Antichagasic, Leishmanicidal, and Trichomonacidal Activity of 2‐Benzyl‐5‐nitroindazole‐Derived Amines

Abstract

Three different series of new 5-nitroindazole derivatives-1-(ω-aminoalkyl)-2-benzylindazolin-3-ones (series A; ten compounds), 3-(ω-aminoalkoxy)-2-benzylindazoles (series B; four compounds) and 3-alkylamino-2-benzylindazoles (series C; five compounds)-have been synthesized and evaluated against the protozoan parasites Trypanosoma cruzi, Leishmania amazonensis, and Trichomonas vaginalis: etiological agents of Chagas disease, cutaneous leishmaniasis, and trichomoniasis, respectively. Many indazoles of series A, B, and C were efficient against T. cruzi. Some compounds in series A, after successfully passing the preliminary screening for epimastigotes, exhibited activity values against amastigotes of several T. cruzi strains that were better than or similar to those shown by the reference drug benznidazole and displayed low nonspecific toxicity against mammalian cells. On the other hand, preliminary studies against promastigotes of L. amazonensis showed high leishmanicidal activity for some derivatives of series A and C. With regard to activity against T. vaginalis, some indazoles of series B and C were rather efficient against trophozoites of a metronidazole-sensitive isolate and showed low nonspecific toxicities toward Vero cell cultures. Additionally, some of these compounds displayed similar activity against metronidazole-sensitive and resistant isolates, showing the absence of cross-resistance between these derivatives and the reference drug.

Activity profile of two 5-nitroindazole derivatives over the moderately drug-resistant Trypanosoma cruzi Y strain (DTU TcII): in vitro and in vivo studies

“…Here, the effectiveness of two promising drug candidates, i.e. 5-nitroindazolinone derivatives 16 and 24, whose trypanocidal profiles in vitro against DTU TcVI parasites have been recently reported (Fonseca-Berzal et al ., 2016 a , 2018), were deeper explored upon T. cruzi using the naturally resistant parasite strain Y (i.e. DTU TcII) under distinct experimental models, both in vitro and in vivo .…”

“…However, such an outstanding profile was not observed after treating in vitro the non-replicative form of T. cruzi (Table 1). This fact has also been detected with other molecules belonging to these two families of 5-nitroindazole derivatives (Fonseca-Berzal et al ., 2016 a , 2018). This particular behaviour has not been observed in 5-nitroindazole derivatives that are substituted at the positions 1 and 3 of the heterocyclic ring, which show similar anti- T. cruzi profiles in vitro against the two clinically relevant forms of the parasite (Muro et al ., 2014; Martín-Escolano et al ., 2018), being this fact also appreciated in other 1,3-disubstituted 5-nitroindazoles previously studied by us (data not published).…”

“…The results obtained in these experiments (Fig. 3 and Supplementary Tables S1 and S2) corroborated the lack of toxicity previously registered in vitro over both L929 (Fonseca-Berzal et al ., 2016 a , 2018) and CC (Supplementary Fig. S1).…”

“…The synthesis of the two 5-nitroindazole derivatives studied in the present work (Fig. 1) was previously described (Fonseca-Berzal et al ., 2016 a , 2018). The numbering initially used for the designation of these molecules in their respective references has been maintained in the present paper, as follows: 1-(2-aminoethyl)-2-benzyl-5-nitro-1,2-dihydro-3 H -indazol-3-one (hydrochloride), compound 16 (Fonseca-Berzal et al ., 2018) and 1-(2-acetoxyethyl)-2-benzyl-5-nitro-1,2-dihydro-3 H -indazol-3-one, compound 24 (Fonseca-Berzal et al ., 2016 a ).…”

“…1) was previously described (Fonseca-Berzal et al ., 2016 a , 2018). The numbering initially used for the designation of these molecules in their respective references has been maintained in the present paper, as follows: 1-(2-aminoethyl)-2-benzyl-5-nitro-1,2-dihydro-3 H -indazol-3-one (hydrochloride), compound 16 (Fonseca-Berzal et al ., 2018) and 1-(2-acetoxyethyl)-2-benzyl-5-nitro-1,2-dihydro-3 H -indazol-3-one, compound 24 (Fonseca-Berzal et al ., 2016 a ). For all the in vitro assays, stock solutions of 16, 24 and BZ – purchased from LAFEPE, Laboratório Farmacêutico do Estado de Pernambuco, Brazil – were prepared in dimethyl sulfoxide (DMSO) and extemporaneously added to the cultures in a final concentration of the solvent lower than 1% (v/v), which has no toxic effect on cultures of mammalian cells and parasites (Fonseca-Berzal et al ., 2015).…”