Insight into structural requirements of antiamoebic flavonoids: 3D‐QSAR and G‐QSAR studies

Plant‐based flavonoids have been found to exhibit strong inhibitory capability against Entamoeba histolytica. So, various QSAR models have been developed to identify the critical features that are responsible for the potency of these molecules. 3D‐QSAR analysis using k‐nearest neighbour molecular field analysis via stepwise forward–backward variable selection method showed best results for both internal and external predictive ability of the model (i.e., q² = 0.64 and pred_r² = 0.56). Also, a group‐based QSAR (G‐QSAR) model was developed based on partial least squares regression combined with stepwise forward–backward variable selection method. It gave best parametric results (r² = 0.74, q² = 0.56 and pred_r² = 0.54) which implied that the model is highly predictive. 3D‐QSAR established that presence/absence of bulk near rings B and C is important in deciding the inhibitory potential of these molecules. Additionally, G‐QSAR provided site‐specific clue wherein modifications related to molecular weight, electronegativity and separation of an oxygen atom in rings A and C can result in enhanced biological activity. To the best of the author's knowledge, this is the first QSAR study of antiamoebic flavonoids, and therefore, we expect the results to be useful in the design of more potent antiamoebic inhibitors.     

Atomic property fields: generalized 3D pharmacophoric potential for automated ligand superposition, pharmacophore elucidation and 3D QSAR

The atomic property fields (APF) concept is introduced as a continuous, multi-component 3D potential that reflects preferences for various atomic properties at each point in space. Atomic property field-based approaches to several key problems in the field of ligand structure-based rational drug discovery and design are investigated. The superposition of ligands on one or multiple molecular templates is performed by Monte-Carlo minimization in the atomic property fields potentials combined with standard force-field energy. The approach is extended to multiple flexible ligand alignments using an iterative procedure, Self-Consistent atomic Property Fields by Optimization (SCAPFOld). The application of atomic property fields and SCAPFOld for virtual ligand screening and 3D Quantitive Structure-Activity Relationship (QSAR) is tested on published benchmarks. The new methods are shown to perform competitively in comparison to current state-of-the-art methods.     

Synthesis and 3D‐QSAR Analysis of 2‐Chloroquinoline Derivatives as H37RV MTB Inhibitors

Frequency of tuberculosis is progressively increasing worldwide. New emerging strains of bacilli that are emerging are resistant to the currently available drugs which make this issue more alarming. In this regard, a series of substituted quinolinyl chalcones, quinolinyl pyrimidines, and pyridines were synthesized and evaluated for their antitubercular activity in vitro against Mycobacterium tuberculosis H₃₇RV. To establish the role of the 2‐chloroquinoline nucleus as a pharmacophoric group and study its influence on the antimycobacterial activity, a 3D‐QSAR study based on CoMFA and CoMSIA was undertaken on this set of 2‐chloroquinoline derivatives. Statistically significant models that are able to well correlate the antimycobacterial activity with the chemical structures of the 2‐chloroquinolines have been developed. The contour maps resulting from the best CoMFA and CoMSIA models were used to identify the structural features relevant to the biological activity in this series of analogs. Further analysis of these interaction‐field contour maps also showed a high level of internal consistency. The information obtained from the field 3‐D contour maps may be fruitfully utilized in the design of more potent 2‐chloroquinoline‐based analogs as potential antitubercular candidates.     

Combined 3D‐QSAR Modeling and Molecular Docking Study on Quinoline Derivatives as Inhibitors of P‐selectin

P‐selectin is a promising target for developing novel atherosclerosis drugs. To understand the structure–activity correlation of quinolines‐based P‐selectin inhibitors, we have carried out a combined molecular docking and three‐dimensional quantitative structure–activity relationship (3D‐QSAR) modeling study. The study has resulted in two types of satisfactory 3D‐QSAR models, including the CoMFA model (r², 0.863; q², 0.589) and CoMSIA model (r², 0.866; q², 0.636), to predict the biological activity of new compounds. The detailed microscopic structures of P‐selectin binding with inhibitors have been studied by molecular docking. We have also developed docking based 3D‐QSAR models (CoMFA with r², 0.934; q², 0.591; CoMSIA with r², 0.896; q², 0.573). The contour maps obtained from the 3D‐QSAR models in combination with the docked binding structures help to better interpret the structure–activity relationship. All of the structural insights obtained from both the 3D‐QSAR contour maps and molecular docking are consistent with the available experimental activity data. The satisfactory results strongly suggest that the developed 3D‐QSAR models and the obtained P‐selectin‐inhibitor binding structures are reasonable for the prediction of the activity of new inhibitors and in future drug design.     

Combined 3D‐QSAR,Molecular Docking,Molecular Dynamics Simulation,and Binding Free Energy Calculation Studies on the 5‐Hydroxy‐2H‐Pyridazin‐3‐One Derivatives as HCV NS5B Polymerase Inhibitors

The NS5B RNA‐dependent RNA polymerase (RdRP) is a promising therapeutic target for developing novel anti‐hepatitis C virus (HCV) drugs. In this work, a combined molecular modeling study was performed on a series of 193 5‐hydroxy‐2H‐pyridazin‐3‐one derivatives as inhibitors of HCV NS5B Polymerase. The best 3D‐QSAR models, including CoMFA and CoMSIA, are based on receptor (or docking). Furthermore, a 40‐ns molecular dynamics (MD) simulation and binding free energy calculations using docked structures of NS5B with ten compounds, which have diverse structures and pIC₅₀ values, were employed to determine the detailed binding process and to compare the binding modes of the inhibitors with different activities. On one side, the stability and rationality of molecular docking and 3D‐QSAR results were validated by MD simulation. The binding free energies calculated by the MM‐PBSA method gave a good correlation with the experimental biological activity. On the other side, by analyzing some differences between the molecular docking and the MD simulation results, we can find that the MD simulation could also remedy the defects of molecular docking. The analyses of the combined molecular modeling results have identified that Tyr448, Ser556, and Asp318 are the key amino acid residues in the NS5B binding pocket. The results from this study can provide some insights into the development of novel potent NS5B inhibitors.     

Tetramethylpiperidine‐substituted phenazines as novel anti‐plasmodial agents

Two novel derivatives of clofazimine [3‐(p‐chloroanilino)‐10‐(p‐chlorophenyl)‐2,10‐dihydro‐2‐isopropylimino)phenazine] and the tetramethylpiperidine (TMP)‐substituted phenazines, B4119 [3‐(3‐chloro‐4‐fluoroanilino)‐10‐(3‐chloro‐4‐fluorophenyl)‐2,10‐dihydro‐2(2,2,6,6‐tetramethylpiper‐4‐ylimino)phenazine] and B4158 [3‐(4‐isopropylanilino)‐10‐(4‐isopropylphenyl)‐2,10‐dihydro‐2‐(2,2,6,6‐tetramethylpiper‐4‐ylimino)phenazine] (1–8 μM), were evaluated for activity against chloroquin‐, quinine‐, and sulfadoxine/pyrimethamine‐sensitive and ‐resistant strains of Plasmodium falciparum in vitro, as well as for their effects on polymerisation of haeme to β‐hematin. By using microscopic and flow cytometric methods, it was found that B4119 and B4158, but not clofazimine, inhibited the growth of sensitive, as well as resistant strains of P. falciparum with IC₅₀ values between 0.22 and 0.7 μM, indicating lack of cross‐resistance. Augmentation of anti‐plasmodial activity was observed when B4119 and B4158 were used in combination with chloroquin or mefloquine. Inhibition of the growth of P. falciparum was associated with interference with haeme polymerisation to β‐hematin in vitro, while administration of B4119 to P. berghei‐infected mice was accompanied by a significant reduction in parasitemia and improved therapeutic activity was observed when this agent was combined with chloroquin. The data presented in this study demonstrate that the TMP‐substitution at position 2 on the phenazine nucleus of riminophenazines confers anti‐plasmodial activity on these compounds. These may prove to be useful forerunners in the design of novel anti‐plasmodial pharmacologic agents. Drug Dev. Res. 50:195–202, 2000. © 2000 Wiley‐Liss, Inc.     

Thiazolyl‐N‐substituted amides: A group of effective anti‐inflammatory agents with potential for local anesthetic properties. Synthesis,biological evaluation,and a QSAR approach

A series of thiazolyl‐N‐substituted amides were synthesized and tested for anti‐inflammatory activity. Their R_M values were determined as an expression of their lipophilicity. Theoretical calculation of their lipophilicity, as clog P and log D_7.4 was also performed. The effect of the synthesized compounds on inflammation, using the carrageenan‐induced mouse paw edema model was studied. In general, the studied compounds were found to be potent anti‐inflammatory agents (23.2–72.1%). Anti‐inflammatory activity was influenced by some structural characteristics of the synthesized compounds. An attempt was made to correlate their biological activity with some physicochemical parameters using a quantitative structure–activity relationship approach (QSAR). A parabolic dependence of activity from clog D_7.4 and a linear dependence from surface tension were found. The anti‐inflammatory activity of the thiazolyl‐amides were found to a great extent to be under pharmacokinetic control. Drug Dev. Res. 48:53–60, 1999. © 1999 Wiley‐Liss, Inc.     

3D‐QSAR studies of cytotoxic heterocyclic quinones using calculated reduction potential

Most quinones with 2–4 fused aromatic rings exhibit cytostatic activity via DNA intercalation that causes enzyme blockade and reading errors during the replication process. The redox activity of quinones plays a role in the DNA cleavage mediated by oxygen or sulfur radicals. To develop novel anticancer agents based on nitrogen‐containing heterocyclic quinones, pharmacophore models of representative molecules with high activity were generated using Genetic Algorithm with Linear Assignment of Hypermolecular Alignment of Database (GALAHAD). A series of compounds were aligned to the selected pharmacophore model and the 3D‐quantitative structure activity relationships (QSAR) were analyzed using comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA), resulting in q² values of 0.734 and r² of 0.951, and q² of 0.803 and r² of 0.917, respectively, in each study. In addition, the potentials for the one‐electron reduction of quinones were calculated from LUMO energies using the semi‐empirical Austin Model 1 (AM1) method. These also showed a good correlation (r² of 0.816) with the cytotoxic activities of the quinones. Drug Dev Res 2009. © 2009 Wiley‐Liss, Inc.     

Combined Molecular Docking, 3D‐QSAR,and Pharmacophore Model: Design of Novel Tubulin Polymerization Inhibitors by Binding to Colchicine‐binding Site

Interference with dynamic equilibrium of microtubule–tubulin has proven to be a useful tactics in the clinic. Based on investigation into the structure–activity relationship (SAR) studies of tubulin polymerization inhibitors obtained from several worldwide groups, we attempted to design 691 compounds covering several main heterocyclic scaffolds as novel colchicine‐site inhibitors (CSIs). Evaluated by a series of combination of commonly used computer methods such as molecular docking, 3D‐QSAR, and pharmacophore model, we can obtain the ultimate 16 target compounds derived from five important basic scaffolds in the field of medicinal chemistry. Among these compounds, compound A‐132 with in silico moderate activity was synthesized, and subsequently validated for preliminary inhibition of tubulin polymerization by immunofluorescence assay. In additional, the work of synthesis and validation of biological activity for other 15 various structure compounds will be completed in our laboratory. This study not only developed a hierarchical strategy to screen novel tubulin inhibitors effectively, but also widened the spectrum of chemical structures of canonical CSIs.     

Molecular Docking and 3D QSAR Studies of Chk2 Inhibitors

Isothiazole‐carboxamidines are potent ATP competitive checkpoint kinases (Chk2) inhibitors. Three‐dimensional quantitative structure–activity relationship models were developed using comparative molecular field analysis and comparative molecular similarity indices analysis. The study was performed using three different geometrical methods. In geometrical method‐1, molecules were fully optimized by PM3 Hamiltonian and aligned using common substructure. This alignment was subsequently used for Ligand‐based comparative molecular field analysis and comparative molecular similarity indices analysis. In receptor‐guided analyses, the receptor coordinates were obtained from public domine (PDB 2cn8). The molecule‐7 was docked into receptor protein using FlexX and two plausible binding modes were identified. These modes were used as templates for geometrical method‐2 and 3. These methods were used for 3D QSAR. The geometrical method‐3‐based comparative molecular field analysis (q ² = 0.75, r ² = 0.87 and r ²_predict = 0.81) and comparative molecular similarity indices analysis (q ² = 0.90, r ² = 0.96 and r ²_predict = 0.75) gave better result. The steric, hydrophobic and hydrogen bond donor fields effects significantly contribute to activity. In this way, the receptor‐guided study presents a more detailed understanding about chk2 active site interactions. The study indicated some modifications to the active molecule which might be valuable to improve the activity.     

Development of potential anti‐cancer agents: Diazenes and derivatives

The call for the discovery of more effective agents to treat cancer has become urgent. Recently, we have synthesized new compounds: diazenes. So far, we have demonstrated that several of them inhibited the growth of tumor cells, but their solubility and biological activity were relatively low. Therefore, new compounds have been synthesized to improve their solubility and biological efficacy. In the present study, we screened cytotoxicity of 26 new diazenes and their derivatives on human cervical carcinoma HeLa cells. The most active compound was tested also on human laryngeal carcinoma, breast adenocarcinoma, and glioblastoma cells, as well as on two drug‐resistant sublines derived from cervical and laryngeal carcinoma cells. Cytotoxicity of new compounds was determined using a colorimetric MTT assay. Results show that diazene SB‐681 was the most efficient one, reducing significantly survival of HeLa cells, with IC₅₀ value of 16.3 μM. This compound applied in low doses inhibited also the growth of other cell lines tested, among which were two drug‐resistant cell lines. The observed activity could be explained by the influence of groups attached to the diazene functionality, namely 2‐chloroethylaminocarbonyl moiety and pentafluorophenyl moiety attached to the diazene nitrogen‐nitrogen double bond. Our data indicate that SB‐681 is a promising leading compound in the development of a novel class of antineoplastic agents. Drug Dev. Res. 61:95–100, 2004. © 2004 Wiley‐Liss, Inc.     

3‐Acetyl‐11‐keto‐β‐boswellic acid loaded‐polymeric nanomicelles for topical anti‐inflammatory and anti‐arthritic activity

Objectives The aim of this study was to develop 3‐acetyl‐11‐keto‐β‐boswellic acid (AKBA)‐loaded polymeric nanomicelles for topical anti‐inflammatory and anti‐arthritic activity. Methods Polymeric nanomicelles of AKBA were developed by a radical polymerization method using N‐isopropylacrylamide, vinylpyrrolidone and acrylic acid. The polymeric nanomicelles obtained were characterized by Fourier transform infrared (FTIR), transmission electron microscopy (TEM) and dynamic light scattering (DLS). In‐vitro and in‐vivo evaluations of AKBA polymeric nanomicelles gel were carried out for enhanced skin permeability and anti‐inflammatory and anti‐arthritic activity. Key findings TEM and DLS results demonstrated that polymeric nanomicelles were spherical with a mean diameter approximately 45 nm. FTIR data indicated a weak interaction between polymer and AKBA in the encapsulated system. The release of drug in aqueous buffer (pH 7.4) from the polymeric nanomicelles was 23 and 55% after 2 and 8 h, respectively, indicating sustained release. In‐vitro skin permeation studies through excised abdominal skin indicated a threefold increase in skin permeability compared with AKBA gel containing the same amount of AKBA as the AKBA polymeric nanomicelles gel. The AKBA polymeric nanomicelle gel showed significantly enhanced anti‐inflammatory and anti‐arthritic activity compared with the AKBA gel. Conclusions This study suggested that AKBA polymeric nanomicelle gel significantly enhanced skin permeability, and anti‐inflammatory and anti‐arthritic activity.     

Synthesis,Antibacterial Activities,and 3D‐QSAR of Sulfone Derivatives Containing 1, 3, 4‐Oxadiazole Moiety

A series of sulfone derivatives containing 1, 3, 4‐oxadiazole moiety were prepared and evaluated for their antibacterial activities by the turbidimeter test. Most compounds inhibited growth of Ralstonia solanacearum (R. solanacearum) from tomato and tobacco bacterial wilt with high potency, among which compounds 5a and 5b exhibited the most potent inhibition against R. solanacearum from tomato and tobacco bacterial wilts with EC₅₀ values of 19.77 and 8.29 μg/mL, respectively. Our results also demonstrated that 5a, 5b , and a number of other compounds were more potent than commercial bactericides Kocide 3000 and Thiodiazole Copper, which inhibited R. solanacearum from tomato bacterial wilt with EC₅₀ values of 93.59 and 99.80 μg/mL and tobacco bacterial wilt with EC₅₀ values of 45.91 and 216.70 μg/mL, respectively. The structure–activity relationship (SAR) of compounds was studied using three‐dimensional quantitative structure–activity relationship (3D‐QSAR) models created by comparative molecular field analysis (CoMFA) and comparative molecular similarity index analysis (CoMSIA) based on compound bioactivities against tomato and tobacco bacterial wilts. The 3D‐QSAR models effectively predicted the correlation between inhibitory activity and steric–electrostatic properties of compounds.