Studies of 4-arylthiazolylhydrazones derived from 1-indanones as Trypanosoma cruzi squalene epoxidase inhibitors by molecular simulations.

Chagas disease or American trypanosomiasis is a parasitic disease caused by the protozoan Trypanosoma cruzi. Its squalene epoxidase (SE) is a target for drug design and development because it is a key enzyme in the biosynthetic pathway of ergosterol, which is essential for the life cycle of the parasite. Previously, we reported that some 4-arylthiazolylhydrazones derived from 1-indanones (TZHs) active against T. cruzi are able to accumulate squalene probably by SE inhibition. In this work, we performed a series of theoretical studies to verify that TZHs act as inhibitors of this enzyme. Since the crystal structure of SE is unknown for all species, we built a 3D enzyme model of T. cruzi SE by homology modeling. Based on this model, we carried out docking, molecular dynamics, and MM/PBSA calculations and the results were compared with those found for the reference inhibitor compound terbinafine (Tbf). The binding free energy values allowed the discrimination between accumulators and non-accumulators of squalene compounds, in agreement with the experimental findings. Pairwise residue free energy decomposition showed that the key amino acids involved in inhibitor binding for TZHs and Tbf were the same. Also, molecular superposition analysis between these compounds revealed high structural similarity. In addition, we proposed a pharmacophore model for T. cruzi SE inhibitors, which confirmed that TZHs and Tbf share chemical features with respect to their biochemical interaction characteristics at similar positions in 3D space. All theoretical calculations suggest that the experimentally observed squalene accumulation is produced by T. cruzi SE inhibition.

N4 -aryl substituted thiosemicarbazones derived from 1-indanones as potential anti-tumor agents for breast cancer treatment.

Breast cancer is the first cause of cancer death in women. Many patients are resistant to current therapies, and even those were sensitive at first may eventually become resistant later. Thiosemicarbazones (TSCs) are synthetic compounds that exhibit several pharmacological activities. In this study, we investigated the potential anti-tumor activity of a set of N4 -arylsubstituted TSCs (N4 -TSCs) on human breast cancer cell lines. Studies on the effect of N4 -TSCs (T1, T2, and T3) were carried on MCF-7, MDA-MB 231, and BT 474 cell lines which differ in their expression of ER, PR, and Her2/neu. Non-transformed MCF-10A breast cell line were used as normal cells. Action of N4 -TSCs were evaluated by proliferation assay, quantification of apoptosis and cell cycle analysis. Modulation of clonogenic efficiency and migratory capacity by N4 -TSCs were also evaluated. We further investigated the effects of N4 -TSCs on ROS level and Ribonucleotide Reductase (RR) activity. We analyzed the action of these compounds on cellular mammosphere-forming capacity. We found that T1 and T2 had specific anti-tumor effect on all breast cancer cell lines based on their pro-apoptotic action and inhibitory effect on clonogenic efficiency and cell migration capacity. We also showed that both compounds increased ROS level and inhibited RR activity. Finally, we found that all N4 -TSCs diminished mammospehere-forming capacity of MCF-7 and BT 474 cells. N4 -TSCs showed specific anti-tumor action on human breast cancer cells independently their biomarkers expression pattern. Our results place these compounds as promising novel anti-tumor drugs with potential therapeutic application against different types of breast cancer.

Synthesis, antiviral evaluation and molecular docking studies of N4-aryl substituted/unsubstituted thiosemicarbazones derived from 1-indanones as potent anti-bovine viral diarrhea virus agents.

A series of N4-arylsubstituted thiosemicarbazones derived from 1-indanones and a set of compounds lacking such substitution in the N4 position of the thiosemicarbazone moiety were synthesized and evaluated for their anti-bovine viral diarrhea virus (BVDV) activity. Among these, derivatives 2 and 15 displayed high activity (EC50=2.7±0.4 and 0.7±0.1µM, respectively) as inhibitors of BVDV replication. Novel key structural features related to the anti-BVDV activity were identified by structure-activity relationship (SAR) analysis. In a previous study, the thiosemicarbazone of 5,6-dimethoxy-1-indanone (5,6-TSC) was characterized as a non-nucleoside inhibitor (NNI) of the BVDV RNA-dependent RNA polymerase. In the present work, cross-resistance assays were performed with the most active compounds. Such studies were carried out on 5,6-TSC resistant BVDV (BVDV-TSCr T1) carrying mutations in the viral polymerase. This BVDV mutant was also resistant to compound 15. Molecular docking studies and MM/PBSA calculations were performed to assess the most active derivatives at the 5,6-TSC viral polymerase binding site. The differences in the interaction pattern and the binding affinity of derivative 15 either to the wild type or BVDV-TSCr T1 polymerase were key factors to define the mode of action of this compound.

QSAR study and conformational analysis of 4-arylthiazolylhydrazones derived from 1-indanones with anti-Trypanosoma cruzi activity.

A set of 4-arylthiazolylhydrazones derived from 1-indanones (TZHs) previously synthesized and assayed against Trypanosoma cruzi, the causative agent of Chagas disease, were explored in terms of conformational analysis. We found that TZHs can adopt four minimum energy conformations: cis (A, B and C) and trans. The possible bioactive conformation was selected by a 3D-QSAR model. Different molecular parameters were calculated to produce QSAR second-generation models. These QSAR results are discussed in conjunction with conformational analysis from molecular modeling studies. The main factor to determine the activity of the compounds was the partial charge at the N(3) atom (qN3). The predictive ability of the QSAR equations proposed was experimentally validated. The QSAR models developed in this study will be helpful to design novel potent TZHs.

Activity on Trypanosoma cruzi, erythrocytes lysis and biologically relevant physicochemical properties of Pd(II) and Pt(II) complexes of thiosemicarbazones derived from 1-indanones.

American trypanosomiasis or Chagas disease, caused by the protist parasite Trypanosoma cruzi (T. cruzi), is a major health concern in Latin America. In the search for new bioactive compounds, eight Pd(II) and Pt(II) complexes of thiosemicarbazones derived from 1-indanones (HL) were evaluated as potential anti-T. cruzi compounds. Their unspecific cytotoxicity was determined on human erythrocytes. Two physicochemical features, lipophilicity and redox behavior, that could be potentially relevant for the biological activity of these complexes, were determined. Crystal structure of [Pd(HL1)(L1)]Cl·CH(3)OH, where HL1=1-indanone thiosemicarbazone, was solved by X-ray diffraction methods. Five of the eight metal complexes showed activity against T. cruzi with IC(50) values in the low micromolar range and showed significantly higher activity than the corresponding free ligands. Four of them resulted more active against the parasite than the reference antitrypanosomal drug Nifurtimox. Anti-T. cruzi activity and selectivity towards the parasite were both higher for the Pd(II) compounds than for the Pt(II) analogues, showing the effect of the metal center selection on the biological behavior. Among both physicochemical features tested for this series of compounds, lipophilicity and redox behavior, only the former seemed to show correlation with the antiproliferative effects observed. Metal coordination improved bioactivity but lead to an increase of mammalian cytotoxicity. Nevertheless, some of the metal complexes tested in this work still show suitable selectivity indexes and deserve further developments.

Synthesis and biological evaluation of some novel 1-indanone thiazolylhydrazone derivatives as anti-Trypanosoma cruzi agents.

A series of novel 4-arylthiazolylhydrazones (TZHs) derived from 1-indanones were synthesized in good yields (66-92%) in a simple procedure using microwave irradiation and then characterized by spectroscopy studies. The compounds were evaluated for their in vitro anti-Trypanosoma cruzi activity against the epimastigote, trypomastigote and amastigote forms of the parasite. Most TZHs displayed excellent activity, and were more potent and selective than the reference drug Benznidazole, used in the current chemotherapy. Analysis of the free sterols from parasite incubated with the compounds showed that inhibition of ergosterol biosynthesis is a possible target for the action of these new TZHs. In particular, TZH 9 emerged as a promising antichagasic compound to be evaluated in animal models.

Thiosemicarbazones derived from 1-indanones as new anti-Trypanosoma cruzi agents.

In the present work, we synthesized a series of thiosemicarbazones derived from 1-indanones with good anti-Trypanosoma cruzi activity. Most of them displayed remarkable trypanosomicidal activity. All the compounds showed nonspecific cytotoxicity on human erythrocytes. The ability of the new compounds to inhibit cruzipain, the major cysteine protease of T. cruzi, was also explored. Thiosemicarbazones 12 and 24 inhibited this enzyme at the dose assayed. This interaction was also studied in terms of molecular docking.

Synthesis, structural characterization, and pro-apoptotic activity of 1-indanone thiosemicarbazone platinum(II) and palladium(II) complexes: potential as antileukemic agents.

In the search for alternative chemotherapeutic strategies against leukemia, various 1-indanone thiosemicarbazones, as well as eight novel platinum(II) and palladium(II) complexes, with the formula [MCl2(HL)] and [M(HL)(L)]Cl, derived from two 1-indanone thiosemicarbazones were synthesized and tested for antiproliferative activity against the human leukemia U937 cell line. The crystal structure of [Pt(HL1)(L1)]Cl·2MeOH, where L1=1-indanone thiosemicarbazone, was solved by X-ray diffraction. Free thiosemicarbazone ligands showed no antiproliferative effect, but the corresponding platinum(II) and palladium(II) complexes inhibited cell proliferation and induced apoptosis. Platinum(II) complexes also displayed selective apoptotic activity in U937 cells but not in peripheral blood monocytes or the human hepatocellular carcinoma HepG2 cell line used to screen for potential hepatotoxicity. Present findings show that, in U937 cells, 1-indanone thiosemicarbazones coordinated to palladium(II) were more cytotoxic than those complexed with platinum(II), although the latter were found to be more selective for leukemic cells suggesting that they are promising compounds with potential therapeutic application against hematological malignancies.

Inhibition of bovine viral diarrhea virus RNA synthesis by thiosemicarbazone derived from 5,6-dimethoxy-1-indanone.

In the present work, we described the activity of the thiosemicarbazone derived from 5,6-dimethoxy-1-indanone (TSC), which we previously characterized as a new compound that inhibits bovine viral diarrhea virus (BVDV) infection. We showed that TSC acts at a point of time that coincides with the onset of viral RNA synthesis and that it inhibits the activity of BVDV replication complexes (RCs). Moreover, we have selected five BVDV mutants that turned out to be highly resistant to TSC but still susceptible to ribavirin (RBV). Four of these resistant mutants carried an N264D mutation in the viral RNA-dependent RNA polymerase (RdRp). The remaining mutant showed an A392E mutation within the same protein. Some of these mutants replicated slower than the wild-type (wt) virus in the absence of TSC, whereas others showed a partial reversion to the wt phenotype over several passages in the absence of the compound. The docking of TSC in the crystal structure of the BVDV RdRp revealed a close contact between the indane ring of the compound and several residues within the fingers domain of the enzyme, some hydrophobic contacts, and hydrogen bonds with the thiosemicarbazone group. Finally, in the mutated RdRp from resistant BVDV, these interactions with TSC could not be achieved. Interestingly, TSC inhibited BVDV replication in cell culture synergistically with RBV. In conclusion, TSC emerges as a new nonnucleoside inhibitor of BVDV RdRp that is synergistic with RBV, a feature that turns it into a potential compound to be evaluated against hepatitis C virus (HCV).

New 1-indanone thiosemicarbazone derivatives active against BVDV.

Identification of new therapeutic agents for the treatment of viral diseases represents an area of active investigation. In an effort to develop new antiviral compounds, a series of 1-indanone thiosemicarbazone derivatives were synthesized. These derivatives were structurally characterized using several spectroscopic techniques and evaluated against bovine viral diarrhoea virus as a surrogate model for hepatitis C virus. Thiosemicarbazone 2m showed potent anti-bovine viral diarrhoea virus activity with a higher selectivity index (SI=80.29) than that of ribavirin (SI=11.64). This result determines the potentiality of these thiosemicarbazones as antiviral agents for the treatment of infections caused by other highly related members of Flaviviridae family, as hepatitis C virus.

Design, synthesis, and biological evaluation of alcyopterosin A and illudalane derivatives as anticancer agents.

The synthesis of alcyopterosin A and a series of new derivatives possessing an illudalane skeleton is described. The DNA binding properties of these compounds have been examined and compared to those of reference drugs using a UV spectroscopy technique. The antitumor activity of selected compounds against a panel of 60 human tumor cell lines was tested in the in vitro anticancer screening of the National Cancer Institute. Redox properties were also evaluated. Tested compounds showed significant DNA affinity, derivatives 6 and 15 exhibited remarkable antiproliferative activity and have been identified as new leads in the antitumor strategies.