RESUMEN
Sleeping sickness, caused by trypanosomes, is a debilitating, neglected tropical disease wherein current treatments suffer from several drawbacks such as toxicity, low activity, and poor pharmacokinetic properties, and hence the need for alternative treatment is apparent. To this effect, we screened in vitro a library of 2-quinazolinone derivatives for antitrypanosomal activity against T.b. brucei and cytotoxicity against HeLa cells. Seven compounds having no overt cytotoxicity against HeLa cells exhibited antitrypanosomal activity in the range of 0.093-45 µM were identified. The activity data suggests that the antitrypanosomal activity of this compound class is amenable to substituents at N1 and C6 positions. Compound 14: having a molecular weight of 238Da, ClogP value of 1 and a total polar surface area of 49 was identified as the most active, exhibiting an IC50 value of 0.093 µM Graphical Abstract.
Asunto(s)
Quinazolinonas/farmacología , Tripanocidas/farmacología , Tripanosomiasis Africana/tratamiento farmacológico , Supervivencia Celular/efectos de los fármacos , Evaluación Preclínica de Medicamentos , Células HeLa , Humanos , Pruebas de Sensibilidad Parasitaria , Quinazolinonas/química , Quinazolinonas/uso terapéutico , Pruebas de Toxicidad Aguda , Tripanocidas/química , Tripanocidas/uso terapéutico , Trypanosoma brucei gambiense/efectos de los fármacos , Trypanosoma brucei rhodesiense/efectos de los fármacos , Tripanosomiasis Africana/parasitologíaRESUMEN
Human African trypanosomiasis is a neglected infectious disease that affects mostly people living in the rural areas of Africa. Current treatment options are limited to just four drugs that have been in use of four to nine decades. The life-threatening toxic side-effects associated with the use of these drugs are disconcerting. Poor efficacy, low oral bioavailability, and high cost are other shortcomings of current HAT treatments. Evaluating the potentials of known hits for other therapeutic areas may be a fast and convenient method to discover new hit compounds against alternative targets. A library of 34 known indanone based chalcones was screened against T.b. brucei and nine potent hits, having IC50 values between 0.5-8.9 µM, were found. The SAR studies of this series could provide useful information in guiding future exploration of this class of compounds in search of more potent, safe, and low cost anti-trypanosomal agents. Graphical Abstract.