Vicente J. Arán

Pharmacological Properties of Indazole Derivatives: Recent Developments

The chemistry of indazole and its N-oxide derivatives is very well-known. Indazole derivatives were extensively studied as bioactive compounds, such as anti-aggregatory and vasorelaxant activity by NO release and increase of cGMP levels and anticancer effects, antimicrobial and antiparasitic properties, among others. Recently, the research and development in the medicinal chemistry of these systems have produced compounds with contraceptive activities for men, for the treatment of osteoporosis, inflammatory disorders and neurodegenerative diseases. On the other hand, indazole N-oxide derivatives were poorly studied as bioactive compounds, but recently compounds with antiparasitic properties were produced. In this presentation, recent developments in the chemistry and medicinal chemistry of indazole and its N-oxide derivatives will be reviewed.

β-Carboline alkaloids in Peganum harmala and inhibition of human monoamine oxidase (MAO)

Peganum harmala L. is a multipurpose medicinal plant increasingly used for psychoactive recreational purposes (Ayahuasca analog). Harmaline, harmine, harmalol, harmol and tetrahydroharmine were identified and quantified as the main beta-carboline alkaloids in P. harmala extracts. Seeds and roots contained the highest levels of alkaloids with low levels in stems and leaves, and absence in flowers. Harmine and harmaline accumulated in dry seeds at 4.3% and 5.6% (w/w), respectively, harmalol at 0.6%, and tetrahydroharmine at 0.1% (w/w). Roots contained harmine and harmol with 2.0% and 1.4% (w/w), respectively. Seed extracts were potent reversible and competitive inhibitors of human monoamine oxidase (MAO-A) with an IC(50) of 27 microg/l whereas root extracts strongly inhibited MAO-A with an IC(50) of 159 microg/l. In contrast, they were poor inhibitors of MAO-B. Inhibition of MAO-A by seed extracts was quantitatively attributed to harmaline and harmine whereas inhibition by root extracts came from harmine with no additional interferences. Stems and leaves extracts were poor inhibitors of MAO. The potent inhibition of MAO-A by seed and root extracts of P. harmala containing beta-carbolines should contribute to the psychopharmacological and toxicological effects of this plant and could be the basis for its purported antidepressant actions.

Heterocycles containing the sulfamide moiety

Publisher Summary This chapter attempts to cover several kinds of heterocycles containing the sulfamide moiety. Earlier reports dealt with cyclic sulfamides, and with the chemistry of thiadiazole and thiadiazine S-oxides. These compounds have also been mentioned in Comprehensive Heterocyclic Chemistry . There has been extensive work on the chemistry and reactions of sulfamide and of alkylsulfamoyl chlorides that include heterocycles of this kind. This chapter offers a more extensive scope, since it covers some aspects of thiadiazines and thiadiazoles, such as tautomerism and aromaticity that had not previously been dealt with. It also includes other heterocycles. This article has been divided on the basis of the nature and size of the heterocyclic ring. The size of the rings range from three- to nine-membered heterocycles, although a ring with 30 members has also been described. A variety of biological activities are reported for different heterocycles containing the sulfamide moiety. For the sake of brevity, they are listed together with their respective structures.

Oxidative Metabolism of the Bioactive and Naturally Occurring β-Carboline Alkaloids, Norharman and Harman, by Human Cytochrome P450 Enzymes

Norharman and harman are naturally occurring beta-carboline alkaloids exhibiting a wide range of biological, psychopharmacological, and toxicological actions. They occur in foods and tobacco smoke and also appear endogenously in humans. In this research, metabolic and kinetic studies with cytochrome P450 enzymes and human liver microsomes showed that beta-carbolines were efficiently oxidized to several ring-hydroxylated and N-oxidation products that were subsequently identified and quantified. 6-Hydroxy- beta-carboline (6-hydroxynorharman and 6-hydroxyharman) was a major metabolite efficiently produced (high kcat and low Km) by P450 1A2 and 1A1 and to a minor extent by P450 2D6, 2C19 and 2E1. 3-Hydroxy-beta-carboline (3-hydroxynorharman and 3-hydroxyharman), another major metabolite, was specifically produced by P450 1A2 and 1A1, whereas beta-carboline-N(2)-oxide (harman-2-oxide and norharman-2-oxide) was produced by P450 2E1. The same pattern of metabolism was confirmed for human liver microsomes. Oxidative metabolism for harman was slightly higher than norharman, but norharman showed lower Km values. The oxidation of beta-carbolines is a detoxication route performed mainly by P450 1A2 and 1A1, with the participation of P450 2D6, 2C19, and 2E1, as additional contributors. Then, individual variations in the levels and activity of these P450s may influence biotransformation of beta-carboline alkaloids and their ultimate biological effects. beta-Carbolines were previously reported as comutagens and/or inhibitors of mutagens activated by P450 1A enzymes such as heterocyclic amines and polycyclic hydrocarbons. Results in this work show that beta-carbolines are good ligands and substrates for P450 1A2/1A1, contributing to the explanation of some of their toxicological effects.

A computer-based approach to the rational discovery of new trichomonacidal drugs by atom-type linear indices

Computational approaches are developed to design or rationally select, from structural databases, new lead trichomonacidal compounds. First, a data set of 111 compounds was split (design) into training and predicting series using hierarchical and partitional cluster analyses. Later, two discriminant functions were derived with the use of non-stochastic and stochastic atom-type linear indices. The obtained LDA (linear discrimination analysis)-based QSAR (quantitative structure-activity relationship) models, using non-stochastic and stochastic descriptors were able to classify correctly 95.56% (90.48%) and 91.11% (85.71%) of the compounds in training (test) sets, respectively. The result of predictions on the 10% full-out cross-validation test also evidenced the quality (robustness, stability and predictive power) of the obtained models. These models were orthogonalized using the Randic orthogonalization procedure. Afterwards, a simulation experiment of virtual screening was conducted to test the possibilities of the classification models developed here in detecting antitrichomonal chemicals of diverse chemical structures. In this sense, the 100.00% and 77.77% of the screened compounds were detected by the LDA-based QSAR models (Eq. 13 and Eq. 14, correspondingly) as trichomonacidal. Finally, new lead trichomonacidals were discovered by prediction of their antirichomonal activity with obtained models. The most of tested chemicals exhibit the predicted antitrichomonal effect in the performed ligand-based virtual screening, yielding an accuracy of the 90.48% (19/21). These results support a role for TOMOCOMD-CARDD descriptors in the biosilico discovery of new compounds.

Antileishmanial, antitrypanosomal, and cytotoxic screening of ethnopharmacologically selected Peruvian plants

Extracts (34) from eight plant species of the Peruvian Amazonia currently used in traditional Peruvian medicine, mostly as antileishmanial remedies and also as painkiller, antiseptic, antipyretic, anti-inflamatory, antiflu, astringent, diuretic, antipoison, anticancerous, antiparasitic, insecticidal, or healing agents, have been tested for their antileishmanial, antitrypanosomal, and cytotoxic activity. Plant species were selected based on interviews conducted with residents of rural areas. The different plant parts were dried, powdered, and extracted by maceration with different solvents (hexane, chloroform, and 70% ethanol–water). These extracts were tested on promastigote forms of Leishmania infantum strain PB75, epimastigote forms of Trypanosoma cruzi strain Y, and the mammalian CHO cell line. Parasite viability and nonspecific cytotoxicity were analyzed by a modified MTT colorimetric assay method. The isolation and identification of pure compounds from selected extracts were performed by column chromatography, gas chromatography mass spectrometry (GC-MS; mixtures), spectroscopic techniques [MS, infrared (IR), ultraviolet (UV)], and mono and two-dimensional 1H and 13C nuclear magnetic resonance (NMR; COSY, HSQC, NOESY) experiments. Chondodendron tomentosum bark and Cedrela odorata were the most active extracts against Leishmania, while C. odorata and Aristoloquia pilosa were the most active against Trypanosoma, followed by Tabebuia serratifolia, Tradescantia zebrina, and Zamia ulei. Six compounds and two mixtures were isolated from Z. ulei [cycasin (1)], T. serratifolia {mixtures 1–2, and naphthoquinones 2-acetyl-4H,9H-naphtho[2,3-b]furan-4,9-dione (2) and 2-(1-hydroxyethyl)-4H,9H-naphtho[2,3-b]furan-4,9-dione (3)}, and C. tomentosum [chondrocurine (4); (S,S′)-12-O-methyl(+)-curine (5); and cycleanine (6)]. Four compounds and the two mixtures exhibited significant activity.

Study of 5-nitroindazoles' anti-Trypanosoma cruzi mode of action: Electrochemical behaviour and ESR spectroscopic studies

New indazole derivatives have been developed to know about structural requirements for adequate anti-Trypanosoma cruzi activity. In relation to position 1 of indazole ring, we have observed that a butylaminopentyl substituent (14) affords good activity, but N-oxidation of omega-tertiary amino moiety yields completely inactive compounds (17, 18); the substituent at position 3 of indazole ring affects drastically the in vitro activity, 3-OH derivative 13 being completely inactive. On the other hand, since compound 22, denitro-analogue of active compound 4, does not show activity, the 5-nitro substituent of indazole ring seems to be essential. Intramolecular cyclization of side chain at position 1 also affords inactive compounds (19, 20). The electrochemical studies showed that the trypanocidal 5-nitroindazole derivatives yielded nitro-anion radical via one-electron process at physiological pH. This electrochemical behaviour occurs in the parasite according to ESR experiment with the T. cruzi microsomal fraction showing that 5-nitroindazole derivatives suffer bio-reduction without reactive oxygen species generation.

New potent 5-nitroindazole derivatives as inhibitors of Trypanosoma cruzi growth: synthesis, biological evaluation, and mechanism of action studies.

New 5-nitroindazole derivatives were developed and their antichagasic properties studied. Eight compounds (14-18, 20, 26 and 28) displayed remarkable in vitro activities against Trypanosoma cruzi (T. cruzi). Its unspecific cytotoxicity against macrophages was evaluated being not toxic at a concentration at least twice that of T. cruzi IC(50), for some derivatives. The electrochemical studies, parasite respiration studies and ESR experiment showed that 5-nitroindazole derivatives not be able to yield a redox cycling with molecular oxygen such as occurs with nifurtimox (Nfx). The study on the mechanism of action proves to be related to the production of reduced species of the nitro moiety similar to that observed with benznidazole.

Characterization, phase-solubility, and molecular modeling of inclusion complex of 5-nitroindazole derivative with cyclodextrins

The slightly water-soluble 5-nitroindazole derivative (5-NI) and its inclusion with either beta-cyclodextrin (betaCD) or Heptakis (2,6-di-O-methyl)-beta-cyclodextrin (DMbetaCD) were investigated. The stoichiometric ratios and stability constants describing the extent of formation of the complexes were determined by phase-solubility measurements obtaining type-A(L) diagrams in both cases. According to the continuous variation method (Jobs plot) a 1:1 stoichiometry has been proposed for the complexes. Also electrochemical studies were carried out on both CDs complexes, where the observed change in the E(PC) value for DMbetaCD indicated a lower feasibility of the nitro group reduction. The detailed spatial configuration is proposed based on two-dimensional NMR methods. These results are further interpreted using molecular modeling studies. The latter results are in good agreement with the experimental data.

Synthesis and potential muscarinic receptor binding and antioxidant properties of 3-(thiadiazolyl)pyridine 1-oxide compounds.

The synthesis of two different series of 3‐(thiadiazolyl)pyridine 1‐oxides containing 1,2,5‐ and 1,2,4‐thiadiazole moiety respectively is described. The potential muscarinic receptor binding together with the antioxidant properties of the new compounds were evaluated.