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
Trichomonas vaginalis (Tv) is the causative agent of the most common, non-viral, sexually transmitted disease in women and men worldwide. Since 1959, metronidazole (MTZ) has been the drug of choice in the systemic treatment of trichomoniasis. However, resistance to MTZ in some patients and the great cost associated with the development of new trichomonacidals make necessary the development of computational methods that shorten the drug discovery pipeline. Toward this end, bond-based linear indices, new TOMOCOMD-CARDD molecular descriptors, and linear discriminant analysis were used to discover novel trichomonacidal chemicals. The obtained models, using non-stochastic and stochastic indices, are able to classify correctly 89.01% (87.50%) and 82.42% (84.38%) of the chemicals in the training (test) sets, respectively. These results validate the models for their use in the ligand-based virtual screening. In addition, they show large Matthews' correlation coefficients (C) of 0.78 (0.71) and 0.65 (0.65) for the training (test) sets, correspondingly. The result of predictions on the 10% full-out cross-validation test also evidences the robustness of the obtained models. Later, both models are applied to the virtual screening of 12 compounds already proved against Tv. As a result, they correctly classify 10 out of 12 (83.33%) and 9 out of 12 (75.00%) of the chemicals, respectively; which is the most important criterion for validating the models. Besides, these classification functions are applied to a library of seven chemicals in order to find novel antitrichomonal agents. These compounds are synthesized and tested for in vitro activity against Tv. As a result, experimental observations approached to theoretical predictions, since it was obtained a correct classification of 85.71% (6 out of 7) of the chemicals. Moreover, out of the seven compounds that are screened, synthesized and biologically assayed, six compounds (VA7-34, VA7-35, VA7-37, VA7-38, VA7-68, VA7-70) show pronounced cytocidal activity at the concentration of 100 mug/ml at 24 h (48 h) within the range of 98.66%-100% (99.40%-100%), while only two molecules (chemicals VA7-37 and VA7-38) show high cytocidal activity at the concentration of 10 mug/ml at 24 h (48 h): 98.38% (94.23%) and 97.59% (98.10%), correspondingly. The LDA-assisted QSAR models presented here could significantly reduce the number of synthesized and tested compounds and could increase the chance of finding new chemical entities with anti-trichomonal activity.
Assuntos
Antitricômonas/química , Desenho de Fármacos , Relação Quantitativa Estrutura-Atividade , Algoritmos , Animais , Antitricômonas/farmacologia , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Fenômenos Químicos , Físico-Química , Biologia Computacional/métodos , Análise Discriminante , Modelos Lineares , Metronidazol/farmacologia , Estrutura Molecular , Quinoxalinas/química , Quinoxalinas/farmacologia , Software , Validação de Programas de Computador , Processos Estocásticos , Trichomonas vaginalis/efeitos dos fármacosRESUMO
Two new series of several alkyl-linked bis(2-thioxo-[1,3,5]thiadiazinan-3-yl) carboxylic acids were synthesized in a two step procedure from the corresponding alkyl bis-dithiocarbamic salt intermediary. The novel compounds were evaluated for their activity in vitro against Trypanosoma cruzi strain CL (clone CL B5) and Trichomonas vaginalis strain JH 31A.
Assuntos
Antitricômonas/síntese química , Ácidos Carboxílicos/síntese química , Tiadiazinas/síntese química , Trichomonas vaginalis/efeitos dos fármacos , Trypanosoma cruzi/efeitos dos fármacos , Animais , Antitricômonas/farmacologia , Ácidos Carboxílicos/farmacologia , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Camundongos , Tiadiazinas/farmacologiaRESUMO
The syntheses and biological evaluation of the first anti-protozoa imidazole N-oxide and benzimidazole N-oxide and their derivatives are reported. They were tested in vitro against two different protozoa, Trypanosoma cruzi and Trichomonas vaginalis. Derivative 7c, ethyl-1-(i-butyloxycarbonyloxy)-6-nitrobenzimid-azole-2-carboxylate, displayed activity on both protozoa. Lipophilicity and redox potential were experimentally determined in order to study the relationship with activity of the compounds. These properties are well related with the observed bioactivity. Imidazole and benzimidazole N-oxide derivatives are becoming leaders for further chemical modifications and advanced biological studies.
Assuntos
Antiprotozoários/síntese química , Benzimidazóis/síntese química , Óxidos N-Cíclicos/síntese química , Imidazóis/síntese química , Animais , Antiprotozoários/química , Antiprotozoários/farmacologia , Benzimidazóis/química , Benzimidazóis/farmacologia , Óxidos N-Cíclicos/química , Óxidos N-Cíclicos/farmacologia , Desenho de Fármacos , Imidazóis/química , Imidazóis/farmacologia , Técnicas In Vitro , Relação Estrutura-Atividade , Trichomonas vaginalis/efeitos dos fármacos , Trypanosoma cruzi/efeitos dos fármacosRESUMO
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.
Assuntos
Macrófagos/efeitos dos fármacos , Malonatos/farmacologia , Nifurtimox/farmacologia , Nitrilas/farmacologia , Tripanossomicidas/farmacologia , Trypanosoma cruzi/efeitos dos fármacos , Animais , Malonatos/toxicidade , Camundongos , Nifurtimox/toxicidade , Nitrilas/toxicidade , Testes de Sensibilidade Parasitária , Tripanossomicidas/toxicidadeRESUMO
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