Carmen Ochoa

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.

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.

In Vitro and in Vivo Assays of 3,5-Disubstituted-Tetrahydro-2H-1,3,5-Thiadiazin-2-Thione Derivatives against Trypanosoma cruzi

Cytotoxicity assays of 24 new 3,5-disubstituted-tetrahydro-2H-1,3,5-thiadiazin-2-thione derivatives were performed. The 17 compounds with higher anti-epimastigote activity and lower cytotoxicity were, thereafter, screened against amastigote of Trypanosoma cruzi. Out of these 17 derivatives S-2d was selected to be assayed in vivo, because of its remarkable trypanocidal properties. To determine toxicity against J774 macrophages, a method based on quantification of cell damage, after 24 h, was used. Cell respiration, an indicator of cell viability, was assessed by the reduction of MTT [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide] to formazan. Anti-amastigote activity was estimated after 48 h by microscopic counts of May Grünwald-Giemsa-stained monolayers. Nifurtimox and benznidazole were used as reference drugs. For the in vivo experiences, mice were infected with 10(4) blood trypomastigotes and then treated during 15 days with S-2d or nifurtimox by oral route. All of the compounds were highly toxic at 100 micro g/ml for macrophages and a few of them maintained this cytotoxicity even at 10 microg/ml. Of the derivatives assayed against amastigotes 3k and S-2d showed an interesting activity, that was held even at 1microg/ml. It is demonstrated that the high anti-epimastigote activity previously reported is mainly due to the non-specific toxicity of these compounds. In vivo assays assessed a reduction of parasitemia after administration of S-2d to infected mice.

Antiparasitic properties of homoallylamines and related compounds

A study of some antiparasitic properties of several homoallylamines and related tetrahydroquinolines and quinolines, previously described, was carried out using in vitro activity assays against the epimastigote form of Trypanosoma cruzi and against Trichomonas vaginalis. Unspecific cytotoxicity against murine macrophages was also studied. Although the antichagasic and trichomonacidal activities are not comparable to those of the standard drugs, nifurtimox and metronidazole, some of the compounds exhibit an interesting specific antiparasitic activity.

Synthesis of 2S-Dioxo Isosteres of Purine and Pyrimidine Nucleosides IV. Selective Glycosylation of 4-Amino-5H-Imidazo [4, 5-c]-1, 2, 6-Thiadiazine 2, 2-Dioxide

Abstract Selective glycosylation of 4-amino-5H-imidazo [4, 5-c]-1, 2, 6-thiadiazine 2, 2-dioxide (1) through its 1-benzyl derivative (2) is described. The structures of the compounds are discussed on the basis of 1H nmr 2D homonuclear chemical shift correlations, NOE difference spectroscopy and iterative analyses.

Solid phase synthesis of 3-(5′-carboxypentyl)-5-substituted tetrahydro-2H-1,3,5-thiadiazin-2-thione derivatives

Abstract The solid phase synthesis of 3-(5′-carboxypentyl)-5-substituted tetrahydro-2 H -1,3,5-thiadiazin-2-thione derivatives 5 is described. 6-Amino- n -hexanoic acid was attached via its C-terminal to hydroxymethyl polystyrene using a ‘SASRIN’ linker. The bound amino acid was converted to the corresponding dithiocarbamate 3 followed by cyclization in the presence of formaldehyde and the corresponding free amino acids to afford 3-(5′-carboxypentyl)-5-substituted tetrahydro-2 H -1,3,5-thiadiazin-2-thiones 4 . The final products were cleaved from the resin and obtained in moderate yields.

Imidazothiadiazine dioxides: synthesis and antiviral activity.

A new series of imidazothiadiazine dioxides, including the first acyclonucleosides derived from this heterocycle moiety, has been synthesized. A wide-spectrum antiviral screening was performed. Some of the N-1 benzyl imidazothiadiazines and the new acyclonucleosides showed interesting anti-CMV or anti-HIV activity. These structures could be considered as new lead compounds for antiviral drug research.

Synthesis and intramolecular cyclization of bisthiadiazinylmethane derivatives

Abstract Bisthiadiazinylmethane derivatives obtained from 1,2,6-thiadiazine 1,1-dioxides and formaldehyde, undergo unusual intramolecular cyclizations to thiadiazino [4,3-g] [2,1,3] benzothiadiazine tetraoxides. The structures of the newly synthesized compounds are discussed on the basis of 1H and 13C-NMR data and X-ray analysis.

Analgesic and antipyretic activities of 1,2,6-thiadiazin-3-one 1,1-dioxides. SAR design of a new analgesic agent

Abstract In order to establish a comparison between biological properties of 1,2,6-thiadiazin-3-one 1,1-dioxides 1 and related active pyrazolones 2 , the analgesic and antipyretic activities of a number of derivatives of both series were evaluated under the same experimental conditions. Some of thiadiazinone derivatives showed analgesic and antipyretic properties like those of their pyrazolone analogues. The activities were subjected to a Hansch analysis and a highly significant correlation with lipophilicity (K′), electronic (δC) and steric (Es) parameters was obtained. The relationship was used to predict further compounds for synthesis and evaluation giving rise to a potent analgesic thiadiazinone derivative 1j . The antiinflammatory activity of 1h and 1j were also tested, but no significant activity was found.

Synthesis of 2-S-dioxo Isosteres of Purine and Pyrimidine Nucleosides. III. Alkyl And Glycosyl Derivatives of Triazolo-and Thiadiazolothiadiazines.

Abstract Synthesis of methyl, glucosyl and ribosyl derivatives of 7-amino-2H, 4H-[1, 2, 3]triazolo [4, 5-c] [1, 2, 6] thiadiazine 5, 5-dioxide (1a) and 7-amino-4H- [1, 2, 5] thiadiazolo [3, 4-c][1, 2, 6] thiadiazine 5, 5-dioxide (2a) is described. The structures of the glycosyl derivatives are discussed on the basis of their PMR- and UV-spectroscopic data.