Letters in Drug Design & Discovery - Volume 11, Issue 3, 2014

Chagas disease is an infection caused by the intracellular protozoan Trypanosoma cruzi. It is estimated that more than 10 million people are infected, with 25 million living in areas at risk. The only drugs currently used in the therapy against this disease are nifurtimox and benznidazole; both, however, are only effective in the acute phase and also highly toxic. Therefore, the development of new drug candidates against this illness is of utmost importance. Cruzain, a cysteine protease involved in intracellular replication and differentiation of T. cruzi, has been selected as an attractive target for the development of new antitrypanosomal agents. In this context, compounds such as chalcones and hydrazides have presented a promising inhibitory activity against cruzain and hence are promising antichagasics. In this work we have applied molecular modeling methods and docking studies to evaluate the stereoeletronic properties of a series of compounds with cruzain inhibitory activity.

In the course of our ongoing program dedicated to the synthesis of anti-proliferative compounds, we prepared new troglitazone derivatives bearing a biphenyle moiety. The chromane heterocycle was further replaced by imidazole and triazole derivatives. Many compounds exhibited fair to high activity towards various cancer cell lines. Among them, compound 17b reduced cell viability leading to only 22-34% viable cells in four cancer cell lines at 10 μM, but unfortunately also led to a low (13%) cell viability of non-malignant primary cultured human hepatocytes at 200 μM. Interestingly, compound 11b also reduced cell viability in colon and liver cancer cell lines (29% and 24% cell viability respectively at 10 μM), but maintained a high cell viability of non-malignant hepatocytes (reaching 71% cell viability at 200 μM), thus exhibiting a huge selectivity.

A QSAR study is reported to predict the binding affinity of a set of 81 modulators for both of human estrogen receptor α and β (ERα and ERβ). In this study, the derived QSAR models were built by forward stepwise multilinear regression (MLR) and nonlinear radial basis function neural networks (RBFNN), respectively. The statistical characteristics of the external test set provided by multiple linear model (R2=0.814, F=61.277, RMS=0.5461 for ERα; R2=0.600, F=21.039, RMS=0.6707 for ERβ) indicated satisfactory stability and predictive ability of the model built. The predictive ability for ERβ of RBFNN model is somewhat superior: R2=0.7691, F=32.012, RMS=0.5764, and the similar result was obtained for ERα of the test set: R2=0.7950, F=54.131 RMS=0.3120. Overall, the appropriate results proved the models to be meaningful and useful to predict and virtual screen of the derivatives with high binding activity.

Semi-synthetic C-10 alkyl thio analogues of the cytotoxic natural alkaloid colchicine have been found to exhibit cytotoxicity towards tumour cell lines at levels comparable to that of the natural product. An efficient synthesis of 10-alkyl thiocolchicines in mild conditions is proposed and the products are studied by 1H and 13C NMR, FT-IR, MS-EI methods and elementary analysis. The crystal structure of 10-ethylthiocolchicine is characterised using X-ray diffraction methods. Cytotoxic activity against selected cancer cell lines for all obtained 10-alkylthio analogues of colchicine is also reported.

A series of 4,5-disubstituted-1,2,4-triazole-3-thione derivatives (4a-e) and their N-Mannich bases (5a-e), together with a S-benzyl derivative (6), were synthesized and evaluated as antimycobacterial and antiproliferative agents. The structures of the compounds were established by IR, 1H-NMR, 13C-NMR and 2D-NMR spectroscopic methods and microanalysis. 4 and 5 were screened for in vitro antimycobacterial activity against Mycobacterium tuberculosis H37Rv (ATCC 27294). Three of the tested compounds (4d, 4e and 5e) were found to be active in the primary screen. Among them, compound 4e was the most potent one with IC90 and IC50 values of 27.5 and 20.8 μg/mL, respectively. Additionally, compounds 4b, 4c, 5b, 5c, 5e and 6 were subjected to the NCI’s in vitro disease-oriented antitumor screening to be evaluated for antitumor activity at a single dose of 10 μM. The S-benzyl derivative 6 exhibited promising antiproliferative activity against leukemia CCRF-CEM, RPMI-8226 and SR, non-small cell lung cancer HOP-92, melanoma UACC-62 and renal cancer UO-31 cell lines.

The paper presents a novel synthesis of AZT modified derivatives via click chemistry. Firstly, the reaction of 2,4-dihydroxyacetophenone (1) with propargyl bromide in acetone gave intermediates 2 in 75% yield. Next, new chalcones 3a-g were obtained in 55-65% yields through the Claisen-Schmidt reaction of 2 with different aromatic aldehydes. These chalcones were then oxidatively cyclized in DMSO in the presence of I2 to furnish new flavones 4a-g in 45-59% yields. Finally, title compounds 5a-g and 6a-g were obtained via click reaction of 3a-h and 4a-h with 3’-Azido-2’- deoxythymidine (AZT). Novel AZT derivatives 5a-g, 6a-g were evaluated for in vitro cytotoxic activity against five cell lines: MCF-7, SK-LU-1, SW480, HepG2 and P388. The result showed that most of AZT derivatives are active to five cell lines, in which compounds 5g and 5e are found to be the most potent cytotoxic activity against SK-LU-1 and P388 cell lines with IC50 value of 8.63 and 9.05 μg/mL, respectively.

A series of 1,3,4-oxadiazole-2-thiol incorporating fatty acid moieties was synthesized. The chemical structure of the synthesized compounds was established by their spectral data, elemental analysis, and their chemical behavior. Their thioglycosides derivatives and the analogous 1,2,4-triazole were also prepared. The in vitro cytotoxicty of the synthesized compounds was screened against two cell lines; breast cell line MCF-7, and liver cell line HepG2. The most potent compound is (E)-5-(heptadec-8-enyl)-1,3,4-oxadiazole-2-thiol 4f with IC50 (2.82 | μg/ml) and (3.87 μg/ml) against breast cell line MCF-7 and liver cell line HepG2 respectively. Molecular Docking study of Bcl-2 was conducted for the most potent compound, its analogues and the lowest cytotoxicty compound. The antimicrobial activity was also screened, compound (E)-5-ethyl-1,3,4-oxadiazole-2-thiol 4a showed a broad spectrum of activity. A relationship between the length of the fatty acid chain and the biological activity was noticed in the tested compounds.

In the present study, 3D-QSAR analysis was performed on a set of 37 TGF-β inhibitors utilizing pharmacophore based alignment to uncover the essential structural and steric features of these newly discovered b-annulated 1,4- dihydropyridine (1,4-DHP) molecules to get better antagonism of the TGF-β receptor. The best 3D-QSAR model identified with PLS factor 4 that had the highest values of external predictability parameters exhibited Q2 (0.8972), and R2 (0.9826) and displayed high values of F (281.9) and low SD (0.0785). This selected model was validated statistically by determining Pearson-r (0.9718) for test set molecules. Contours thus obtained from different properties generated using our QSAR model explained the variation in the activity of dataset with respect to different attachments in the core structure. This would help to make suitable structural modifications in 1, 4-DHP molecules so as to make a better complementary fit to the active site of TGF-β receptor, which in turn would improve the potency of newly designed molecules.

Cholinesterases (ChEs) play a vital role in the regulation of cholinergic transmission. The inhibition of ChEs is considered to be involved in increasing acetylcholine level in the brain and thus has been implicated in the treatment of Alzheimer’s disease. We have designed and synthesized a series of novel indole derivatives and screened them for inhibition of acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). Most of the tested compounds exhibited inhibitory activity against AChE and BChE. Among them 4f and 6e showed the highest AChE inhibitory activity with IC50 91.21±0.06 and 68.52±0.04 μM, respectively. However compound 5a exhibited the highest inhibitory activity against BChE (IC50 55.21±0.12 μM).

Transthyretin (TTR) is a homotetrameric plasma protein that has been associated with numerous human amyloid diseases. Although Tafamidis has recently been approved for the treatment of TTR familial amyloid polyneuropathy (FAP), there is still a need persists for drugs that are more effective in the treatment of TTR amyloidosis diseases. Therefore, we propose ligand-based and structure-based pharmacophore models were generated in this study based on the chemical features present in active TTR amyloidosis inhibitors and the binding information of TTR-DZ2 complex, respectively, to screen chemical databases to identify potential drug candidates. Subsequently, the hits with good fit values were filtered based on absorption-distribution-metabolism-excretion-toxicity (ADMET), as well as molecular docking and receptor- specific scores. Furthermore, their binding stabilities were validated using 10-ns molecular dynamics (MD) simulations. Finally, only 2 compounds (NSC 246123 and Compound 52292) that exhibited higher binding affinities than that of Tafamidis were identified as potential leads. To our knowledge, this report is the first pharmacophorebased virtual screening study presenting the discovery of novel TTR amyloidosis inhibitors. The findings should be a useful guide for the rapid identification of novel therapeutic agents from chemical databases.

Here we employed simple chemistry for the synthesis of a new potent series of benzo[b]thiophene containing 2-carbonylchlorides (1), 2-isopropyl carboxamides (2), 2-(piperidin-1-yl)-methanones (3) by nucleophilic chloro cyclocondensation of substituted-cinnamic acids with thionyl chloride to afford benzo[b]thiophene nucleus. The constitution of the products has been delineated by elemental analysis and spectral analyses. The products were assayed for their in vitro antimicrobial assay at different concentrations which were compared with Ampicillin, Chloramphenicol, Ciprofloxacin, Norfloxacin and Griseofulvin as standard drug available. The structure activity relationships of synthesized compounds are also studied. The preliminary in vitro biological screening of the title compounds revealed that compounds 2b, 2c, 2e, 3c and 3h exhibited significant (maximum) antibacterial activities where other compounds showed moderate to low activity.

Nineteen N'-(benzylidene)-2-[(pyrimidin-2-yl)thio]acetohydrazides were obtained via the nucleophilic addition- elimination reaction of 2-[(pyrimidin-2-yl)thio)]acetohydrazide with aromatic aldehydes. The synthesized compounds were tested in vitro against various bacteria by microdilution. Among these compounds, N'-(3- hydroxybenzylidene)-2-[(pyrimidin-2-yl)thio]acetohydrazide (3l) was found to be the most potent derivative (MIC 7.8- 15.62 μg/mL) against Staphylococcus aureus (ATCC 6538), Staphylococcus epidermidis (ATCC 12228), and Escherichia coli (O157:H7-Clinical isolate), respectively. This outcome confirms that m-hydroxyphenyl moiety may have a considerable influence on antibacterial activity of the series tested. In the view of the results of the current work, further research can be carried out on the development of new effective antibacterial agents by the modification of compound 3l.

The interaction of hepcidin (HEPC) and ferroportin (FPN) is an essential event in iron homeostasis. HEPC binds to FPN, and subsequently degrades it through phosphorylation and ubiquitination. Present work described a computational study to identify interfacial residues involved in FPN–HEPC interactions. We have predicted three-dimensional structure of human FPN using homology modeling followed by docking analysis and molecular dynamics simulations. Our study revealed that FPN has HEPC-binding sites on extracellular loops: ECL4, ECL5 and ECL6. The provided outcome is consistent with mutagenesis studies on FPN. We have identified several electrostatic interactions between charged residues Asp325 (ECL4), ECL5 (Glu448) and Glu518 (ECL6) of FPN with residues His3, Arg16, Lys18 of HEPC, which are essentially important for interfacial contact between them. These results provide an evidence for structural basis of FPN–HEPC interactions and their future clinical application.

N-[(7-pyridin-4-yl-2, 3-dihydro-benzofuran-2-yl) methyl]-(4-methyl-1, 2, 3-thiadiazole-5-yl)-Formamide (1) was synthesized and its immunosuppressive activity was evaluated. The results showed it had highly immunosuppressive activity and can be studied as lead compound in the development of immunosuppressant agent.

A new series of (1R,5R)-(-)-3-arylidenenopinones was synthesized from (1S,5S)-(-)-β-pinene which was a natural chemical from pine tree, and their ultraviolet absorption characteristics were investigated. (1R,5S)-(+)-nopinone was obtained from (1S,5S)-(-)-β-pinene by selective oxidation, and then it was reacted with benzaldehyde, phydroxybenzaldehyde, vanillin, o-vanillin, p-chlorobenzaldehyde, and p-methylaldehyde in the presence of alkali catalysts to get (1R,5R)-(-)-3-arylidenenopinones including (1R,5R)-(-)-3-benzylidenenopinone (1), (1R,5R)-(-)-3-(4′-hydroxybenzylidene) nopinone (2), (1R,5R)-(-)-3-(4′-hydroxy-3′-methoxybenzylidene)nopinone (3), (1R,5R)-(-)-3-(2′-hydroxy-3′- methoxybenzylidene)nopinone (4), (1R,5R)-(-)-3-(4′-chlorolbenzylidene)nopinone (5) (1R,5R)-(-)-3-(4′-methylbenzylidene) nopinone (6), and (1R,5R)-(-)-3-(furan-2′-ylmethylene)nopinone (7). The structures of (1R,5R)-(-)-3-arylidenenopinones were determined by FT-IR, 1H NMR, 13C NMR and GC-MS techniques. Their ultraviolet absorption characteristics and light stability was further examined. The results showed that compounds 1, 2, 5, 6 and 7 could be used as B-type UV absorbents, and compounds 3 and 4 had both functions as UV-A and UV-B types absorbents because of their wide range of UV absorption at 200-390 nm and 280-290 nm respectively. The light stability sequence of these compounds was (6)≈(7)>(3)>(5)>(2)>(1)>(4).