title: The effect of 3-(biphenyl-4-yl)-3-hydoxyquinuclidine (BPQ-OH) and metronidazole on Trichomonas vaginalis: a comparative study.
abstract: Trichomonas vaginalis causes trichomoniasis in humans, a sexually transmitted disease commonly treated with metronidazole (MTZ), a drug that presents some toxicity, causing undesirable side effects. In addition, an increase in metronidazole-resistant parasites has been reported. Thus, the development of alternative treatment is recommended. To date, the search for antiparasitic drugs has been based on different approaches: identification of active natural products, identification of parasite targets, and the use of available compounds active against other pathogenic microorganisms. Here, we analyzed the in vitro antiproliferative and ultrastructural effects on T. vaginalis of BPQ-OH, a hydroxiquinuclidine derivative that inhibits squalene synthase and is active against several protozoa and fungi. We also compared the effects of BPQ-OH on T. vaginalis and mammalian cells with those of MTZ. We found that BPQ-OH inhibits in vitro proliferation of T. vaginalis, with an IC50 of 46 μM after 24 h. Although this IC50 is 16 times higher than that of MTZ (1.8 μM), BPQ-OH is less toxic for human cell lines than MTZ, with LC50 values of 2,300 and 70 μM, and selective indexes of 50 and 39, respectively. Ultrastructural analyses demonstrated that BPQ-OH induced alterations in T. vaginalis, such as rounded and wrinkled cells, membrane blebbing and intense vacuolization, leading to cell death, whereas MTZ also caused significant changes, including a decrease in hydrogenosomes size and endoflagellar forms. Our observations identify BPQ-OH as a promising leading compound for the development of novel anti-T. vaginalis drugs and highlight the need for further testing this molecule using experimentally infected animals.
authors.affiliation: Universidade Santa Úrsula, Rua Jornalista Orlando Dantas 59, Botafogo, CEP 22231-010, Rio de Janeiro, Brazil.
authors.forename: Débora Afonso Silva
authors.initials: DA
authors.lastname: Rocha
authors.forename: Ivone
authors.initials: I
authors.lastname: de Andrade Rosa
authors.forename: Julio A
authors.initials: JA
authors.lastname: Urbina
authors.forename: Wanderley
authors.initials: W
authors.lastname: de Souza
authors.forename: Marlene
authors.initials: M
authors.lastname: Benchimol
mesh_terms: D000818:Animals; D000981:Antiprotozoal Agents / Q000494:pharmacology*; D018938:Caco-2 Cells; D049109:Cell Proliferation / Q000187:drug effects; D013186:Farnesyl-Diphosphate Farnesyltransferase / Q000037:antagonists & inhibitors; D006367:HeLa Cells; D006801:Humans; D008795:Metronidazole / Q000494:pharmacology*; D015388:Organelles / Q000187:drug effects; D011812:Quinuclidines / Q000494:pharmacology*; D014246:Trichomonas vaginalis / Q000166:cytology / Q000187:drug effects* / Q000648:ultrastructure
chemical_list: C099381:3-(biphenyl-4-yl)-3-hydroxyquinuclidine; D000981:Antiprotozoal Agents; D011812:Quinuclidines; D008795:Metronidazole; D013186:Farnesyl-Diphosphate Farnesyltransferase
references.citation: Enzyme. 1988;39(2):90-4
references.pmid: 2840276
references.citation: Biochem Pharmacol. 1996 Jun 14;51(11):1477-87
references.pmid: 8630089
references.citation: Parasitol Res. 2012 Jun;110(6):2581-7
references.pmid: 22205352
references.citation: Arch Gynecol Obstet. 2010 Nov;282(5):503-5
references.pmid: 19940998
references.citation: J Med Chem. 2001 Mar 15;44(6):909-16
references.pmid: 11300872
references.citation: FEMS Microbiol Lett. 2011 Feb;315(1):72-8
references.pmid: 21175744
references.citation: Mol Biochem Parasitol. 2002 Nov-Dec;125(1-2):35-45
references.pmid: 12467972
references.citation: Methods. 1999 Jun;18(2):104-8
references.pmid: 10356340
references.citation: J Infect Dis. 2008 Feb 15;197(4):548-54
references.pmid: 18275275
references.citation: Cancer Res. 1976 Mar;36(3):930-6
references.pmid: 1253180
references.citation: Int J Parasitol. 1994 Aug;24(5):695-703
references.pmid: 7928072
references.citation: J Med Chem. 1996 Jul 19;39(15):2971-9
references.pmid: 8709131
references.citation: Exp Parasitol. 2005 Dec;111(4):230-8
references.pmid: 16198340
references.citation: Antimicrob Agents Chemother. 2007 Nov;51(11):4049-61
references.pmid: 17709461
references.citation: Exp Cell Res. 2002 May 15;276(1):32-9
references.pmid: 11978006
references.citation: Proc Natl Acad Sci U S A. 1993 Jan 1;90(1):80-4
references.pmid: 8419946
references.citation: Antimicrob Agents Chemother. 2001 Jun;45(6):1810-4
references.pmid: 11353630
references.citation: Cell Res. 2003 Aug;13(4):239-49
references.pmid: 12974614
references.citation: Exp Parasitol. 1984 Feb;57(1):93-103
references.pmid: 6692888
references.citation: J Antimicrob Chemother. 1975 Mar;1(1):121-6
references.pmid: 1080756
references.citation: J Clin Microbiol. 2000 Feb;38(2):763-7
references.pmid: 10655382
references.citation: Parasitol Res. 2004 Jan;92(2):159-70
references.pmid: 14673646
references.citation: Antimicrob Agents Chemother. 2006 Jan;50(1):162-70
references.pmid: 16377682
references.citation: Br J Vener Dis. 1982 Dec;58(6):394-9
references.pmid: 6983379
references.citation: Parasitol Res. 2013 May;112(5):2063-7
references.pmid: 23455944
references.citation: Can Med Assoc J. 1962 Apr 7;86(14):665
references.pmid: 20327097
references.citation: Cancer Epidemiol Biomarkers Prev. 2006 May;15(5):939-45
references.pmid: 16702374
references.citation: Histochem Cell Biol. 2006 May;125(5):545-56
references.pmid: 16273383
references.citation: Parasitol Res. 2012 Jun;110(6):2551-6
references.pmid: 22218924
references.citation: Mem Inst Oswaldo Cruz. 2011 Dec;106(8):1055-7
references.pmid: 22241134
references.citation: J Gen Microbiol. 1973 May;76(1):135-45
references.pmid: 4541833
references.citation: Parasitol Res. 2008 Jul;103(2):443-8
references.pmid: 18463895
references.citation: Antimicrob Agents Chemother. 1976 Sep;10(3):476-82
references.pmid: 791102
references.citation: Virology. 1959 Jul;8(3):396-7
references.pmid: 13669362
references.citation: J Parasitol. 1957 Aug;43(4):488-90
references.pmid: 13463700
references.citation: Am J Obstet Gynecol. 2004 Jan;190(1):281-90
references.pmid: 14749674
references.citation: J Antimicrob Chemother. 2006 Jul;58(1):59-65
references.pmid: 16702175