title: Highly potent anti-leishmanial derivatives of hederagenin, a triperpenoid from Sapindus saponaria L.
abstract: Leishmaniasis is a neglected tropical disease (NTDs), endemic in 88 countries that affect more than 12 million people. Current drugs are limited due to their toxicity, development of biological resistance, length of treatment and high cost. Thus, the search for new effective and less toxic treatments is an urgent need. In this study, we report the synthesis of 3 new amide derivatives of hederagenin (22-24) with yields between 70% and 90%, along with 57 other derivatives of hederagenin (1-21, 25-60) carrying different groups at C-28 previously reported by our group, and the results of their in vitro ability to inhibit the growth of Leishmania infantum. Some derivatives (3, 4, 44, 49 and 52), showed activity at micromolar level and low toxicity against BGM and HepG2 cells. Moreover, the ability of hederagenin derivatives 3 (IC50= 9.7 μM), 4 (12 μM), 44 (11 μM) and 49 (2 μM), to prevent proliferation of intracellular amastigote forms of L. infantum and their higher selectivity index and low toxicity compared to commercial positive drug control of choice (potassium antimonyl tartrate trihydrate) (IC50= 80 μM, SI = 0.1), make these compounds promising candidates for the treatment of leishmaniasis.
authors: Department of Chemistry, Universidade Federal de Minas Gerais, Av. Pres Antônio Carlos 6627, Campus Pampulha, CEP 31270-901, Belo Horizonte, MG, Brazil; Department of Chemistry, Universidade Federal de Viçosa, Av. P. H Rolf, s/n, CEP 36570-000, Viçosa, MG, Brazil.
authors: Diego
authors: D
authors: Rodríguez-Hernández
authors: Department of Chemistry, Universidade Federal de Minas Gerais, Av. Pres Antônio Carlos 6627, Campus Pampulha, CEP 31270-901, Belo Horizonte, MG, Brazil; Department of Chemistry, Universidade Federal de Viçosa, Av. P. H Rolf, s/n, CEP 36570-000, Viçosa, MG, Brazil. Electronic address: lcab@ufmg.br.
authors: Luiz C A
authors: LCA
authors: Barbosa
authors: Department of Chemistry, Universidade Federal de Viçosa, Av. P. H Rolf, s/n, CEP 36570-000, Viçosa, MG, Brazil.
authors: Antonio J
authors: AJ
authors: Demuner
authors: Department of Parasitology, Universidade Federal de Minas Gerais, Av. Pres Antônio Carlos 6627, Campus Pampulha, CEP 31270-901, Belo Horizonte, MG, Brazil.
authors: Raquel M
authors: RM
authors: de Almeida
authors: Department of Parasitology, Universidade Federal de Minas Gerais, Av. Pres Antônio Carlos 6627, Campus Pampulha, CEP 31270-901, Belo Horizonte, MG, Brazil. Electronic address: fujiwara@icb.ufmg.br.com.
authors: Ricardo T
authors: RT
authors: Fujiwara
authors: Department of Parasitology, Universidade Federal de Minas Gerais, Av. Pres Antônio Carlos 6627, Campus Pampulha, CEP 31270-901, Belo Horizonte, MG, Brazil.
authors: Sebastião R
authors: SR
authors: Ferreira
mesh_terms: D000981:Antiprotozoal Agents / Q000737:chemistry* / Q000494:pharmacology* / Q000633:toxicity; D056945:Hep G2 Cells; D006801:Humans; D042541:Intracellular Space / Q000187:drug effects / Q000469:parasitology; D018314:Leishmania infantum / Q000187:drug effects*; D009828:Oleanolic Acid / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology / Q000633:toxicity; D029750:Saponaria / Q000737:chemistry*; D013329:Structure-Activity Relationship
chemical_list: D000981:Antiprotozoal Agents; D009828:Oleanolic Acid; C025763:hederagenin
keywords: Anti-leishmanial activity; Hederagenin derivatives; Leihmania infantum; Pentacyclic triterpenes; Triazole compounds