Letters in Drug Design & Discovery - Volume 13, Issue 7, 2016

Background: In the recent years, the researches about HDAC inhibitors have become more and more extensive. Objective: This study explored molecular docking mode and three-dimensional quantitative structureactivity relationship (3D-QSAR) of 18 novel HDAC inhibitors involving in quinolone structure. Results: The molecular docking results showed that PHE198 might be a potential active residue against 18 HDAC inhibitors. 3D-QSAR model using Topomer CoMFA possessed high predictive ability (q2, 0.637; r2, 0.966). Conclusion: Based on the results derived from molecular docking and 3D-QSAR studies, we designed several new compounds with potential inhibitory activity. We wish this study can provide some instructions for the design and structural transformation of novel potent quinolone-based HDAC inhibitors.

In our previous work, some promising hits for Mtb-ASADH were identified using pharmacoinformatics approaches. Total ten compounds were selected for biological evaluation against Mtb- ASADH, nine of these were selected from virtual screening employing shape based and pharmacophore models and remaining one was designed from analog design. Cysteine has been reported as a covalently bonded inhibitor for Mtb-ASADH in a crystal structure (PDB ID: 3TZ6). Six out of ten compounds showed good inhibition of Mtb-ASADH. All these six molecules ZINC00108239, ZINC36358489, NSC4862, NSC109187, NSC51108, NSC226144 and S-carboxymethyl-L-cysteine showed IC50 values ranging from 65-100 μM. The binding mode analysis of S-carboxymethyl-L-cysteine, which showed highest inhibitory activity among tested compounds, exhibited binding interactions with catalytic residues Arg99, Arg249, Lys227 and His256. These studies can be further exploited for lead optimization and rational drug designing to find new leads against Tuberculosis.

Research in the area of cancer treatment has undergone a paradigm shift from design of new anticancer agents to efficient drug delivery systems trying to overcome cytotoxicity aspects and bioavailability problems. We have reported earlier two cyclic peptides [WR]4 and [WG(triazole-KRNH2)] 3 for the delivery of phosphopeptides and have considered them for the purpose of enhancing delivery of anticancer drugs. This study attempts to understand at the molecular level self-assembly of cyclic peptides containing tryptophan and arginine residues and their suitability as molecular transporters of anti-HIV and anticancer agents. Ab initio molecular orbital calculations coupled with molecular dynamics simulation studies are reported along with flow cytometry results to show self-assemblage of these cyclic peptides induced by counterions. Our results show the suitability of [WR]4 system in enhancing the delivery of lamivudine and dasatinib in conformity with experimental results. The conformational flexibility, charge environment and HLB of these peptides play an important role in determining their drug delivery capabilities. To our knowledge, this is the first attempt to explain the self-assembly and molecular transporter properties of these systems at the molecular level.

Background: Alpha-glucosidase is the key enzyme involved in catalyzing the carbohydrate alpha-glucosidase through hydrolysis. It is implicated in several metabolic pathways, including carbohydrate digestion in the intestine, and glycoprotein and glycolipid processing. Alpha-glucosidase inhibitors are currently being investigated for their therapeutic effect against some diseases such as diabetes, cancer, hepatitis B and human immunodeficiency virus (HIV). Objective: The aim of this review is to clarify the effect of alpha-glucosidase inhibitors in the treatment of some diseases, and to evaluate the structure-activity relationship of about 270 inhibitors isolated from about 60 plants. Methods: We reviewed 121 articles published between 1965 and 2013 (PubMed and Sciencedirect). All the molecules structures were provided in ChemDraw software. Results and Conclusions: In this work we elucidated the therapeutic effect of alpha-glucosidase inhibitors against some diseases and we concluded that alpha-glucosidase flavonoid inhibitors (representing 22% of the reviewed inhibitors) have common components that are responsible of their inhibitory activity. The general structure of these inhibitors is composed of three rings. It seems that the hydroxyl groups in each ring have an important role in the α-glucosidase inhibitory activity.

Objective: To evaluate apoptotic activity of Viviparous bengalensis flesh extracted purified fraction VB-P4 on fibroblast like synoviocyte cells (FLS). Methods: Purified fraction VB-P4 was analyzed for apoptotic activity on synoviocyte cell. The cells were treated with VB-P4 (40 μg/mL) for 24 hrs. Morphological analysis through phase contrast microscope, MTT assay for cytotoxicity study, interleukins level analysis, CD3, CD4, CD8 activities study through flow cytometry, apoptotic activity study using annexin V- FITC, immunofluorescence study of caspase 3, and agarose gel for DNA breakage were done using synoviocyte cell. Results: VB-P4 treatment on synovial cell showed lack of matured synoviocyte cell with respect to osteoarthritic control cells. MTT assay showed significant decrease in formazan complex formation after treatment with VB-P4 in dose dependent manner. Decreased levels of interleukins (TNF-α, IL-1α, CINC-1, IL-17, MMP-1, Cathepsin K) on synoviocyte cells also confirmed reduced osteoarthritis after treatment with VB-P4 (40 μg/mL). Flow cytometric analysis of monoclonal antibody (CD3, CD4, and CD8) exhibited increased expression on synovial cell surface after treatment with VBP4. Annexin-V FITC study showed 76.90% early apoptosis and 7.95% late apoptotic cell after treatment with VB-P4 which confirmed apoptotic activity of VB-P4 on osteoarthritic synoviocyte cells. Agarose gel electrophoresis showed that VB-P4 (40 μg/mL) worked on nuclear localization of synoviocyte which is shown by smeary bands and florescence cell micrograph. Upregulation of caspase 3 confirmed apoptosis due to VB-P4 treatment on synoviocyte cell. Conclusion: The findings showed that fresh water snail flesh extracted purified fraction VB-P4, exhibited apoptotic activity on osteoarthritic synoviocyte cell through caspase mediated pathway.

Protein models are useful in structure-based protein engineering applications, including designing drugs, redesigning enzyme specificity, and designing new folds in proteins. Predicting loop structures is considered the main challenge in protein 3-D structure modeling. The flexibility of loop regions dictates the need for special attention to their conformations. In this paper, we report on the implementation of iterative stochastic elimination (ISE) optimization technology for the ab initio modeling of protein variable regions (loops). The ISE algorithm was tested on a benchmark of 70 structurally refined loops. The median root-mean-square deviation (RMSD) of the loop residues was 1.5Å, with 80% of the targets conforming to the native with RMSD lower than 2.0Å. The median-backbone, heavy-atom global RMSD of the loop predictions were 0.67Å for short loops (4-6 residues), 0.88Å for medium loops (7-9 residues), 1.68Å for long loops (10-12 residues) and 2.76Å for very long loops (13-16 residues). In addition to the accurate modeling of short, medium and long loops, the current method provided us with ensembles of conformations, which are crucial for studying the dynamic nature of loops, mainly on the surfaces of proteins. The proposed technique could be incorporated into modules for generating homologybased models and for flexible docking.

Quantitative structure activity relationship (QSAR) studies have been performed on the 27 molecules belonging to a series of 2,3,6-trisubstituted quinazolin-4(3H)-one derivatives for their antitumor activity. To explore the relationship between structure and activity, various chemometric tools have been employed such as Factor Analysis-Multiple Linear Regressions (FA-MLR), Artificial Neural Network (ANN) analysis and Principle Component Regression (PCR) methods. The models exhibited good correlation coefficient (r2) and cross validated correlation coefficient (q2) for all methods. It was found that ANN method gave better results indicating that the topological (IC4 and MPC06), constitutional (nf) and geometrical (G (N..S)) parameters were the most significant parameters for the antitumor activity indicating that novel potent analogs can be synthesized by altering these descriptor characteristics.

Chalcone derivatives are known for their numerous biological activities which include the interference of microtubule dynamics instability and are good candidates as an antimitotic agent that can be beneficial in the treatment of cancer. In the work described here, two series of chalcone derivatives including two newly synthesised derivatives were assessed for their antiproliferative activity and inhibition and promoting effects of tubulin polymerization. Antiproliferative activity was evaluated using the Microculture Tetrazolium (MTT) Assay while disruption of the mictotubule dynamics instability was investigated by the Tubulin Polymerization Assay. Both assays were carried out using human colon adenocarcinoma grade II (HT-29) cells. Compounds in series 5 showed strong inhibitory activity on the growth of HT-29 cells with IC50 ranging from 19.26 to 36.95 μM. Two of the chalcone derivatives, compound 5a and 5c were found to be active as an inhibitor and a promoter towards the microtubule dynamics respectively. Compounds with a dimethoxy benzene group on Ring B showed inhibitory effect of the HT-29 cells growth while furan on Ring A showed inhibitory effect on tubulin polymerization. These compounds are worthy to be investigated further as potential antimitotic agents.

The emergence of antibiotic resistance has made most of the first-line antibiotics ineffective. The search of novel antimicrobial entities is, therefore, vigorously pursued. We report here the resistance reversal potential of a monoterpene, tschimganin (1), against various strains of MDR Staphylococcus aureus. Compound 1 was isolated from Ferula ovina (Bioss). Bioss. By using flow cytometry, the bacterial cell membrane depolarization by tschimganin (1) was studied. Lucigenin chemiluminescence assay was employed to evaluate the generation of reactive oxygen species (ROS) in multi-drug resistant (MDR) bacterial cells. The reversal of multi-drug resistance by tschimganin (1), in combination with selected antibiotics, was also evaluated through fractional inhibitory concentration index (FICI) assay. The ultra-structural changes in bacterial cells after the treatment of tschimganin (1) were studied by using scaning and transmission electron microscopy. The anti-bacterial activity of tschimganin (1) in the presence of blood (ex vivo) was also studied. Tschimganin (1) facilitates the anionic probe to enter in to the depolarized bacterial cell membrane and binds with the lipid rich cellular components. Most importantly, it reverse the drug resistance and augment the sensitivity of already failed drugs by lowering their minimum inhibitory concentrations (MICs). Monoterpene, tschimganin (1) (Ferula ovina (Bioss). Bioss) was thus identified as a new resistance reversal agent against multi-drug resistant Staphylococcus aureus.

Objective: The objective of the study was to synthesize a series of 3-chloro-4-(substituted phenyl)-1-(5-styryl-1, 3, 4-thiladiazole-2-yl) azetidin-2-one / 2-(substituted phenyl)-3-(5-styryl-1, 3, 4- thiadiazole-2-yl)-thiazolidin-4-one and screened for their possible anti-inflammatory activity by carrageenan induced paw edema in rats. Method: The synthesis of 2-amino-5-styryl-1, 3, 4-thiadiazole, an intermediate was carried out by oxidative cyclization method. In the current study, thiosemicarbazone (I) was subjected to oxidative cyclization using ferric chloride as an oxidising agent, to get 2- amino- 5- styryl -1, 3, 4-thiadiazole (II). Futhermore, compound (II) was reacted with different aromatic aldehydes in methanol to form N-(4-sustituted)- 5- styryl- 1, 3, 4-thiadiazol-2-amine (III a-h). Compound (III ah) was reacted with chloroacetyl chloride in triethylamine to form 2-azetidinone derivatives bearing 1, 3, 4-thiadiazole nucleus (IV a-h). Compound (III a-h) on cyclocondensation with mercaptoacetic acid leads to the formation of 4- thiazolidinone derivatives bearing 1, 3, 4-thiadiazole nucleus (V a-h). Results: The synthesis of the targeted compounds IVa-h and Va-h was confirmed through their MP, IR, 1H-NMR and mass spectrum studies. Compounds IVa, IVb and IVc (56.32, 61.11 and 58.24 % inhibition) exhibited significant antiinflammatory activity than that of diclofenac (65.13% inhibition). Conclusion: It may be concluded that the presence of methoxy, nitro and hydroxyl phenyl groups substituting 2- azetidinone bearing 1, 3, 4-thiadiazole showed significant anti-inflammatory activity.

A series of 6-diethylaminoquinazolin-4(3H)-ones with bulky aryl rings at C2 were designed to cover the vacant space of ligand binding pocket of topoisomerase (topo) I-DNA complex. The desired derivatives were synthesized by thermal cyclodehydration/ dehydrogenation reactions of 5-diethylaminoanthranilamide with substituted aromatic aldehydes. The cytotoxicity of these compounds was evaluated against human epidermoid carcinoma (KB), hepatocellular carcinoma (Hep-G2), human lung carcinoma (LU-1) and human breast carcinoma cells (MCF-7). Most of the synthesized compounds exhibited more potent cytotoxicity than the standard anticancer agent, ellipticine. Among the tested compounds, quinazolinone 1l was the most cytotoxic against all cancer cell lines (IC50: 0.02–0.08 μM). Docking study showed that the new 2-aryl-6- diethylaminoquinazolinones possibly inhibit topo I activities to exhibit anticancer properties.

A series of novel ethyl 1-(2-(4-(2-amino-5-(ethoxycarbonyl) phenyl) piperazin-1-yl) ethyl)-2-(2-(substituted) pyridin-3-yl)-1H-benzo[d]imidazole-5-carboxylate analogues were synthesized and screened as p38 MAP kinase inhibitors. The 4-chlorophenoxy substitution in the 2nd position of the pyridyl moiety (5i) gave effective inhibition of p38 with IC50 17μM. Moreover, the synthesized benzimidazole derivatives possess a significant antiproliferative activity against blood-leukemia (CCRF-CEM), colon (HCT-116) and breast (MDA-MB-468) cancer cell lines. Based on the report, we discussed structure-activity relationship (SAR) study of synthesized benzimidazole derivatives. Molecular modelling performed for the identification of most active compounds by using three dimensional crystal structures of MAPK p38, provide a disclosed binding template of these inhibitors in the active site of their respective enzyme.

Objective: The goal of this study was to prepare and characterize superparamagnetic iron oxide-polyethylene glycol-chlorotoxin(SPIO-PEG-CTX) nanoparticles and validate their magnetic resonance imaging properties in vitro. Materials and Methods: SPIO (superparamagnetic iron oxide) was prepared using the coprecipitation method by dropping a solution of ferric iron (Fe3+) and ferrous iron (Fe2+) in a molar ratio of 2:1 to the alkaline solution (OH-). The SPIO was modified with PEG (polyethylene glycol) and CTX (chlorotoxin) on the surface. The particle size and its distribution were analyzed using a laser particle size analyzer, and the core shape was studied using transmission electron microscopy. 3.0T MRI was performed on the SPIO and SPIO-PEG-CTX solutions. Results: The particle sizes of SPIO and SPIO modified by PEG-silane were between 20 nm and 35 nm with a uniform configuration. In vitro magnetic resonance signals of the SPIO and SPIO-PEG-CTX solution had the same variations. With increasing concentrations of the solutions, the signal intensity increased at T1WI, but decreased at T2WI. Conclusion: SPIO-PEG-CTX nanoparticles were prepared and analyzed using in vitro MRI, which provided the theoretical basis for further study of the nanoparticles for use in the early diagnosis of hepatocellular carcinoma.

A series of novel biphenyl derivatives with α-aminophosphonate moiety was designed and successively synthesized through Suzuki-Miyaura and Kabachnik-Fields reaction. The structures of the target compounds were confirmed by 1H NMR, 13C NMR, 31P NMR, IR and H MRS. The antiviral activity against tobacco mosaic virus (TMV) and cucumber mosaic virus (CMV) indicated that most of the target compounds exhibited certain anti-TMV and good anti-CMV activities, respectively, in which compound 4d displayed higher anti-TMV activity and compound 4s exhibited higher anti-CMV activity than the commercial agent Ningnanmycin.

Two groups of amphipathic peptides, based on the Schiffer/Edmundson helical-wheel model, were designed, synthesized and their antimicrobial and hemolytic activities were studied. The first group includes the peptides X-RWLRLLWRFLRL- NH2, where X=H, Ac, Ahx (aminohexanoic) and Myr (Myristoyl). Specific substitutions were introduced in the hydrophobic /hydrophilic face or the N-terminal group in order to investigate how these modifications affect their antimicrobial activity. The second group comprises three analogs of aurein 1.2 H- GLFDIIKKIAESF-NH2, a natural antimicrobial amphipathic peptide, obtained by replacing Gly with Ala, Val and Leu successively. The influence of these modifications on the reactivity of aurein was also studied. The helical conformation of the synthetic peptides was evaluated by circular dichroism. Comments regarding the nature, the total charge and the availability of the N-terminal groups are discussed in relation to the antimicrobial reactivity of the reported peptides.