JAC Advance Access originally published online on October 8, 2002
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Journal of Antimicrobial Chemotherapy (2002) 50, 629-637
© 2002 The British Society for Antimicrobial Chemotherapy
3-[4'-Bromo-(1,1'-biphenyl)-4-yl]-N, N-dimethyl-3-(2-thienyl)-2-propen-1-amine: synthesis, cytotoxicity, and leishmanicidal, trypanocidal and antimycobacterial activities
1 Instituto de Química, Biological Chemistry Laboratory, Universidade Estadual de Campinas, Campinas, C.P. 6154, CEP 13083-970, SP; 2 Department of Biochemistry and Immunology, Faculdade de Medicina de Ribeirão, Universidade de São Paulo, Ribeirão Preto, SP; 3 Instituto Adolfo Lutz, Ribeirão Preto, SP; 4 Instituto de Biologia, Universidade Estadual de Campinas, Campinas, SP; 5 Department of Immunology, IOC, Fundação Oswaldo Cruz, RJ; 6 Department of Ultra-structure and Cellular Biology, IOC, Fundação Oswaldo Cruz, RJ; 7 NCA, Univesidade de Mogi das Cruzes, Mogi das Cruzes, SP, Brazil
Received 6 August 2001; returned 20 April 2002; revised 10 May 2002; accepted 25 July 2002
Current therapies for Chagas’ disease, leishmaniasis and tuberculosis are unsatisfactory because of the failure rates, significant toxicity and/or drug resistance. In this study, the compound 3-[4'-bromo-(1,1'-biphenyl)-4-yl]-N,N-dimethyl-3-(2-thienyl)-2-propen-1-amine (IV) was synthesized and its trypanocidal, leishmanicidal and antimycobacterial activities were investigated. The cytotoxicity was determined on V79 cells with three endpoints: nucleic acid content, 3-(4,5-dimethylthiazole-2-yl)-2,5-diphenyl tetrazolium bromide reduction and Neutral Red uptake. This compound was active against different species of mycobacteria and different life cycle stages of Trypanosoma cruzi. In experiments with trypomastigotes performed at 4°C in the presence of blood, the activity was 8.8-fold more active than the standard drug, Crystal Violet. Higher activity was achieved against Leishmania amazonensis, with an ED50/24 h of 3.0 ± 0.3 µmol/L. The effect against trypanosomatids, which suggests high activity of compound IV against promastigotes of L. amazonensis and amastigotes of T. cruzi, stimulated further studies in vitro with amastigotes interiorized in macrophages and with in vivo models. Our results indicate that mammalian V79 cells are less susceptible to the action of compound IV than promastigotes of L. amazonensis (8.0–13.3-fold) and axenic amastigotes of T. cruzi (3.5–5.9-fold).
* Corresponding author. Tel: +55-19-3788-3149; Fax: +55-19-3788-3023; E-mail: duran{at}iqm.unicamp.br