protein could effectively prevent degradation of polypeptide, and purified fusion protein could effectively stimulate neutralization antibody after immunizing mice. The selected antibody from antibody library constructed with high titer antiserum spleen cells of mice had very different ability to neutralize the HSV-2 in vitro. In this study, we provide an approach to produce thioredoxin and HSV-2 glycoprotein B amino terminus polypeptide fusion protein, which could using as a potential and novel target for structure based drug designing to control the infections of HSV-2.