María Font

Design, Synthesis, and Biological Evaluation of Phosphoramide Derivatives as Urease Inhibitors

The design, synthesis, and biological evaluation of phosphoramide derivatives as urease inhibitors to reduce the loss of ammonia has been carried out. Forty phosphorus derivatives were synthesized and their inhibitory activities evaluated against that of jack bean urease. In addition, in vivo assays have been carried out. All of the compounds were characterized by IR, (1)H NMR, MS, and elemental microanalysis. In some cases, detailed molecular modeling studies were carried out, and these highlighted the interaction between the enzyme active center and the compounds and also the characteristics related to their activity as urease inhibitors. According to the IC(50) values for in vitro inhibitory activity, 12 compounds showed values below 1 microM and 8 of them represent improvements of activity in comparison to the commercial urease inhibitor N-n-butylthiophosphorictriamide (NBPT) (100 nM) (AGROTAIN). On the basis of the activity results and the conclusions of the molecular modeling study, a structural model for new potential inhibitors has been defined.

Selenium and Clinical Trials: New Therapeutic Evidence for Multiple Diseases

The understanding of the essential role of selenium (Se) in human health has increased substantially in recent decades. Micronutrient deficiencies are very common in the general population and may be even more common in patients with different pathologies due to genetic or environmental causes and prescription drug use. Selenium is used by people in the prevention and/or treatment of different disorders including cardiovascular disease, osteoarthritis, rheumatoid arthritis, hypothyroidism, stroke, atherosclerosis, cancer susceptibility and treatment, HIV, AIDS, neuronal diseases such as Alzheimer or amyotrophic lateral sclerosis, pancreatitis, depression, and diabetes amongst others. Several mechanisms have been suggested to mediate the biological effects of Se and these include antioxidant defence systems, synthesis and stability of metabolites that act as intermediates implicated in diverse selenoproteins expression pathways oxidative metabolism, immune system modulation, DNA intercalators, kinase regulation, enzymatic cofactor, and gene expression. A number of clinical trials in recent years have provided convincing evidence of the central role of this element, either alone or in combination with other micronutrients or antioxidants, in the prevention and treatment of multiple diseases. Based on these studies this review focuses on the advances made so far in the study of mechanisms and applications of selenium compounds that could be suitable for chronic diseases.

Synthesis and in vitro anticancer activities of some selenadiazole derivatives.

A novel series of fourteen substituted selenadiazoles has been synthesized and the compounds tested for their in vitro antiproliferative and cytotoxic activities. The tests were carried out against leukemia (CCRF‐CEM), colon (HT‐29), lung (HTB‐54), and breast (MCF‐7) cancer cells. In order to assess the selectivity of the compounds under investigation the assays were also carried out on two non‐tumoral lines – one mammary (184B5) and one bronchial epithelium (BEAS‐2B) cell line. Assay‐based antiproliferative activity studies revealed that seven derivatives (2a, 2c, 2e, 2f, 2g, 3a, and 3b) exhibited good activity against MCF‐7 cells: for instance, 2c and 2f inhibited cell growth with nanomolar GI50 values. Compound 2f had a better antitumoral profile than vinorelbine and paclitaxel, two drugs that are used as first‐line treatments in advanced, recurrent, and/or metastatic cancer. In the other cell lines the compounds showed moderate activity or were inactive – with the exception of 2a, which was also found to have antiproliferative activity. Modulation of the cell cycle and apoptotic effects of active compounds were further evaluated in MCF‐7 cells. Of these, 6‐bromo[1,2,5]selenadiazolo[3,4‐b]pyridine (2a) was the most active, with an apoptogenic effect 3.9 times higher than that of camptothecin, which was used as a positive control. Compound 2a also provoked cell cycle arrest with a significant decrease in the G0/G1 phase cell population and an increase in S and G2/M cells, thus suggesting mitotic arrest prior to metaphase.

New 5H-1,2,4-triazino[5,6-b]indole and aminoindole derivatives. Synthesis and studies as inhibitors of blood platelet aggregation, anti-hypertensive agents and thromboxane synthetase inhibitors

Abstract This paper reports the synthesis of a series of 5H-1,2,4-triazino[5,6-b]indole 3 and 4, and aminoindole 12–23, derivatives, obtained from isatin 1 and from oxoindole 5, respectively. All the new compounds were studied as antihypertensive agents in spontaneously hypertensive rats (SHR), and as inhibitors of platelet aggregation in guinea pig whole blood, induced by arachidonic acid (AA), adenosin-5′-diphosphate (ADP) or collagen. The most active antiaggregating compounds were also studied as thromboxane A2 synthetase inhibitors.

Structural Characteristics of Phosphoramide Derivatives as Urease Inhibitors. Requirements for Activity

Taking as a reference the structural characteristics of a set of compounds that act as jack bean ( Canavalia ensiformis) urease inhibitors, namely, phenylphosphorodiamidate (PPD), N- n-butylthiophosphorictriamide (NBPT), and N- n-butylphosphorictriamide (NBPTO), we have studied the structure-activity relationships of a series of phosphoramide derivatives for which the activity as urease inhibitors in both in vitro and in vivo assays is known. Molecular modeling studies were carried out, and the results highlighted the relevance of characteristics such as the presence of intramolecular hydrogen bonds, the volume of the fragment involved in the enzyme interaction, and the degree of conformational freedom as well as the HOMO orbital and atomic orbital contributions to the HOMO orbital, electron density, and PEM distributions on the activity of these compounds as urease inhibitors. These data, along with the preliminary docking study carried out, allow us to propose a union mode to the active site of the enzyme for these compounds.

Indoles and pyridazino[4,5-b]indoles as nonnucleoside analog inhibitors of HIV-1 reverse transcriptase

Summary The synthesis and the study of the activity of new indol-2-carboxamides and pyridazino[4,5- b ]indoles as inhibitors of HIV-1 reverse transcriptase (RT) are presented. The activity of the compounds synthesized as inhibitors of different types of HIV-1 RT (wild type enzyme and mutant forms P236L, Y 181C and P236L/Y181C) was evaluated. The activity of the most active compounds was investigated in the syncytia reduction in vitro assay, in HIV-1 IIIB -infected HT4lacZ-1 cells. Their potential cytotoxicity was determined in parallel. Two lead compounds, N -[1-[2-(3-isopropylamino)pyridyl]piperazin]-5,6-methylenedioxy indol-2-carboxamide 7q and N -[1-[2-(3-ethylamino)pyridyl]piperazin]-5,6-methylenedioxyindol-2-carboxamide 7s have been identified.

Synthesis and antiproliferative activity of novel selenoester derivatives.

A series of 31 new selenoesters were synthesized and their cytotoxic activity was evaluated against a prostate cancer cell line (PC-3). The most active compounds were also tested against three tumoural cell lines (MCF-7, A-549 and HT-29) and one non-tumour prostate cell line (RWPE-1). Thirteen compounds showed significant activity towards all tumour cells investigated, and some of them were even more potent than etoposide and cisplatin, which were used as reference drugs. Because of their pronounced potency and/or selectivity, four analogues (5, 21, 28 and 30), were selected in order to assess their redox properties related to a possible redox modulating activity. The glutathione peroxidase (GPx) assay showed slight activity for compound 30 and the 2,2-diphenyl-1-picrylhydrazyl-(DPPH) assay showed a weak activity for compounds 5 and 28. The present results revealed that analogues 5, 21, 28 and 30 might serve as a useful starting point for the design of improved anti-tumour agents.

Synthesis and Pharmacological Screening of Several Aroyl and Heteroaroyl Selenylacetic Acid Derivatives as Cytotoxic and Antiproliferative Agents

The synthesis and cytotoxic activity of a series of twenty six aroyl and heteroaroyl selenylacetic acid derivatives of general formula Ar-CO-Se-CH2-COOH or Heterar-CO-Se-CH2-COOH are reported. The synthesis was carried out by reaction of acyl chlorides with sodium hydrogen selenide, prepared in situ, and this led to the formation of sodium aroylselenides that subsequently reacted with α-bromoacetic acid to produce the corresponding selenylacetic acid derivatives. All of the compounds were tested against a prostate cancer cell line (PC-3) and some of the more active compounds were assessed against a panel of four human cancer cell lines (CCRF-CEM, HTB-54, HT-29, MCF-7) and one mammary gland-derived non-malignant cell line (184B5). Some of the compounds exhibited remarkable cytotoxic and antiproliferative activities against MCF-7 and PC-3 that were higher than those of the reference compounds doxorubicin and etoposide, respectively. For example, in MCF-7 when Ar = phenyl, 3,5-dimethoxyphenyl or benzyl the TGI values were 3.69, 4.18 and 6.19 μM. On the other hand, in PC-3 these compounds showed values of 6.8, 4.0 and 2.9 μM. Furthermore, benzoylselenylacetic acid did not provoke apoptosis nor did it perturb the cell cycle in MCF-7.

Innovative Lead Compounds and Formulation Strategies As Newer Kinetoplastid Therapies

The protozoan diseases leishmaniasis, human African trypanosomiasis (HAT) and Chagas disease (CD) are responsible for substantial global morbidity and mortality in tropical and subtropical regions. Environmental changes, drug resistance and immunosuppression are contributing to the emergence and spread of these diseases. In the absence of safe and efficient vaccines, chemotherapy, together with vector control, remains the most important measure to control kinetoplastid diseases. Nevertheless, the current chemotherapeutic treatments are clearly inadequate because of their toxic effects, generation of resistances as well as route and schedules of administration not adapted to the field-conditions. This review overlooks the strategies that can be addressed to meet immediately the patient needs such as the reconsideration of current regimens of administration and the rational combination of drugs in use. In the medium-long term, due to new methodologies of medicinal-chemistry, the screening from natural products and the identification of new therapeutic targets, new lead compounds have great chance to advance through the drug development pipeline to clinic. Modern pharmaceutical formulation strategies and nanomedicines also merit a place in view of the benefits of a single dose of liposomal Amphotericin B (AmBisome®) against visceral leishmaniasis. BBB-targeted nanodevices could be suited for selective delivery of drugs against HAT encephalitic phase. Bioadhesive nanoparticles can be proposed to enhance the bioavailability of drugs after oral administration by reason of improving the drug solubility, and permeability across the intestinal epithelia.

Argentine plant extracts active against polymerase and ribonuclease H activities of HIV-1 reverse transcriptase

Lipophilic and hydrophilic extracts of four Argentine plants (Gamochaeta simplicaulis Cabr. 1, Achyrocline flaccida Wein. D. C. 2, Eupatorium buniifolium H. et A. 3, and Phyllanthus sellowianus Muell. Arg. 4) were examined in vitro for their ability to inhibit the polymerase and ribonuclease H (RNase H) activities of human immunodeficiency virus type 1 (HIV‐1) reverse transcriptase (RT) (wild and Y181C mutant types). The active extracts were also examined as inhibitors of viral replication in HLT4LacZ‐1IIIB cell cultures, evaluating their cytotoxicity in parallel. Infusions 2I and 4I, among the crude extracts, showed the highest activity. These extracts were refractioned into four fractions; 2I4 and 4I4 were active as inhibitors of DNA‐polymerase (wild and Y181C types) and RNase H activities. These fractions were potent as inhibitors of viral replication and were not cytotoxic. Refractionation of 2I4 yielded five new fractions, two of which, 2I4‐4 and 2I4‐5, showed notable activity. Refractionation of 4I4 yielded four new fractions; of these, 4I4‐3 and 4I4‐4 were active. The marked biological activity found in the infusion of A. flaccida and P. sellowianus makes them sufficiently attractive to be considered in the combined chemotherapy of the disease. Copyright