Letters in Drug Design & Discovery - Volume 6, Issue 8, 2009

The aromatase enzyme is responsible for conversion of androgens to phenolic estrogens. The five-dimensional quantitative structure-activity relationships (5D-QSAR) of a series of androstenedione analogs developed as aromatase inhibitors were studied using the Raptor program. The best model (N=47, q2=0.660, R2=0.719) showed contributions of the hydrophobic, hydrogen-bond-donating and hydrogen-bond-accepting fields to the activity. The model was also externally validated using 12 compounds (test set) not included in the model generation process. The statistical parameters from the model indicate that the data are well fitted and have good predictive ability. Thus it was possible to generate and to validate aromatase receptor surrogates through the prediction of relative free energies of aromatase inhibitors binding in receptor- modeling studies.

Organophosphate nerve agents are still considered as potential threats in both military and terrorism situations. They are potent irreversible inhibitors of acetylcholinesterase in central and also in peripheral compartment. Huperzine A (Hup A) is a reversible AChE inhibitor that crosses the blood-brain barrier. It is presently approved for human use or is in course of clinical trials for the treatment of Alzheimer's disease. This compound has also been successfully tested for pretreatment of organophosphate poisoning. In this study Hup A was tested as a prophylaxis against two V-nerve agents (VX and Russian VX). According to the obtained results, Hup A was able to partially protect AChE in the blood, diaphragm and brain against inhibition caused by Russian VX and VX.

3D-QSAR models of twenty six furanones as inhibitors of bacterial quorum sensing (QS) were established by using comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA). The statistical results showed that the 3D-QSAR models derived from CoMFA were superior to those generated from CoMSIA. The optimal CoMFA model exhibited good cross-validated q2 and conventional r2 values at 0.639 and 0.992 respectively. The external test sets ( 2 pred r ) value of 0.56 further confirmed the predictive capacity of the resultant CoMFA models. A set of 3D contour plots based on the CoMFA models revealed that modifications at C2, C3 and C5 of the furanones may be valuable to improve the inhibition activities of QS. Results showed that both the steric and electrostatic factors should appropriately be taken into account in development of potent QS inhibitors.

In this paper, we reported the design, and synthesis of a series of novel pterin derivates i.e. 8a∼f, 9a∼f and 10a∼d. Their inhibitory activity against inducible nitric oxide synthase (iNOS) was evaluated in vitro. It was demonstrated that 4-alkoxypterin derivatives with acylation of 2-amino group showed potent inhibitory activity against iNOS, especially 8c, 8f and 10c.

Checkpoint-1 kinase plays an important role in the G2M cell cycle control, therefore its inhibition by small molecules is of great therapeutic interest in oncology. In this paper, we have reported the virtual screening of an in-house library of 2499 pyranopyrazole derivatives against the ATP-binding site of Chk1 kinase using Glide 5.0 program, which resulted in six hits. All these ligands were docked into the site forming most crucial interactions with Cys87, Glu91 and Leu15 residues. From the observed results these ligands are suggested to be potent inhibitors of Chk1 kinase with sufficient scope for further elaboration.

Quantitative 3-D pharmacophore model was generated using 30 chemically diverse H3 receptor antagonists and tested for its productiveness using a large test set. It had 2 hydrogen bond acceptor lipids, 1 positive ionizable and 1 hydrophobic feature. Pharmacophore analysis suggested the structural features required for increased H3 receptor activity.

Ten artemisinin derivatives containing a piperazine at C-10 linked with ether or ester were designed and synthesized. All the derivatives have improved antiproliferative activity against cancer cell lines, including multidrug resistance (MDR) phenotypes. Compounds linked with ether are more effective than compounds linked with ester.

QSAR has been established for 73 Indole-carbaldehyde derivatives acting as Cannabinoid receptor 2 agonists. The best model was developed using six descriptors from topological, thermodynamic, spatial and electrotopological class. The model had r2 value of 0.888, PRESS value of 7.825, XV r2 value of 0.841 and test set correlation value 0.881.

Parasite, Leishmania infantum, is the causative agent of visceral leishmaniasis (kala-azar), a fatal disease, if remains untreated. As it is showing resistance to the currently available drugs, search for new drug targets is essential for novel drug discovery. In-silico analysis of complete genome of Leishmania infantum as well as comparison with human genome and genes available in database of essential gene resulted in identification of 40 genes of Leishmania infantum as potential drug targets. These genes code for proteins that are necessary for the survival of parasite and include Methyl transferase cell division protein, transporter proteins, ribonucleoside hydrolase, regulator proteins and proteins involved in pathogenesis. These genes and gene products are excellent targets for antileishmanial drugs.

The multifactorial pathogenesis of Alzheimer's disease (AD) suggests that drug treatments with two or more mechanisms of action, acting in a complementary manner, could be more efficacious to patients suffering from the disease. In an effort to develop new therapies to treat AD, a series of 5,6-dihydro-benzo[c]acridin-7-ol derivatives (5a-5q) were synthesized and evaluated for their AchE-inhibition and neuron-protection effects. Preliminary biological tests suggested that these compounds exhibited mild AchE-inhibition and commendable neuroprotection activities. Compounds 5m, 5n, 5p had noticeable neuron-protection as compared with tacrine and nimodipine.

This was an open label, balanced, randomized, three-treatment, three-sequence, three period, single-dose, crossover bioavailability study in which healthy adults (age18-45 years) were randomized to receive sustained release tablets of Voveran SR (Product R), Nac SR (Product A) and Reactin SR (Product B) each containing diclofenac sodium 100 mg with at least 3 days wash out between treatments. Eighteen healthy, adult, male, human subjects who met the inclusion and exclusion criteria as described in the protocol were enrolled in the study. Pharmacokinetic parameters like Tmax, Cmax, AUC 0-t, AUC 0-∞, AUC0-t/ AUC 0-∞, Kel, T1/2 & MRT were calculated for the Products A, B and R. Product A fared better than product B in some bioequivalence parameters. However, both the test products (Nac SR and Reactin SR) were not bioequivalent to product R (Voveran SR).

A series of novel ethyl 2-(1-aminocyclobutyl)-5-(benzoyloxy)-6-hydroxy-pyrimidine-4-carboxylate derivatives 8(a-i) were synthesized by nucleophilic substitution reaction of ethyl 2-(1-aminocyclobutyl)-5-(benzoyloxy)-6-hydroxypyrimidine- 4-carboxylate (7) with different substituted aliphatic/aromatic sulfonyl chlorides (R-SO2-Cl). All the synthesized compounds were characterized by IR, 1H NMR and LC/MS analysis. The synthesized compounds were evaluated for their antioxidant activity by diphenylpicrylhydrazyl (DPPH) assay and also by hydroxy radical induced DNA strand scission assay. Among the synthesized compounds 8c, 8f and 8i showed promising antioxidant activity.