Antiprotozoal QSAR modelling for trypanosomiasis (Chagas disease) based on thiosemicarbazone and thiazole derivatives

Chagas disease, caused by the protozoan parasite Trypanosoma cruzi, remains a neglected endemic infection that affects around 8 million people worldwide and causes 12,000 premature deaths per year. Traditional chemotherapy is limited to the nitro-antiparasitic drugs Benznidazole and Nifurtimox, which present serious side effects and low long-term efficacy. Several research efforts have been made over the last decade to find new chemical structures with better effectiveness and tolerance than standard anti-Chagas drugs. Among these, new sets of thiosemicarbazone and thiazole derivatives have exhibited potent in vitro activity against T. cruzi, especially for its extracellular forms (epimastigote and trypomastigote). In this work, we have developed three antiprotozoal quantitative structure-relationship (QSAR) models for Chagas disease based on the in vitro activity data reported as IC50 (μM) and CC50 (μM) over the last decade, particularly by Lima-Leite's group in Brazil. The models were developed using the replacement method (RM), a technique based on Multivariable Linear Regression (MLR), and external and internal validation methodologies, like the use of a test set, Leave-one-Out (LOO) cross-validation and Y-Randomization. Two of these QSAR models were developed for trypomastigotes form of the parasite Trypanosoma cruzi, one based on IC50 and the other on CC50 data; while the third QSAR model was developed for its epimastigotes form based on CC50 activity. Our models presented sound statistical parameters that endorses their prediction capability. Such capability was tested for a set of 13 hitherto-unknown structurally related aromatic cyclohexanone derivatives.Fil: Nossa González, Diana Lisseth. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad Pedagógica y Tecnológica de Colombia; ColombiaFil: Gómez Castaño, Jovanny Arles. Universidad Pedagógica y Tecnológica de Colombia; ColombiaFil: Rozo Núñez, Wilson E.. Universidad Pedagógica y Tecnológica de Colombia; ColombiaFil: Duchowicz, Pablo Román. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Instituto de Investigaciones Fisicoquímicas Teóricas y Aplicadas. Universidad Nacional de La Plata. Facultad de Ciencias Exactas. Instituto de Investigaciones Fisicoquímicas Teóricas y Aplicadas; Argentin