Evaluation of the Trypanocidal and Immunomodulatory Effects of LDT409, a Cardanol Derivative from Cashew Nut Shell Liquid

Abstract

Chagas disease (CD), caused by Trypanosoma cruzi, is a neglected tropical illness with significant public health impact, particularly due to its cardiac manifestations. Current etiological treatments, benznidazole and nifurtimox, are limited by prolonged administration, adverse effects, and low cure rates, especially in chronic cases. Natural products, such as cashew nut shell liquid (CNSL), are a promising source of bioactive compounds with trypanocidal and immunomodulatory properties, combined with low production costs - a valuable advantage in addresing neglected tropical diseases. LDT409, a synthetic saturated cardanol derivative from CNSL, was designed as a fatty acid mimetic and partial agonist of peroxisome proliferator-activated receptors (PPARs), nuclear transcription factors that regulate lipid metabolism and attenuate inflammation by modulating immune responses. In CD, PPARs regulate host– parasite interactions by promoting anti-inflammatory immune polarization, which mitigates tissue-damaging inflammation but may also increase susceptibility to T. cruzi infection. In this study, we evaluated the trypanocidal activity and immunomodulatory effects of LDT409 using in vitro assays and an in vivo murine model of acute CD. Our findings indicate that LDT409 treatment was associated with a reduction in peak parasitemia and with modulation of the host immune response, characterized by a shift toward a Th2/Th17 profile and attenuation of a Th1-driven pro-inflammatory response, concomitant with reduced cardiac damage. Notably, the underlying mechanisms of these effects, including the involvement of PPARs, remain to be clarified. Together, these observations suggest that LDT409 may represent a promising, cost-effective, and sustainable compound for further investigation in the context of Chagas disease.