Non-stochastic quadratic fingerprints and LDA-based QSAR models in hit and lead generation through virtual screening: theoretical and experimental assessment of a promising method for the discovery of new antimalarial compounds.

In order to explore the ability of non-stochastic quadratic indices to encode chemical information in antimalarials, four quantitative models for the discrimination of compounds having this property were generated and statistically compared. Accuracies of 90.2% and 83.3% for the training and test sets, respectively, were observed for the best of all the models, which included non-stochastic quadratic fingerprints weighted with Pauling electronegativities. With a comparative purpose and as a second validation experiment, an exercise of virtual screening of 65 already-reported antimalarials was carried out. Finally, 17 new compounds were classified as either active/inactive ones and experimentally evaluated for their potential antimalarial properties on the ferriprotoporphyrin (FP) IX biocrystallization inhibition test (FBIT). The theoretical predictions were in agreement with the experimental results. In the assayed test compound C5 resulted more active than chloroquine. The current result illustrates the usefulness of the TOMOCOMD-CARDD strategy in rational antimalarial-drug design, at the time that it introduces a new family of organic compounds as starting point for the development of promising antimalarials.

Quantitative Structure Antitumoral-Activity Relationships of Thiadiazinthione Derivatives Using the Novel Hybrid Molecular Index pMRc / s. t

The recently defined molar-refractivity-partition index was applied to a family of 1,3,5- thiadiazin-2-thione derivatives in order to establish quantitative structure-antitumoral models. The goal of this effort is to establish the relationships between the structure and biological response of these compounds. Method. After the splitting of the sample in two sets, their indices were correlated against the measured biological activity. The combined use of our index with others had been able to describe not only the topologic but also the London dispersive forces of any fragment in relation to the biological response of the sets. Results. The obtained models showed correlation coefficients of 0,87 and 0,81 respectively linking structural and biological features of the molecules. The mean relative error values were less than 7 percent. According to the models, the activity of the first sample is related mostly to molecular topology and dispersive forces. Sample two activity was associated to the size and branching of the substituents, and also to the London forces. Conclusion. The index was able to discriminate between pure topological features and those related to dispersive forces(AU)

A linear discrimination analysis based virtual screening of trichomonacidal lead-like compounds: outcomes of in silico studies supported by experimental results.

A computational (virtual) screening test to identify potential trichomonacidals has been developed. Molecular structures of trichomonacidal and non-trichomonacidal drugs were represented using stochastic and non-stochastic atom-based quadratic indices and a linear discrimination analysis (LDA) was trained to classify molecules regarding their antiprotozoan activity. Validation tests revealed that our LDA-QSAR models recognize at least 88.24% of trichomonacidal lead-like compounds and suggest using this methodology in virtual screening protocols. These classification functions were then applied to find new lead antitrichomonal compounds. In this connection, the biological assays of eight compounds, selected by computational screening using the present models, give good results (87.50% of good classification). In general, most of the compounds showed high activity against Trichomonas vaginalis at the concentration of 100 microg/ml and low cytotoxicity to this concentration. In particular, two heterocyclic derivatives (VA7-67 and VA7-69) maintained their efficacy at 10 microg/ml with an important trichomonacidal activity (100.00% of reduction), but it is remarkable that the compound VA7-67 did not show cytotoxic effects in macrophage cultivations. This result opens a door to a virtual study considering a higher variability of the structural core already evaluated, as well as of other chemicals not included in this study.

Synthesis and antiparasitic properties of new 4-N-benzylamino-4-hetarylbut-1-enes.

New derivatives of 4-N-benzylamino-4-hetarylbut-1-ene containing a pyridyl nucleus were synthesized from benzylamines and pyridine aldehydes. N-oxide derivatives were obtained from these homoallylamines. Study of the antiparasitic properties of obtained pyridine derivatives as well as of four related benzazepines previously described, was carried out using cytotoxicity assays against Trichomonas vaginalis and epimastigote form of Trypanosoma cruzi protozoa. Compounds showing activity against epimastigote T. cruzi were tested against the amastigote form; unspecific cytotoxicity against macrophages was also studied.

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.

Quantitative structure antitumoral-activity relationships of thiadiazinthione derivatives using the novel hybrid molecular index pMRchi.

PURPOSE: The recently defined molar-refractivity-partition index was applied to a family of 1,3,5- thiadiazin-2-thione derivatives in order to establish quantitative structure-antitumoral models. The goal of this effort is to establish the relationships between the structure and biological response of these compounds. METHOD: After the splitting of the sample in two sets, their indices were correlated against the measured biological activity. The combined use of our index with others had been able to describe not only the topologic but also the London dispersive forces of any fragment in relation to the biological response of the sets. RESULTS: The obtained models showed correlation coefficients of 0.87 and 0.81 respectively linking structural and biological features of the molecules. The mean relative error values were less than 7%. According to the models, the activity of the first sample is related mostly to molecular topology and dispersive forces. Sample two activity was associated to the size and branching of the substituents, and also to the London forces. CONCLUSION: The index was able to discriminate between pure topological features and those related to dispersive forces.

Synthesis and nematocide activity of S-glycopyranosyl-6,7-diarylthiolumazines.

6,7-Diaryl derivatives of mono and di-S-glycopyranosylthiolumazine derivatives 5-8 were prepared to test their nematocide activity. In vitro tests against Caenorhabditis elegans were performed and it was found that monosubstituted derivatives 5-7 showed higher activity than the corresponding unsubstituted 2-thiolumazines 1-3, whilst 2-S,4-S-di-glycopyranosylpteridine derivative 8 was inactive in contrast to unsubstituted derivative 4. In order to check whether the lack of activity of 8 was due to the two bulky substituents of the pteridine nucleus, 2-S,4-S-dimethyl derivative 9 was synthesized and assayed showing also lack of activity. A theoretical study on the stability of the different possible tautomers of compound 4 was carried out in an attempt to explain some, in appearance, anomalous (13)C NMR data of this compound.

4-Aryl(benzyl)amino-4-heteroarylbut-1-enes as building blocks in heterocyclic synthesis. 4. Synthesis of 4, 6-dimethyl-5-nitro(amino)-2-pyridylquinolines and their antiparasitic activities.

New nitro- and aminoquinoline derivatives containing a pyridyl nucleus were synthesized from 6, 8-disubstituted 4-methyl-2-pyridylquinolines, which were prepared from N-pyridylmethylidenanilines. The anti-chagasic and trichomonacidal in vitro activity, as well as the cytotoxic properties towards macrophages of some of these compounds were evaluated. Although some of the compounds showed only moderate activity it was possible to establish some structure-activity relationships.

Determination of lipophilic descriptors of antihelmintic 6,7-diaryl-pteridine derivatives useful for bioactivity predictions.

The liquid chromatographic retention factors extrapolated to pure water, k'(w), for several 6,7-diaryl-pteridine derivatives in both an octadecylsilane (ODS) and an immobilized artificial membrane column (IAM.PC.DD2), using acetonitrile-aqueous buffer pH = 7.45 as mobile phase, were obtained. The logarithms of the k'(w) values in the IAM.PC.DD2 column, log k'(w) (IAM), show good correlation with the calculated values of the octanol-water partition coefficients, log P(o/w), showing that the chromatographic parameter can be used as lipophilicity descriptor for the studied pteridines. However, interactions other than the lipophilic ones seem to be involved in the ODS column. Previous studies have shown that pteridines have antihelmintic properties. In spite of the complexity of the studied biological system as compared with the chromatographic one, good correlation between the descriptors obtained in the IAM column and biological activity (expressed as the log of the inhibitory concentration required to obtain up to 50% in the reduction of population growth of nematodes, log IC(50)) was observed.

In vitro and in vivo anti-Trypanosoma cruzi activity of a novel nitro-derivative.

Nitroarylidenemalononitriles and their cyanoacetamide derivatives with remarkable anti-epimastigote properties, were synthesized attempting to obtain new 3,5-diamino-4-(5'-nitroarylidene)-4H-thiadiazine 1,1-dioxide derivatives, which in previous reports had shown anti-Trypanosoma cruzi activity. Tests to evaluate the cytotoxicity of compounds were performed on J774 macrophages. 5-nitro-2-thienyl-malononitrile (5NO2TM), was the only product which maintained a high anti-epimastigote activity at concentrations in which it was no longer cytotoxic, thus it was assayed against intracellular amastigotes. Its anti-amastigote activity was similar to that of nifurtimox. Afterwards in vivo toxicity and anti-chagasic activity were determined. A reduction in parasitemia was observed.

In vitro and in vivo anti-Trypanosoma cruzi activity of a novel nitro-derivative

Nitroarylidenemalononitriles and their cyanoacetamide derivatives with remarkable anti-epimastigote properties, were synthesized attempting to obtain new 3,5-diamino-4-(5'-nitroarylidene)-4H-thiadiazine 1,1-dioxide derivatives, which in previous reports had shown anti-Trypanosoma cruzi activity. Tests to evaluate the cytotoxicity of compounds were performed on J774 macrophages. 5-nitro-2-thienyl-malononitrile (5NO2TM), was the only product which maintained a high anti-epimastigote activity at concentrations in which it was no longer cytotoxic, thus it was assayed against intracellular amastigotes. Its anti-amastigote activity was similar to that of nifurtimox. Afterwards in vivo toxicity and anti-chagasic activity were determined. A reduction in parasitemia was observed

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.

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 µg/ml for macrophages and a few of them maintained this cytotoxicity even at 10 µg/ml. Of the derivatives assayed against amastigotes 3k and S-2d showed an interesting activity, that was held even at 1µg/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

Heridas penetrantes de colon. estudio comparativo de técnicas de reparación primaria en un solo plano con polipropileno y la convencional en dos planos en un modelo experimental / Wounds penetrating of colon: comparative study of first technics reparation in plane with propylene and the two plane in experimental model

El objetivo de este trabajo, es demostrar que la reparación primaria en un solo plano con polipropileno, es efectiva y segura, para el manejo de las lesiones penetrantes de colon cuando se compara con la técnica convencional en dos planos; para esto se utilizaron, animales de experimentación , alos cuales se le practicó perforación en un segmento del colon y fueron reparados con dichas técnicas. Se evaluó el tiempo empleado para la realización de cada una de las técnicas, el cual fue menor en un solo plano, la respuesta a la tolerancia de la vía oral y la restitución del tránsito intestinal fue similar en ambas técnicas. No hubo lugar de línea de sutura en ninguno de los grupos experimentales y en cuanto a la estenosis de la luz intestinal se observó una mayor proporción no significativa, en el grupo reparado con la técnica convencional. En los estudios histopatológicos se observó mayor fibrosis, presencia de úlcera, respuesta inflamatoria, y por ende mayor disrupción de al capa muscular, cuando se utiliza la técnica convencional. Se concluye que la técnica en un plano con polipropileno es efectiva y segura para las reparaciones de las heridas penetrantes de colon , al compararlas con la técnica convencional