title: In vitro antileishmanial, trypanocidal, and Mammalian cell activities of diverse n,n' -dihetaryl substituted diamines and related compounds.
abstract: The leishmaniasis and Chagas diseases constitute a serious public health problem worldwide with few and ineffective treatment options. The search for new antiparasitic candidates at the initial steps of drug discovery and development is still necessary. The synthesis of 22 de novo synthetized N,N'-dihetaryl-alkyldiamine derivatives and in vitro antiparasitic activity were evaluated for the first time against intracellular and extracellular forms of Leishmania (Leishmania) infantum, L. (Viannia) panamensis, L. (Leishmania) amazonensis, and Trypanosoma cruzi. Additionally, the toxicity on mammalian cells was determined. Some of these substituted N,N'-diamines (25-35 % of the tested compounds) showed interesting results against free-living forms of parasites with activities at the inhibitory concentration (IC 50 ) level of 1.96 to 28.83 μM for L. (L.) infantum promastigotes and IC50 of 0.02 to 5.31 μM for T. cruzi epimastigotes. No activity at the IC50 level on intracellular amastigotes of T. cruzi was observed. However, N (1),N (2)-dibenzylethane-1,2-diamine 5a revealed an important activity against the intracellular amastigotes of L. infantum (IC50 25.42 μM ±0.33) and L. panamensis (IC50 58.20 μM ±3.23), while their analogue N(1),N(4) -dibenzylbutane-1,4-diamine 5c resulted in activity only against L. panamensis (IC50 11.19 μM ±0.20) without toxicity on Vero and THP-1 mammalian cells. The active compounds against intracellular parasites with low toxicity in mammalian cells may be considered for future studies in experimental models.
authors: Centro de Investigación de Enfermedades Tropicales, CINTROP, Departamento de Ciencias Básicas, Escuela de Medicina, Universidad Industrial de Santander, Bucaramanga, Colombia.
authors: Sandra M
authors: SM
authors: Leal
authors: Diego F
authors: DF
authors: Amado
authors: Vladimir V
authors: VV
authors: Kouznetsov
authors: Patricia
authors: P
authors: Escobar
keywords: Drug discovery; Leishmania (Leishmania) infantum; Leishmania (Viannia) panamensis; Mammalian cell toxicity; N,N′-Dihetaryl-alkyldiamine derivatives; Trypanosoma cruzi
references: Int J Parasitol. 2005 May;35(6):637-46
references: 15862577
references: Acta Trop. 2011 May;118(2):87-96
references: 21420925
references: Acta Trop. 2010 Jul-Aug;115(1-2):5-13
references: 20382097
references: Parasitol Res. 2009 Aug;105(2):519-28
references: 19347363
references: Arch Pharm (Weinheim). 2005 Jan;338(1):32-7
references: 15674802
references: Amino Acids. 2007 Aug;33(2):359-66
references: 17610127
references: Biochem Soc Trans. 2003 Apr;31(2):415-9
references: 12653650
references: Bioorg Med Chem Lett. 2002 May 6;12(9):1263-7
references: 11965367
references: Antimicrob Agents Chemother. 2007 Feb;51(2):438-45
references: 17116678
references: J Org Chem. 2007 May 11;72(10):3790-9
references: 17439285
references: Trends Parasitol. 2005 Nov;21(11):508-12
references: 16150644
references: Bioorg Med Chem. 2010 Jul 1;18(13):4721-39
references: 20627590
references: Acta Trop. 2010 Jul-Aug;115(1-2):55-68
references: 19900395
references: Bioorg Med Chem Lett. 2004 Feb 9;14(3):615-9
references: 14741254
references: Pharmaceuticals (Basel). 2010 Mar 25;3(4):810-838
references: 27713281
references: Front Microbiol. 2012 Aug 06;3:283
references: 22888328
references: Antimicrob Agents Chemother. 1991 Jul;35(7):1403-7
references: 1929300
references: Antimicrob Agents Chemother. 1993 Oct;37(10):2235-8
references: 8257150
references: Proc Natl Acad Sci U S A. 1989 Jan;86(2):651-5
references: 2463635
references: Bioorg Med Chem Lett. 2002 Feb 25;12(4):659-62
references: 11844694
references: Biomed Pharmacother. 2009 Jan;63(1):40-2
references: 18262385
references: Bioorg Med Chem Lett. 2008 Jan 1;18(1):184-7
references: 18024033
references: Bioorg Med Chem Lett. 2012 Feb 15;22(4):1712-5
references: 22248858
references: Mem Inst Oswaldo Cruz. 2009 Jul;104 Suppl 1:41-5
references: 19753456
references: Nat Prod Commun. 2012 Jan;7(1):133-6
references: 22428267
references: Biochem J. 2008 Jan 15;409(2):563-9
references: 17916066