Second Generation of Mannich Base-Type Derivatives with in Vivo Activity against Trypanosoma cruzi

Abstract

Chagas disease is a potentially life-threatening and neglected tropical disease caused by Trypanosoma cruzi. One of the most important challenges related to Chagas disease is the search for new, safe, effective, and affordable drugs since the current therapeutic arsenal is inadequate and insufficient. Here, we report a simple and cost-effective synthesis and the biological evaluation of the second generation of Mannich base-type derivatives. Compounds 7, 9, and 10 showed improved in vitro efficiency and lower toxicity than benznidazole, in addition to no genotoxicity; thus, they were applied in in vivo assays to assess their activity in both acute and chronic phases of the disease. Compound 10 presented a similar profile to benznidazole from the parasitological perspective but also yielded encouraging data, as no toxicity was observed. Moreover, compound 9 showed lower parasitaemia and higher curative rates than benznidazole, also with lower toxicity in both acute and chronic phases. Therefore, further studies should be considered to optimize compound 9 to promote its further preclinical evaluation.

Antichagasic profile of a Series of Mannich Base‐Type Derivatives: Design, Synthesis, in vitro Evaluation, and Computational Studies Involving Iron Superoxide Dismutase

“…Mannich bases are versatile synthetic building blocks, which can be easily yielded into a range of potential derivatives to be employed in the field of medicinal chemistry . These derivatives have been synthesized through various methodologies described in the bibliography . A large number of Mannich base derivatives with potential antiparasitic activity have been reported .…”

“…A large number of Mannich base derivatives with potential antiparasitic activity have been reported . In addition, our research group also reported the high potential trypanocidal activity of different Mannich bases . At this point, it is noteworthy to mention that our studies suggested that the presence of a carbonyl group, piperazine and its linked phenyl ring are relevant for the antitrypanosomatid activity of these compounds (Figure ) .…”

“…Mannich bases have demonstrated this parasitic activity . Our research group has evaluated the in vitro and in vivo activity of some Mannich derivatives against CD, finding promising results that encouraged us to continue with preclinical studies of leading compounds and in the search for new potential candidates …”

“…First, alkylation of amines ( 1‐3, 5 and 10–17 ) by β‐haloalkyl ketones and arylamines as reported by Martin Escolano et al. was undertaken; second, the Michael addition reaction between vinyl ketones and arylamines ( 4, 6–9 and 24–26 ) described in the literature; third, the Mannich reaction of methyl ketones with the respective arylamine and 1,3‐dioxolane was executed ( 18‐23 ) based on our previous experience and published literature . In this paper, the synthesis routes are shown in Schemes and .…”

“…Finally, derivatives 18–26 ( Scheme ) were prepared by incorporating a cyclopropyl moiety linked to the carbonyl group and different aromatic amines (piperazine, phenethylamine or aniline). Additionally, according to our previous results, substituents such as F, Cl or CF 3 in the para position of the aromatic group linked to the amine had promising antichagasic profiles . Considering the target product profile (TPP) for the development of new drugs, we considered the employment of simple and cost‐effective synthetic routes for the synthesis of these compounds.…”