Biomedical subjects

R Gozalbes

Publications and source records attributed to R Gozalbes.

8 recordsLinked to original sources

PubMed2004

Synthesis of new fluoroquinolones and evaluation of their in vitro activity on Toxoplasma gondii and Plasmodium spp.

The synthesis of four new computer-designed fluoroquinolones which have been predicted by QSAR analysis to be active against the protozoa Toxoplasma gondii is described. These compounds are inhibitory in vitro for T. gondii. One of these compounds has a remarkably high activity comparable to that of trovafloxacin. It combines the basic cyclopropyl-quinoline structure of gatifloxacin or moxifloxacin with the C-7 6-amino-3-azabicyclo[3.1.0]hexyl side chain of trovafloxacin. The four compounds are also inhibitory for blood stages of Plasmodium falciparum though at high concentration. These results confirm the potential of quinolones as anti-T. gondii and antimalarial drugs but also show that the QSAR models for T. gondii cannot be reliably extended for screening antimalarial activity.

Animals↗

PubMed2004

[New methodologic approaches in antimalarial molecular research].

The estimated worldwide incidence of Plasmodium falciparum malaria is about 500 million cases a year. In tropical areas, the dramatic increase of resistance to most antimalarial drugs is directly responsible for persistent widespread high endemicity and related morbidity. The search to identify new drug targets and agents is a high priority. However the value of standard pharmacological research methods is greatly diminished by technical problems involving in vitro and in vivo modeling of malaria infection. In recent decades new mathematical tools have been developed to predict drug properties and to estimate biological activity in silico. Various approaches have been proposed based on 2D or 3D descriptions of the chemical structure of the drug and target followed by mathematical and statistical characterization of their interaction. These techniques are now widely used in medicinal chemistry and have proven their efficacy for screening the anti-malarial activity of numerous molecules in large databases and for virtual synthesis. Incorporating new knowledge from the genomic studies of Plasmodium has markedly increased the performance and range of application of these tools for identifying new drug targets against malaria.

Antimalarials↗

PubMed2002

Use of molecular topology for the prediction of physico-chemical, pharmacokinetic and toxicological properties of a group of antihistaminic drugs.

We used molecular connectivity to search mathematical models for predicting physico-chemical (e.g. the partition coefficient, P), pharmacokinetic (e.g. the time of maximum plasma level, and toxicological properties (lethal dose, LD) for a group of antihistaminic drugs. The results obtained clearly reveal the high efficiency of molecular topology for the prediction of these properties. Randomization and cross-validation by use of leave-one-out tests were also performed in order to assess the stability and the prediction ability of the connectivity functions selected.

Histamine H1 Antagonists↗

PubMed2002

Application of topological descriptors in QSAR and drug design: history and new trends.

Powerful methodologies for drug design and drug database screening and selection are presently available. Studies relating the structure of molecules to a property or a biological activity by means of statistical tools (QSPR and QSAR studies, respectively) are particularly relevant. An important point for this methodology is the use of good structural descriptors that are representative of the molecular features responsible for the relevant activity. Topological indices (TIs) are two-dimensional descriptors which take into account the internal atomic arrangement of compounds, and which encode in numerical form information about molecular size, shape, branching, presence of heteroatoms and multiple bonds. The usefulness of TIs in QSPR and QSAR studies has been extensively demonstrated, and they have also been used as a measure of structural similarity or diversity by their application to databases virtually generated by computer. In this article we will briefly review the history of TIs, their advantages and limitations with respect to other descriptors, and their possibilities in drug design and database selection. These applications rely on new computational techniques such as virtual combinatorial synthesis, virtual computational screening or inverse QSAR.

Algorithms↗

PubMed2000

Prediction of quinolone activity against Mycobacterium avium by molecular topology and virtual computational screening.

We conducted a quantitative structure-activity relationship study using a database of 158 quinolones previously tested against Mycobacterium avium-M. intracellulare complex in order to develop a model capable of predicting the activity of new quinolones against the M. avium-M. intracellulare complex in vitro. Topological indices were used as structural descriptors and were related to anti-M. avium-M. intracellulare complex activity by using the linear discriminant analysis (LDA) statistical technique. The discriminant equation thus obtained correctly classified 137 of the 158 quinolones, including 37 of a test group of 44 randomly chosen compounds. This model was then applied to 24 quinolones, including recently developed fluoroquinolones, whose MICs were subsequently determined in vitro by using the Alamar blue microplate assay; the biological results confirmed the model's predictions. The MICs of these 24 quinolones were then treated by multilinear regression (MLR) to establish a model capable of classifying them according to their in vitro activities. Using this model, a good correlation between measured and predicted MICs was found (r(2) = 0.88; r(2)(cv) [cross-validation correlation] = 0.82). Moxifloxacin, sparfloxacin, and gatifloxacin were the most potent against the M. avium- M. intracellulare complex, with MICs of 0.2, 0.4, and 0.9 microg/ml, respectively. Finally, virtual modifications of these three drugs were evaluated in LDA and MLR models in order to determine the importance of different substituents in their activity. We conclude that the combination of molecular-topology methods, LDA, and MLR provides an excellent tool for the design of new quinolone structures with enhanced activity.

4-Quinolones↗

PubMed2000

Anti-toxoplasma activities of 24 quinolones and fluoroquinolones in vitro: prediction of activity by molecular topology and virtual computational techniques.

The apicoplast, a plastid-like organelle of Toxoplasma gondii, is thought to be a unique drug target for quinolones. In this study, we assessed the in vitro activity of quinolones against T. gondii and developed new quantitative structure-activity relationship models able to predict this activity. The anti-Toxoplasma activities of 24 quinolones were examined by means of linear discriminant analysis (LDA) using topological indices as structural descriptors. In parallel, in vitro 50% inhibitory concentrations (IC(50)s) were determined in tissue culture. A multilinear regression (MLR) analysis was then performed to establish a model capable of classifying quinolones by in vitro activity. LDA and MLR analysis were applied to virtual structures to identify the influence of each atom or substituent of the quinolone ring on anti-Toxoplasma activity. LDA predicted that 20 of the 24 quinolones would be active against T. gondii. This was confirmed in vitro for most of the quinolones. Trovafloxacin, grepafloxacin, gatifloxacin, and moxifloxacin were the quinolones most potent against T. gondii, with IC(50)s of 0.4, 2.4, 4.1, and 5.1 mg/liter, respectively. Using MLR analysis, a good correlation was found between measured and predicted IC(50)s (r(2) = 0.87, cross-validation r(2) = 0.74). MLR analysis showed that the carboxylic group at position C-3 of the quinolone ring was not essential for anti-Toxoplasma activity. In contrast, activity was totally dependent on the presence of a fluorine at position C-6 and was enhanced by the presence of a methyl group at C-5 or an azabicyclohexane at C-7. A nucleophilic substituent at C-8 was essential for the activity of gatifloxacin and moxifloxacin.

4-Quinolones↗

PubMed1999

Molecular search of new active drugs against Toxoplasma gondii.

Molecular connectivity has been applied to the search of new compounds with activity against the protozoan Toxoplasma gondii, using a stepwise linear discriminant analysis (SLDA) which is able to classify a compound according its activity either as active or as inactive. Among the selected compounds, andrographolide and dibenzotiophene sulfone stand out, both with IC50 values lower than 1 microgram/ml, which are comparable to these of drugs such as sulfamethoxazole, pyrimethamine and trimethoprim, with IC50 values equal to 1.1, 0.04 and 2.31 micrograms/ml, respectively. These results confirm the usefulness of our topological approach for the selection and design of new-lead drugs active against Toxoplasma gondii.

Animals↗

PubMed1999

Discovery of new antimalarial compounds by use of molecular connectivity techniques.

Molecular connectivity has been applied to the search for new compounds with antimalarial activity. Linear discriminant analysis and connectivity functions were used to select several potentially suitable drugs which were tested for antimalarial properties by use of an in-vitro micro test which estimates parasite growth by measurement of incorporation of [3H]hypoxanthine. Hexetidine stands out among the compounds selected. Activity assays were performed with Plasmodium falciparum passou and 3CD7 strains, for which the IC50 values (doses resulting in 50% inhibition) were 320 and 400 ng mL(-1), respectively. These results are comparable with those obtained for quinine chlorhydrate (IC50 = 60 and 107.8 ng mL(-1)) and chloroquine sulphate (IC50 = 231 and 415 ng mL(-1)), the drugs used for reference. These results demonstrate the usefulness of our topological approach for the selection and design of new lead drugs active against Plasmodium falciparum.

Animals↗