29 research outputs found
Promising hit compounds against resistant trichomoniasis: Synthesis and antiparasitic activity of 3-(ω-aminoalkoxy)-1-benzyl-5-nitroindazoles
A series of 11 3-(ω-aminoalkoxy)-1-benzyl-5-nitroindazoles (2–12) has been prepared starting from 1-benzyl-5-nitroindazol-3-ol 13, and evaluated against sensitive and resistant isolates of the sexually transmitted protozoan Trichomonas vaginalis. Compounds 2, 3, 6, 9, 10 and 11 showed trichomonacidal profiles with IC50 < 20 µM against the metronidazole-sensitive isolate. Moreover, all these compounds submitted to cytotoxicity assays against mammalian cells exhibited low non-specific cytotoxic effects, except compounds 3 and 9 which displayed moderate cytotoxicity (CC50 = 74.7 and 59.1 µM, respectively). Those compounds with trichomonacidal effect were also evaluated against a metronidazole-resistant culture. Special mention deserve compounds 6 and 10, which displayed better IC50 values (1.3 and 0.5 µM respectively) than that of the reference drug (IC50 MTZ = 3.0 µM). The high activity of these compounds against the resistant isolate reinforces the absence of cross-resistance with the reference drug. The remarkable trichomonacidal results against resistant T. vaginalis isolates suggest the interest of 3-(ω-aminoalkoxy)-1-benzyl-5-nitroindazoles to be considered as good prototypes to continue in the development of new drugs with enhanced trichomonacidal activity, aiming to increase the non-existent drugs to face clinical resistance efficiently for those patients in whom therapy with 5-nitroimidazoles is contraindicated
New 1-aryl-3-substituted propanol derivatives as antimalarial agents
This paper describes the synthesis and in vitro antimalarial activity against a P.
falciparum 3D7 strain of some new 1-aryl-3-substituted propanol derivatives. Twelve of
the tested compounds showed an IC50 lower than 1 μM. These compounds were also tested
for cytotoxicity in murine J774 macrophages. The most active compounds were evaluated
for in vivo activity against P. berghei in a 4-day suppressive test. Compound 12 inhibited
more than 50% of parasite growth at a dose of 50 mg/kg/day. In addition, an FBIT test was
performed to measure the ability to inhibit ferriprotoporphyrin biocrystallization. This data
indicates that 1-aryl-3-substituted propanol derivatives hold promise as a new therapeutic
option for the treatment of malaria
Relationship between biological behaviour and randomly amplified polymorphic DNA profiles of Trypanosoma cruzi strains
Determination of internal transcribed spacer regions (ITS) in Trichomonas vaginalis isolates and differentiation among Trichomonas species
In vitro trichomonacidal activity and preliminary in silico chemometric studies of 5-nitroindazolin-3-one and 3-alkoxy-5-nitroindazole derivatives
A selection of 1,2-disubstituted 5-nitroindazolin-3-ones (1-19) and 3-alkoxy-5-nitroindazoles substituted at positions 1 (20-24) or 2 (25-39) from our in-house compound library were screened in vitro against the most common curable sexually transmitted pathogen, Trichomonas vaginalis. A total of 41% of the studied molecules (16/39) achieved a significant activity of more than 85% growth inhibition at the highest concentration assayed (100 Âg mL). Among these compounds, 3-alkoxy-5-nitroindazole derivatives 23, 24, 25 and 27 inhibited parasite growth by more than 50% at 10 Âg mL. In addition, the first two compounds (23, 24) still showed remarkable activity at the lowest dose tested (1 Âg mL), inhibiting parasite growth by nearly 40%. Their specific activity towards the parasite was corroborated by the determination of their non-specific cytotoxicity against mammalian cells. The four mentioned compounds exhibited non-cytotoxic profiles at all of the concentrations assayed, showing a fair antiparasitic selectivity index (SI > 7·5). In silico studies were performed to predict pharmacokinetic properties, toxicity and drug-score using Molinspiration and OSIRIS computational tools. The current in vitro results supported by the virtual screening suggest 2-substituted and, especially, 1-substituted 3-alkoxy-5-nitroindazoles as promising starting scaffolds for further development of novel chemical compounds with the main aim of promoting highly selective trichomonacidal lead-like drugs with adequate pharmacokinetic and toxicological profiles.The Research Group ‘Antiparasitic Therapy’ (Ref. 911120) of the Universidad Complutense de Madrid and CEI Moncloa (cluster of i-Medicine) is gratefully acknowledged by all the authors.Peer Reviewe
Determination of internal transcribed spacer regions (ITS) in Trichomonas vaginalis isolates and differentiation among Trichomonas species
The nucleotide sequence of the 5.8S rRNA gene and the flanked internal transcribed spacer (ITS) regions of six Trichomonas vaginalis isolates with different metronidazole sensitivity and geographic origin were genotyped. A multiple sequence alignment was performed with different sequences of other isolates available at the GenBank/EMBL/DDBJ databases, which revealed 5 different sequence patterns. Although a stable mutation in position 66 of the ITS1 (C66T) was observed in 26% (9/34) of the T. vaginalis sequences analyzed, there was 99.7% ITS nucleotide sequence identity among isolates for this sequence. The nucleotide sequence variation among other species of the genus Trichomonas ranged from 3.4% to 9.1%. Surprisingly, the % identity between T. vaginalis and Pentatrichomonas hominis was ~. 83%. There was >. 40% divergence in the ITS sequence between T. vaginalis and Tritrichomonas spp., including Tritrichomonas augusta, Tritrichomonas muris, and Tritrichomonas nonconforma and with Tetratrichomonas prowazeki. Dendrograms grouped the trichomonadid sequences in robust clades according to their genera. The absence of nucleotide divergence in the hypervariable ITS regions between T. vaginalis isolates suggests the early divergence of the parasite. Importantly, these data show this ITS1-5.8S rRNA-ITS2 region suitable for inter-species differentiation. © 2014 Elsevier B.V.Peer Reviewe
SHORT COMMUNICATION - Biological Variability in Clinical Isolates of Trichomonas vaginalis
Eighteen clinical isolates of Trichomonas vaginalis  were
obtained from women who attended health centers of the Goverment of
Madrid. A total of 1,848 vaginal specimens recovered during the
gynaecological examination were seeded in culture tubes containing
liquid Diamond medium. Pathogenicity to mice was determined after
intraperitoneal inoculation of mice by quantification of mortality and
gross damage to abdominal organs. As could be expected, a broad
variability was obtained, being some of the isolates more virulent than
the reference strain. Regarding to metronidazole susceptibility, none
resistant isolate was found but different degrees of susceptibility
were determined