Synthesis, antileishmanial activity and molecular modeling of new 1-aryl/alkyl-3-benzoyl/cyclopropanoyl thiourea derivatives.

Due to the lack of effective vaccine(s) against leishmania and also pharmacokinetics issues of current drugs, it is necessary to discover new antileishmanial agents. Within this particular study, a series of novel 1-aryl/alkyl-3-benzoyl/cyclopropanoyl thiourea derivatives were synthesized (yields 69-84%) and evaluated as antileishmanial compounds (1-11). Synthetic derivatives were subjected to in vitro antileishmanial assessment against Leishmania major promastigotes by colorimetric MTT assay. Compounds 3 (IC50 38.54 µg/mL), 5 (IC50 84.75 µg/mL) and 10 (IC50 70.31 µg/mL) exhibited higher activities after 48 h but were less potent than amphotericin B (IC50 0.19 µg/mL). Antileishmanial activities indicated priority of 5-methyl-4-phenyl thiazole over furyl methyl substituents and 4-phenyl thiazole on thiourea nitrogen. N-myristoyltransferase (NMT) was selected as a validated L. major target for molecular docking studies. In silico results indicated the contribution of hydrophobic, π-stacking and H-bond interactions in binding to target. Most of the synthesized derivatives had lower binding affinities to human NMT (hNMT) than leishmanial enzyme. Docking conformations of top-ranked selective binders (compounds 3 and 5) were subjected to 50 ns MD simulations inside L. major HMT (LmNMT) active site. MD trajectories were used to extract RMSD, RMSF, Rg and durability of intramolecular/intermolecular H-bonds of the complex. It was observed that compound 3 escaped from LmNMT binding site during simulation period and no stable complex could be envisaged. Unlike 3, compound 5 attained stable binding conformation with converged stability parameters. Although mechanistic details for antileishmanial effects of synthesized derivatives are to be explored, current results may be implicated in further structure-guided approach toward potent antileishmanial agents.

Synthesis of New Thioureas Derivatives and Evaluation of Their Efficacy as Proliferation Inhibitors in MCF-7 Breast Cancer Cells by Using 99mTc-MIBI Radiotracer.

BACKGROUND AND OBJECTIVES: Anti-tumor activity of some thioureas derivatives is well documented in literature and received considerable attention. The present study aims to synthesize and characterize some novel thioureas and carbonylthioureas as anti-tumor agents for MCF-7 breast cancer cells in vitro and in vivo. MATERIALS AND METHODS: Several 1-allyl-3-(substituted phenyl), N,N'-(phenylene) bis(3- allyldithithiourea) and 1-cyclopropanecarbonyl-3-(substituted phenyl)-thioureas derivatives were synthesized and confirmed by FT-IR spectroscopy, NMR and 13C-NMR. Anti-tumor activity of these compounds was determined by various in vitro and in vivo assays including; MTT, tumor volume measurement as well as,99mTc-MIBI tumor uptake in MCF-7 tumor bearing nude mice. RESULTS: Among all of the synthesized compounds, some thioureas derivatives [3i] and [4b] at 100 nM concentration exhibited significant inhibitory effects on the proliferation of MCF-7 cell in vitro. However, this inhibition was not observed in HUVEC human endothelial normal cells. In vivo anti-tumor effects of the synthesized compounds on MCF-7 xenograft mouse models demonstrated a reduction in the tumor volume for various concentrations between 2 to 10 mg/kg after 21 days. These effects were comparable with Tamoxifen as standard anti-estrogen drug. According to the 99mTc-MIBI biodistribution result, treatment of MCF-7 bearing nude mice with both [3i] and [4b] compounds at the maximum concentration (10 mg/kg) can lead to a significant decrease of 99mTc- MIBI tumor uptake. CONCLUSION: Compounds [3i] and [4b] suppressed the growth of MCF-7 cells in the xenograft nude mice at the doses that were well-tolerated. Our study suggests that these new compounds with their significant anti-tumor effects, may serve as useful candidates for breast cancer therapy.

Amination of aryl halides with aqueous ammonia catalyzed by green recyclable poly(4-vinylpyridine)-supported copper iodide nanoparticles catalyst.

In this research efficient procedure for the amination of aryl halides with aqueous ammonia in the presence of poly(4-vinylpyridine)-supported copper iodide nanoparticles catalyst is reported. A wide range of aryl halides including aryl iodides and aryl bromides are converted into the corresponding aniline derivatives. The experimental procedure with poly(4-vinylpyridine)-supported copper iodide nanoparticles catalyst is quite straightforward and it is recycled up to 3 consecutive runs by simple filtration.