In vitro evaluation and in vivo efficacy of nitroimidazole-sulfanyl ethyl derivatives against Leishmania (V.) braziliensis and Leishmania (L.) mexicana

Abstract

The aim of this study was to synthesize several small molecules of the type 5-nitroimidazole-sulfanyl and evaluate biological properties against the main Leishmania species that cause cutaneous leishmaniasis in Venezuela. Final compounds 4-7 were generated through simple nucleophilic substitution of 1-(2-chloroethyl)-2-methyl-5-nitroimidazole 3 with 2-mercaptoethanol, 1-methyl-2-mercaptoethanol, and 2-thyolacetic acid derivative. Compound 8 was synthesized via a coupling reaction between 7 and (S)-Methyl 2-amino-4-methylpentanoate hydrochloride. The inhibitory concentrations of (3, 4, 7, 8) against Leishmania (L.) mexicana and (V.) braziliensis in promastigotes and experimentally infected macrophages were determined by in vitro activity assays. Compounds 7 and 8 shown high activity against both species of Leishmania and were selected for the in vivo evaluation. Animals were infected with promastigotes of the two species and divided into four groups of ten ( 10) animals and a control group. Intralesional injection way was used for the treatment. The parasitological diagnostic after treatment was obtained by PCR using species specific oligonucleotides. The two Leishmania species were susceptible to compounds 7 and 8 in vivo assays. The results indicated that both compounds reduce significantly (96%) the size of the lesion and cure 63% of the mice infected with L (L) mexicana or L (V) braziliensis as was determined by PCR. The results are indicating that both compounds may represent an alternative treatment for these two Leishmania species.

Using 5-Nitroimidazole Derivatives against Neglected Tropical Protozoan Diseases: Systematic Review

“…As a result, an in vivo evaluation was conducted using mouse models of cutaneous leishmaniasis (CL). This evaluation showed that both compounds reduced 96% of the lesions and cured 63% of the mice [32]. Recent studies have been directed toward quinoline and metronidazole hybrids as a potential solution for VL.…”

“…As a result, an in vivo evaluation was conducted using mouse models of cutaneous leishmaniasis (CL). This evaluation showed that both compounds reduced 96% of the lesions and cured 63% of the mice [32]. Subsequently, they found that compounds 55c, 60, 61, and 62 reduced the growth of promastigotes of L. mexicana and L. braziliensis, and they measured the mean inhibitory concentrations (IC 50 ) against intracellular amastigotes of both species (Table 8).…”

“…Subsequently, they carried out nucleophilic substitution reactions with 2-mercaptoethanol, 1-methyl-2-mercaptoethanol, and a derivative of 2-thioacetic acid, resulting in the formation of compounds 60 and 61. Compound 62 was obtained through a coupling reaction with (S)-methyl 2-amino-4-methylpentanoate (Figure 13) [32]. Subsequently, they found that compounds 55c, 60, 61, and 62 reduced the growth of promastigotes of L. mexicana and L. braziliensis, and they measured the mean inhibitory concentrations (IC50) against intracellular amastigotes of both species (Table 8).…”

“…Subsequently, they carried out nucleophilic substitution reactions with 2-mercaptoethanol, 1-methyl-2-mercaptoethanol, and a derivative of 2-thioacetic acid, resulting in the formation of compounds 60 and 61. Compound 62 was obtained through a coupling reaction with (S)-methyl 2-amino-4-methylpentanoate (Figure13)[32].…”