RESUMO
Bond-based quadratic indices, new TOMOCOMD-CARDD molecular descriptors, and linear discriminant analysis (LDA) were used to discover novel lead trichomonacidals. The obtained LDA-based quantitative structure-activity relationships (QSAR) models, using nonstochastic and stochastic indices, were able to classify correctly 87.91% (87.50%) and 89.01% (84.38%) of the chemicals in training (test) sets, respectively. They showed large Matthews correlation coefficients of 0.75 (0.71) and 0.78 (0.65) for the training (test) sets, correspondingly. Later, both models were applied to the virtual screening of 21 chemicals to find new lead antitrichomonal agents. Predictions agreed with experimental results to a great extent because a correct classification for both models of 95.24% (20 of 21) of the chemicals was obtained. Of the 21 compounds that were screened and synthesized, 2 molecules (chemicals G-1, UC-245) showed high to moderate cytocidal activity at the concentration of 10 microg/ml, another 2 compounds (G-0 and CRIS-148) showed high cytocidal activity only at the concentration of 100 microg/ml, and the remaining chemicals (from CRIS-105 to CRIS-153, except CRIS-148) were inactive at these assayed concentrations. Finally, the best candidate, G-1 (cytocidal activity of 100% at 10 microg/ml) was in vivo assayed in ovariectomized Wistar rats achieving promising results as a trichomonacidal drug-like compound.
Assuntos
Antitricômonas/química , Antitricômonas/farmacologia , Desenho Assistido por Computador , Avaliação Pré-Clínica de Medicamentos/métodos , Software , Trichomonas vaginalis/efeitos dos fármacos , Adulto , Animais , Antitricômonas/uso terapêutico , Análise Discriminante , Farmacorresistência Bacteriana , Feminino , Humanos , Estrutura Molecular , Ovariectomia , Ratos , Ratos Wistar , Tricomoníase/tratamento farmacológicoRESUMO
Eighteen clinical isolates of Trichomonas vaginalis were obtained from women who attended health centers of the Government of Madrid. A total of 1,848 vaginal specimens recovered during the gynaecological examination were seeded in culture tubes containing liquid Diamond medium. Pathogenicity to mice was determined after intraperitoneal inoculation of mice by quantification of mortality and gross damage to abdominal organs. As could be expected, a broad variability was obtained, being some of the isolates more virulent than the reference strain. Regarding to metronidazole susceptibility, none resistant isolate was found but different degrees of susceptibility were determined.
Assuntos
Tricomoníase/parasitologia , Trichomonas vaginalis/patogenicidade , Animais , Antitricômonas/farmacologia , Feminino , Humanos , Metronidazol/farmacologia , Camundongos , Testes de Sensibilidade Parasitária , Tricomoníase/tratamento farmacológico , Trichomonas vaginalis/efeitos dos fármacos , VirulênciaRESUMO
Eighteen clinical isolates of Trichomonas vaginalis were obtained from women who attended health centers of the Goverment of Madrid. A total of 1,848 vaginal specimens recovered during the gynaecological examination were seeded in culture tubes containing liquid Diamond medium. Pathogenicity to mice was determined after intraperitoneal inoculation of mice by quantification of mortality and gross damage to abdominal organs. As could be expected, a broad variability was obtained, being some of the isolates more virulent than the reference strain. Regarding to metronidazole susceptibility, none resistant isolate was found but different degrees of susceptibility were determined