Antiparasitic and anti-inflammatory activities of ß-lapachone-derived naphthoimidazoles in experimental acute Trypanosoma cruzi infection

Abstract

BACKGROUND Chagas disease, which is caused by the protozoan Trypanosoma cruzi, is endemic to Latin America and mainly affects low-income populations. Chemotherapy is based on two nitrocompounds, but their reduced efficacy encourages the continuous search for alternative drugs. Our group has characterised the trypanocidal effect of naphthoquinones and their derivatives, with naphthoimidazoles derived from β-lapachone (N1, N2 and N3) being the most active in vitro. OBJECTIVES In the present work, the effects of N1, N2 and N3 on acutely infected mice were investigated. METHODS in vivo activity of the compounds was assessed by parasitological, biochemical, histopathological, immunophenotypical, electrocardiographic (ECG) and behavioral analyses. FINDINGS Naphthoimidazoles led to a decrease in parasitaemia (8 dpi) by reducing the number of bloodstream trypomastigotes by 25-50% but not by reducing mortality. N1 protected mice from heart injury (15 dpi) by decreasing inflammation. Bradycardia was also partially reversed after treatment with N1 and N2. Furthermore, the three compounds did not reverse hepatic and renal lesions or promote the improvement of other evaluated parameters. MAIN CONCLUSION N1 showed moderate trypanocidal and promising immunomodulatory activities, and its use in combination with benznidazole and/or anti-arrhythmic drugs as well as the efficacy of its alternative formulations must be investigated in the near future.

Characterization and trypanocidal activity of a β-lapachone-containing drug carrier

“…In recent years, this quinone has attracted considerable attention, particularly in cancer research [ 48 – 50 ] . The trypanocidal activity of β-Lap and its derivatives has also been extensively demonstrated in vitro and in vivo [ 51 , 52 ] . However, low water solubility [ 26 ] and inactivation of β-Lap in the presence of blood and serum limit its systemic administration and clinical applications for the treatment of CD [ 13 , 25 ] .…”

Experimental Combination Therapy with Amiodarone and Low-Dose Benznidazole in a Mouse Model of Trypanosoma cruzi Acute Infection

“…ECG recordings and analysis were performed in physically restrained (nonsedated) mice at 14 dpi, according to previous studies ( 66 ). Briefly, all mice were fixed in the supine position, and transducers were carefully placed under the skin in accordance with the preferential derivation (DII).…”

Natural naphthoquinones and their derivatives as potential drug molecules against trypanosome parasites

“…; Hussain et al, 2007). These are used traditionally in Brazil as an anti‐inflammatory, antimalarial, antiparasitic, antiseptics, and anticancer medicine (Cascabulho et al, 2020; de Andrade‐Neto et al, 2004; Li et al, 2000; Strauch et al, 2019). β‐Lapachone and its synthetic derivatives have been extensively developed and investigated for their anti‐trypanosomatids activities against T. cruzi , T. brucei , and Leishmania spp.…”