title: Synthesis, cytotoxicity, and in vitro antileishmanial activity of mono-t-butyloxycarbonyl-protected diamines.
abstract: Leishmania amazonensis is the etiologic agent of the cutaneous and diffuse leishmaniasis. This species is often associated with drug resistance, and the conventional treatments exhibit high toxicity for patients. Therefore, the search for new antileishmanial compounds is urgently needed since there is no vaccine available. In this study, using the in vitro traditional drug screening test, we have analyzed the effects of a series of diaminoalkanes monoprotected with t-butyloxycarbonyl (BOC) against L. amazonensis. Among the 18 tested compounds, 6 exhibited antileishmanial activity (2, 7-9, 17, and 18). Best IC(50) values (10.39 ± 0.27 and 3.8 ± 0.42 μg/mL) were observed for compounds 17 and 18 (H(2)N(CH(2))nNHBoc, n = 10 and 12), respectively. Although those compounds had higher lipophilicity as indicated by their cLog P values, compound 17 was very toxic. Determination of the selective indexes indicated that 50% of the active compounds were very toxic for HepG2 cells. However, compounds 2, 8, and 18 had good lipophilicity and were less toxic among all polyamine derivatives tested. The chemical properties of antileishmanial diamine derivatives, such as lipophilicity and cytotoxicity, are relevant factors for the design of new drugs. A higher lipophilicity is likely to improve the chances of reaching this intracellular parasite.
authors: Instituto de Tecnologia em Fármacos-Far Manguinhos, Fundação Oswaldo Cruz/FIOCRUZ, 21041-250 Rio de Janeiro, RJ, Brazil.
authors: Alessandra C
authors: AC
authors: Pinheiro
authors: Marcele N
authors: MN
authors: Rocha
authors: Paula M
authors: PM
authors: Nogueira
authors: Thaís C M
authors: TC
authors: Nogueira
authors: Liana F
authors: LF
authors: Jasmim
authors: Marcus V N
authors: MV
authors: de Souza
authors: Rodrigo P
authors: RP
authors: Soares
mesh_terms: D000818:Animals; D000981:Antiprotozoal Agents / Q000138:chemical synthesis* / Q000494:pharmacology* / Q000633:toxicity; D045744:Cell Line, Tumor; D003959:Diamines / Q000138:chemical synthesis* / Q000494:pharmacology* / Q000633:toxicity; D056945:Hep G2 Cells; D006801:Humans; D020128:Inhibitory Concentration 50; D007891:Leishmania / Q000187:drug effects*; D007928:Lethal Dose 50; D008264:Macrophages / Q000187:drug effects / Q000469:parasitology; D051379:Mice; D008807:Mice, Inbred BALB C
chemical_list: D000981:Antiprotozoal Agents; D003959:Diamines