ABSTRACT
AIM: Metronidazole is the most widely used drug in trichomoniasis therapy. However, the emergence of metronidazole-resistant Trichomonas vaginalis isolates calls for the search for new drugs to counter the pathogenicity of these parasites. RESULTS: Classification models for predicting the antitrichomonas activity of molecules were built. These models were employed to screen antiprotozoal drugs, from which 20 were classified as active. The in vitro experiments showed moderate to high activity for 19 of the molecules at 10 µg/ml, while 3 compounds yielded higher activity than the reference at 1 µg/ml. The 11 most active chemicals were evaluated in vivo using Naval Medical Research Institute (NMRI) mice. CONCLUSION: Benznidazole showed similar results as metronidazole, and can thus be considered as a potential candidate in antitrichomonas therapy.
Subject(s)
Antiprotozoal Agents/chemistry , Antiprotozoal Agents/pharmacology , Drug Repositioning/methods , Trichomonas Infections/drug therapy , Trichomonas vaginalis/drug effects , Animals , Antiprotozoal Agents/therapeutic use , Discriminant Analysis , Drug Resistance , Female , Humans , Metronidazole/chemistry , Metronidazole/pharmacology , Metronidazole/therapeutic use , Mice , Nitroimidazoles/chemistry , Nitroimidazoles/pharmacology , Nitroimidazoles/therapeutic use , Trichomonas Vaginitis/drug therapyABSTRACT
A series of new 21 chloroquine heterocyclic hybrids containing either benzylamino fragment or N-(aminoalkyl)thiazolidin-4-one moiety were synthesized and screened for their antimalarial activity against chloroquine (CQ)-sensitive 3D7 and multidrug-resistance Dd2 strains of Plasmodium falciparum. Although no compounds more active than CQ against 3D7 was found; against Dd2 strain, six compounds, four of them with benzylamino fragment, showed an excellent activity, up to 3-fold more active than CQ. Non specific cytotoxicity on J774 macrophages was observed in some compounds whereas only two of them showed liver toxicity on HepG2 cells. In addition, all active compounds inhibited the ferriprotoporphyrin IX biocrystalization process in concentrations around to CQ. In vivo preliminary results have shown that at least two compounds are as active as CQ against Plasmodium berghei ANKA.
Subject(s)
Antimalarials/chemistry , Antimalarials/pharmacology , Chloroquine/chemistry , Chloroquine/pharmacology , Malaria, Falciparum/drug therapy , Plasmodium falciparum/drug effects , Thiazolidines/chemistry , Thiazolidines/pharmacology , Animals , Antimalarials/chemical synthesis , Cell Line , Cell Survival/drug effects , Chloroquine/chemical synthesis , Drug Resistance, Multiple , Hep G2 Cells , Humans , Mice , Thiazolidines/chemical synthesisABSTRACT
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 IC(50) lower than 1 microM. 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.
Subject(s)
Antimalarials/chemistry , Plasmodium berghei/drug effects , Plasmodium falciparum/drug effects , Propanols/chemistry , Animals , Antimalarials/chemical synthesis , Antimalarials/pharmacology , Cell Line , Inhibitory Concentration 50 , Macrophages/drug effects , Mice , Propanols/chemical synthesis , Propanols/pharmacologyABSTRACT
Lymphoproliferation inhibition and cytotoxicity of a number of lipidic aminoacids, aminoalcohols and diamines were evaluated as a preliminary screening to select potential immunomodulators. The four most potent/less toxic compounds were submitted to delayed hypersensibility (DTH) assays to define the best to be evaluated further Graft-vs-Host, NO production and other immunoevaluation (CD4(+), CD45, CD8, CD11b, I-Ek, and NK cells) assays, to establish their immunomodulation potential for being further considered as auxiliary agents for vaccination against some parasitic infections. Compounds 5d, 6d, 6f, 7a, and 9a, fairly inhibited the lymphoproliferation (71.6-79.5%, at 3.2-2.4 nM), while the aminoalcohol derivative 6f and the diamine 7a gave the most promising results in the DTH assays. Diamine derivative 8b induced nitrite production on normal macrophages, whereas compounds 6f and 7a induced nitrite production on LPS pre-stimulated macrophages. These two last compounds have been selected to follow in vivo vaccination assays.
Subject(s)
Amino Alcohols/chemistry , Amino Alcohols/pharmacology , Diamines/chemistry , Diamines/pharmacology , Immunologic Factors/chemical synthesis , Immunologic Factors/pharmacology , Amino Alcohols/chemical synthesis , Amino Alcohols/toxicity , Cell Proliferation/drug effects , Diamines/chemical synthesis , Diamines/toxicity , Hydrophobic and Hydrophilic Interactions , Immunologic Factors/chemistry , Immunologic Factors/toxicity , Molecular Structure , Nitrites/metabolism , Structure-Activity RelationshipABSTRACT
In order to explore the ability of non-stochastic quadratic indices to encode chemical information in antimalarials, four quantitative models for the discrimination of compounds having this property were generated and statistically compared. Accuracies of 90.2% and 83.3% for the training and test sets, respectively, were observed for the best of all the models, which included non-stochastic quadratic fingerprints weighted with Pauling electronegativities. With a comparative purpose and as a second validation experiment, an exercise of virtual screening of 65 already-reported antimalarials was carried out. Finally, 17 new compounds were classified as either active/inactive ones and experimentally evaluated for their potential antimalarial properties on the ferriprotoporphyrin (FP) IX biocrystallization inhibition test (FBIT). The theoretical predictions were in agreement with the experimental results. In the assayed test compound C5 resulted more active than chloroquine. The current result illustrates the usefulness of the TOMOCOMD-CARDD strategy in rational antimalarial-drug design, at the time that it introduces a new family of organic compounds as starting point for the development of promising antimalarials.
Subject(s)
Antimalarials/chemistry , Antimalarials/pharmacology , Drug Design , Drug Evaluation, Preclinical/statistics & numerical data , Algorithms , Antimalarials/classification , Chloroquine/pharmacology , Computer Simulation , Crystallization , Hemin/chemistry , Heterocyclic Compounds/chemistry , Heterocyclic Compounds/pharmacology , Models, Molecular , Molecular Conformation , Quantitative Structure-Activity Relationship , Reproducibility of ResultsABSTRACT
Eighteen clinical isolates of Trichomonas vaginalis were obtained from women who attended health centers of the Government 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.
Subject(s)
Trichomonas Infections/parasitology , Trichomonas vaginalis/pathogenicity , Animals , Antitrichomonal Agents/pharmacology , Female , Humans , Metronidazole/pharmacology , Mice , Parasitic Sensitivity Tests , Trichomonas Infections/drug therapy , Trichomonas vaginalis/drug effects , VirulenceABSTRACT
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
Subject(s)
Humans , Animals , Female , Mice , Trichomonas Infections , Trichomonas vaginalis , Antitrichomonal Agents , Metronidazole , Parasitic Sensitivity Tests , Trichomonas Infections , Trichomonas vaginalis , VirulenceABSTRACT
Once known some biological characteristics of six Trypanosoma cruzi strains, randomly amplified polymorphic DNA (RAPD) analysis was made. Cluster analysis by UPGMA (unweighted pair group method analysis) was then applied both to biological parameters and RAPD profiles. Inspection of the UPGMA phenograms indicates identical clusters, so supporting that usefulness of biological parameters to characterization of T. cruzi strains still remains
Subject(s)
Animals , DNA, Protozoan/analysis , Random Amplified Polymorphic DNA Technique/methods , Trypanosoma cruzi/genetics , Trypanosoma cruzi/physiology , Behavior, Animal/physiology , Genetic HeterogeneityABSTRACT
Biological parameters of five Trypanosoma cruzi strains from different sources were determined in order to know the laboratory behaviour of natural populations. The parameters evaluated were growth kinetics of epimastigotes, differentiation into metacyclic forms, infectivity in mammalian cells grown in vitro and parasite susceptibility to nifurtimox, benznidazole and gentian violet. Differences in transformation to metacyclic, in the percentage of infected cells as well as in the number of amastigotes per cell were observed among the strains. Regarding to pharmacological assays, Y strain was the most sensitive to the three assayed compounds. These data demonstrate the heterogeneity of natural populations of T. cruzi, the only responsible of infection in humans
