Structure-activity relationship and mechanism of action studies of manzamine analogues for the control of neuroinflammation and cerebral infections.

Structure-activity relationship studies were carried out by chemical modification of manzamine A (1), 8-hydroxymanzamine A (2), manzamine F (14), and ircinal isolated from the sponge Acanthostrongylophora. The derived analogues were evaluated for antimalarial, antimicrobial, and antineuroinflammatory activities. Several modified products exhibited potent and improved in vitro antineuroinflammatory, antimicrobial, and antimalarial activity. 1 showed improved activity against malaria compared to chloroquine in both multi- and single-dose in vivo experiments. The significant antimalarial potential was revealed by a 100% cure rate of malaria in mice with one administration of 100 mg/kg of 1. The potent antineuroinflammatory activity of the manzamines will provide great benefit for the prevention and treatment of cerebral infections (e.g., Cryptococcus and Plasmodium). In addition, 1 was shown to permeate across the blood-brain barrier (BBB) in an in vitro model using a MDR-MDCK monolayer. Docking studies support that 2 binds to the ATP-noncompetitive pocket of glycogen synthesis kinase-3beta (GSK-3beta), which is a putative target of manzamines. On the basis of the results presented here, it will be possible to initiate rational drug design efforts around this natural product scaffold for the treatment of several different diseases.

Three-dimensional quantitative structure-farnesyltransferase inhibition analysis for some diaminobenzophenones.

A 3D-QSAR investigation of 95 diaminobenzophenone yeast farnesyltransferase (FT) inhibitors selected from the work of Schlitzer et al. showed that steric, electrostatic, and hydrophobic properties play key roles in the bioactivity of the series. A CoMFA/CoMSIA combined model using the steric and electrostatic fields of CoMFA together with the hydrophobic field of CoMSIA showed significant improvement in prediction compared with the CoMFA steric and electrostatic fields model. The similarity of the 3D-QSAR field maps for yeast FT inhibition activity (from this work) and for antimalarial activity data (from previous work) and the correlation between those activities are discussed.

Imidazole-containing farnesyltransferase inhibitors: 3D quantitative structure-activity relationships and molecular docking.

One of the most promising anticancer and recent antimalarial targets is the heterodimeric zinc-containing protein farnesyltransferase (FT). In this work, we studied a highly diverse series of 192 Abbott-initiated imidazole-containing compounds and their FT inhibitory activities using 3D-QSAR and docking, in order to gain understanding of the interaction of these inhibitors with FT to aid development of a rational strategy for further lead optimization. We report several highly significant and predictive CoMFA and CoMSIA models. The best model, composed of CoMFA steric and electrostatic fields combined with CoMSIA hydrophobic and H-bond acceptor fields, had r (2) = 0.878, q (2) = 0.630, and r (pred) (2) = 0.614. Docking studies on the statistical outliers revealed that some of them had a different binding mode in the FT active site based on steric bulk and available active site space, explaining why the predicted activities differed from the experimental activities.

Glycogen synthase kinase-3 inhibition by 3-anilino-4-phenylmaleimides: insights from 3D-QSAR and docking.

Glycogen synthase kinase-3, a serine/threonine kinase, has been implicated in a wide variety of pathological conditions such as diabetes, Alzheimer's disease, stroke, bipolar disorder, malaria and cancer. Herein we report 3D-QSAR analyses using CoMFA and CoMSIA and molecular docking studies on 3-anilino-4-phenylmaleimides as GSK-3alpha inhibitors, in order to better understand the mechanism of action and structure-activity relationship of these compounds. Comparison of the active site residues of GSK-3alpha and GSK-3beta isoforms shows that all the key amino acids involved in polar interactions with the maleimides for the beta isoform are the same in the alpha isoform, except that Asp133 in the beta isoform is replaced by Glu196 in the alpha isoform. We prepared a homology model for GSK-3alpha, and showed that the change from Asp to Glu should not affect maleimide binding significantly. Docking studies revealed the binding poses of three subclasses of these ligands, namely anilino, N-methylanilino and indoline derivatives, within the active site of the beta isoform, and helped to explain the difference in their inhibitory activity.

2-N-Methyl modifications and SAR studies of manzamine A.

Quaternary carbolinium salts have been reported to show improved antimalarial activity and reduced cytotoxicity as compared to electronically neutral beta-carbolines. In this study, mono- and di-methylated quaternary carbolinium cations of manzamine A were synthesized and evaluated for their in vitro antimalarial and antimicrobial activity, cytotoxicity, and also their potential for glycogen synthase kinase (GSK-3beta) inhibition using molecular docking studies. Among the analogs, 2-N-methylmanzamine A (2) exhibited antimalarial activity (IC(50) 0.7-1.0microM) but was less potent than manzamine A. However the compound was significantly less cytotoxic to mammalian kidney fibroblasts and the selectivity index was in the same range as manzamine A.

QSAR analysis of some fused pyrazoles as selective cyclooxygenase-2 inhibitors: a Hansch approach.

Quantitative structure activity relationships (QSAR) for two unique series of centrally fused pyrazole ring systems have been studied for selective cyclooxygenase-2 inhibitory activity. Several statistically significant QSAR models were developed and suggest that hydrophobicity of entire molecules and a fluorine atom substitution at position 8 of the non benzene sulphonyl ring fused with central pyrazole core of series 1 compounds is crucial for improved COX-2 selectivity. Various structural and physicochemical stipulations to improve the inhibitory activities of the enzymes among individual series of compounds are also discussed. The conclusions derived may serve as an example to advance the design of new selective COX-2 inhibitors.