Letters in Drug Design & Discovery - Volume 7, Issue 8, 2010

Pleiotropic effects of therapeutic statins have been frequently reported. The role of p38 MAP kinase has been advanced. In this paper, atorvastatin (containing a terphenylic system), rosuvastatin and fluvastatin, which are important drugs of the statin class, were docked into the active site of p38 MAP kinase where the selective and highly potent inhibitor SB 203580, a fluoro-phenyl pyridinylimidazole derivative, possessing a terphenylic system, binds. The protein-statin complexes near the ATP binding pocket reinforce the hypothesis of p38 MAP kinase as one possible molecular target for statin drugs.

A series of eleven (E)-2-benzothiazole hydrazones were synthesized and evaluated for their in vitro anticancer activities against three neoplastic cancer cells: HL-60 (leukemia), MDAMB-435 (breast) and HCT-8 (colon). Two of them, 3e and 3f, showed good cytotoxicity activity for HL-60. The results also demonstrated that compound 3f seems to be selective to HL-60 cell line, appearing as a good prototype for an antileukemia lead molecule.

Epidermal growth factor receptor (EGFR) protein tyrosine kinases (PTKs) are known for its role in cancer. QSAR studies were performed on a set of 137 analogs of quinazoline using MDS vlife science QSAR plus module by using Multiple Linear Regression (MLR), Principal Component Regression (PCR) and Partial Least Squares (PLS) Regression methods. Among these, MLR method has shown a very promising result as compared to other two methods and a QSAR model was generated by a training set of 100 molecules with correlation coefficient (r2) of 0.884, significant cross validated correlation coefficient (q2) of 0.800, F test of 39.5149, r2 for external test set (pred_r2) 0.5902, coefficient of correlation of predicted data set (pred_r2se) 0.7438 and degree of freedom 83. In the selected descriptors, alignment independent descriptors T_2_C_5 (11.74%) and T_2_O_7 (-11.27%) are the most important descriptors in predicting EGFR inhibitory activity. Electron withdrawing group at anilino quinazolines enhances the activity as evident by positive value of T_F_Cl_4 (2.07%). In addition, for quinazoline substituents, estate contribution descriptors, SaaCHE -index and Ssss NE-index have a large deactivating effect.

HIV protease inhibition has been one of the most effective methods of preventing HIV multiplication in infected organisms. Because of the complementarity that exists between the HIV protease active site and the molecules of substituted fullerenes, these compounds have been used as effective HIV protease inhibitors. In this paper, QSAR models based on experimental half maximum effective concentration (EC50) of substituted fullerenes have been developed. The three descriptors used to build the QSAR models make reference to the properties of the full molecule of the substituted fullerenes or to the properties of fragments of the molecule such as the fullerene core or substituent arms.

Azasteroids constitute a class of modified steroids in which one or more carbon atoms in the steroid ring system have been substituted with nitrogen atom, having human 5α-reductase inhibitory activities for the management of benign prostatic hyperplasia (BPH). We have performed ligand based 3D-QSAR study using Self Organizing Molecular Field Analysis (SOMFA) on a series of 4-azasteroids including clinically used drug Finasteride. The SOMFA studies results indicate significant q2 (0.809), r2 (0.834) and F-test (70.060) values showing good predictive ability. The analysis of SOMFA grids provides an insight for generation of optimal molecular architecture for better human 5α-reductase inhibitory activity.

In our efforts to find new whitening agent from natural resources, we focused on wood of Artocarpus heterophyllus which shows anti-melanogenesis activity. By activity-guided fractionation of A. heterophyllus wood extract, norartocarpetin (1) and artocarpesin (2) were isolated. These compounds have 4-substituted resorcinol moiety in B ring, which is an important substructure for revealing the tyrosinase inhibitory activity. Also, the effect of albanin A (3) which has 4-substituted resorcinol moiety at B ring with prenyl substituent at C-3 position, was examined for comparison. The IC50 values of mushroom tyrosinase inhibitory activity of norartocarpetin (1), artocarpesin (2) and albanin A (3) were 1.7, 8.5 and 463 μM, respectively. In melanin formation inhibition on B16 melanoma cells, the IC50 of these compounds (1-3) were 209.1, 45.1 and 40.1 μM, respectively. The roles of each substructure of flavones having 4-substituted resorcinol moiety with or without prenyl substituent on tyrosinase and melanin biosynthesis in B16 melanoma cells were discussed.

In this work we report the tuberculostatic profile of a series of 5-phenyl-1,3,4-thiadiazole-2-arylhydrazone derivatives (1a-m). The evaluation of their in vitro antibacterial activity against Mycobacterium tuberculosis H37Rv was expressed as the minimum inhibitory concentration (MIC) in μg/mL. The compounds 1g and 1h exhibited inhibitory activity of 6.25 μg/mL and 1.25 μg/mL respectively, and can be considered as a good start point for the discovery of new lead compounds in the field of multi-drug resistant tuberculosis.

Two lithocholic acid (LCA) derivatives — mono- and diesters (newly synthetised) — are studied for their main conformational preferences, by Raman spectroscopy coupled to theoretical (DFT) methods. Raman bands characteristic of each compound were assigned, allowing an accurate and rapid identification of this kind of systems. The conformational preferences of the LCA diester were related with its ability to function as a model for artificial receptors, displaying a tailored structural profile.

Peroxynitrite scavenging activity of eighteen substituted flavonoid derivatives was subjected to classical quantitative structure activity relationship (QSAR) analysis using electrotopological state (E-state) atom parameter. For the development of the QSAR models, statistical techniques like stepwise multiple linear regression and partial least squares (PLS) were used. Based on the internal validation and external prediction statistics stepwise (Q2 = 0.842) and PLS (R2 pred = 0.614) methods were found to the best models, respectively. The equations also satisfy the Fmax criteria suggested by Livingstone and Salt. All the models indicate the impact of the phenyl ring at position 2. Proper positioning of hydroxyl group in the phenyl ring is important for activity. Based on the findings, the models show the utility of E-state parameters in QSAR study for better understanding about the contribution of atoms or fragments in the molecules towards the biological activity.