title: 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.
abstract: 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 degrees 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 ED(50)/24 h of 3.0 +/- 0.3 micro mol/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).
authors.affiliation: Instituto de Química, Biological Chemistry Laboratory, Universidade Estadual de Campinas, Campinas, C P 6154, CEP 13083-970, SP, Brazil.
authors.forename: Ana O
authors.initials: AO
authors.lastname: de Souza
authors.forename: Fernando P
authors.initials: FP
authors.lastname: Hemerly
authors.forename: Adriana C
authors.initials: AC
authors.lastname: Busollo
authors.forename: Patrícia S
authors.initials: PS
authors.lastname: Melo
authors.forename: Gérzia M C
authors.initials: GM
authors.lastname: Machado
authors.forename: Cristiana C
authors.initials: CC
authors.lastname: Miranda
authors.forename: Ricardo M
authors.initials: RM
authors.lastname: Santa-Rita
authors.forename: Marcela
authors.initials: M
authors.lastname: Haun
authors.forename: Leonor L
authors.initials: LL
authors.lastname: Leon
authors.forename: Daisy N
authors.initials: DN
authors.lastname: Sato
authors.forename: Solange L
authors.initials: SL
authors.lastname: de Castro
authors.forename: Nelson
authors.initials: N
authors.lastname: Durán
mesh_terms: D000588:Amines / Q000138:chemical synthesis / Q000494:pharmacology; D000818:Animals; D000900:Anti-Bacterial Agents / Q000138:chemical synthesis / Q000494:pharmacology; D000981:Antiprotozoal Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D000995:Antitubercular Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D001713:Biphenyl Compounds / Q000138:chemical synthesis / Q000494:pharmacology; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D007891:Leishmania / Q000187:drug effects* / Q000502:physiology; D008826:Microbial Sensitivity Tests / Q000706:statistics & numerical data; D009169:Mycobacterium tuberculosis / Q000187:drug effects / Q000502:physiology; D014344:Trypanocidal Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D014349:Trypanosoma cruzi / Q000187:drug effects / Q000502:physiology
chemical_list: D000588:Amines; D000900:Anti-Bacterial Agents; D000981:Antiprotozoal Agents; D000995:Antitubercular Agents; D001713:Biphenyl Compounds; D014344:Trypanocidal Agents