Drug screening using shape-based virtual screening andin vitroexperimental models of cutaneous Leishmaniasis

Abstract

Cutaneous leishmaniasis (CL) is one of the most disregarded tropical neglected disease with the occurrence of self-limiting ulcers and triggering mucosal damage and stigmatizing scars, leading to huge public health problems and social negative impacts. Pentavalent antimonials are the first-line drug for CL treatment for over 70 years and present several drawbacks in terms of safety and efficacy. Thus, there is an urgent need to search for non-invasive, non-toxic and potent drug candidates for CL. In this sense, we have implemented a shape-based virtual screening approach and identified a set of 32 hit compounds. In vitro phenotypic screenings were conducted using these hit compounds to check their potential leishmanicidal effect towards Leishmania amazonensis (L. amazonensis). Two (Cp1 and Cp2) out of the 32 compounds revealed promising antiparasitic activities, exhibiting considerable potency against intracellular amastigotes present in peritoneal macrophages (IC50 values of 9.35 and 7.25 μm, respectively). Also, a sterile cidality profile was reached at 20 μm after 48 h of incubation, besides a reasonable selectivity (≈8), quite similarly to pentamidine, a diamidine still in use clinically for leishmaniasis. Cp1 with an oxazolo[4,5-b]pyridine scaffold and Cp2 with benzimidazole scaffold could be developed by lead optimization studies to enhance their leishmanicidal potency.

Phenotypic investigation of 4-nitrophenylacetyl- and 4-nitro-1H-imidazoyl-based compounds as antileishmanial agents

“…The parasites in the lesions were mechanically dispersed by pipetting and used for the assays. The compounds were tested on (1) extracellular AFs; (2) intracellular amastigote forms (IA) in PMMs and (3) BALB/c mouse models infected with amastigotes as recently described (Cardoso Santos et al ., 2021). PMMs were obtained from Swiss male mice (18–20 g) inoculated with 3% Brewer thioglycollate medium (Merck) previously diluted in water and autoclaved.…”