Abstract
The 4-aminoquinoline scaffold represents a promising platform for designing anti-trypanosomatid agents targeting essential survival pathways in Leishmania and T. cruzi. Herein we demonstrated the potential of the dehydroxylated isoquines (deOH-IQ) and isotebuquines (deOH-ITBQ) against in vitro and in vivo models of cutaneous leishmaniasis (CL) and acute Chagas disease (CD). The most active compounds displayed excellent in vitro efficacy against non-infectious and intracellular infective forms of L. braziliensis and T. cruzi, with low EC(50) magnitudes. A detailed cytotoxicity analysis across diverse mammalian cells led to the identification of three compounds with high selectivity indexes (S.I. >10-40). The roles of lipophilicity (log P ∼5.03-6.2) and acidic ionization constants (pK (a2) ∼ 8.0-9.5) in modulating antitrypanosomicidal activity were confirmed. The most promising candidates 2c, 3b and 3c showed excellent ADME-properties, including a good aqueous solubility (0.75-10 mg mL(-1)), adequate hepatic-microsomal and -cytosolic stability, low hematotoxicity (IC(50) >300 μM), no mutagenicity and acceptable predicted drug-likeness. In a mouse model of CL, subcutaneous administration of compound 3b demonstrated significant therapeutic efficacy and a high survival rate. This treatment led to a significant reduction in footpad nodules, outperforming glucantime, and a notable reduction in parasite load burden (∼47%), comparable to the reference drug. In a mouse model of CD, compound 3c, under oral treatment, showed moderate efficacy with good survival rate. Overall, compound 3b emerges as a promising preclinical leishmanicidal candidate for CL and deHO-ITBQ represents a platform for further designs.