ABSTRACT
Leishmaniasis, a vector-borne parasitic disease caused by Leishmania protozoa, is one of the most neglected tropical diseases in terms of drug discovery and development. Current treatment is based on a limited number of chemotherapeutic agents all of which present either/or resistance issues, severe toxicities and adverse reactions associated with extended treatment regimens, and high cost of therapy. Dinitroanilines are a new class of drugs with proven in vitro antileishmanial activity. In previous work a liposomal formulation of one dinitroaniline (TFL) was found to be active against Leishmania parasites in a murine model of visceral leishmaniasis (VL) and in the treatment of experimental canine leishmaniasis. In this study we have investigated the use of dinitroaniline analogues (TFL-A) associated to liposomes, as means to further improve TFL antileishmanial activity. The potential of the liposomal formulations was assessed in vitro against Leishmania infantum promastigotes and intracellular amastigotes and in vivo in a murine model of zoonotic VL. Free and liposomal TFL-A were active in vitro against Leishmania parasites, and they also exhibited reduced cytotoxicity and haemolytic activity. Treatment of infected mice with liposomal TFL-A reduced the amastigote loads in the spleen up to 97%, compared with the loads for untreated controls. These findings illustrate that chemical synthesis of new molecules associated with the use of Nano Drug Delivery Systems that naturally target the diseased organs could be a promising strategy for effective management of VL.
Subject(s)
Antiprotozoal Agents/administration & dosage , Leishmania infantum/drug effects , Leishmaniasis, Visceral/drug therapy , Lipids/chemistry , Trifluralin/administration & dosage , Animals , Antiprotozoal Agents/chemical synthesis , Antiprotozoal Agents/toxicity , Cell Line , Chemistry, Pharmaceutical , Disease Models, Animal , Hemolysis/drug effects , Humans , Leishmania infantum/growth & development , Leishmania infantum/parasitology , Leishmaniasis, Visceral/parasitology , Liposomes , Mice, Inbred BALB C , Parasite Load , Spleen/parasitology , Technology, Pharmaceutical/methods , Trifluralin/chemical synthesis , Trifluralin/toxicityABSTRACT
A series of new analogues of trifluralin (TFL) were synthesized and characterized in view of changing the unfavorable properties that limits its use as antileishmanial agent. Some of the TFL analogues display more activity than a standard drug (miltefosine) against the promastigote forms of Leishmania infantum and Leishmania donovani and the intracellular form (THP-1 infected with L. infantum). All analogues showed a clear advantage over miltefosine, as they are not hemolytic. Some analogues can conjugate these characteristics with reduced cell toxicity and improved intracellular activity.
Subject(s)
Antiprotozoal Agents/chemistry , Antiprotozoal Agents/pharmacology , Leishmania/drug effects , Leishmaniasis/drug therapy , Trifluralin/chemistry , Trifluralin/pharmacology , Antiprotozoal Agents/chemical synthesis , Cell Death/drug effects , Cell Line , Erythrocytes/drug effects , Hemolysis/drug effects , Humans , Leishmania donovani/drug effects , Leishmania infantum/drug effects , Trifluralin/chemical synthesisABSTRACT
The efficacy of a series of dinitroaniline herbicide derivatives for the treatment of Cryptosporidium parvum infections has been studied. The lead compounds oryzalin (compound 1) and trifluralin (compound 2) have low water solubility (<3 ppm) which was alleged to be a major contributor to their poor pharmacokinetic availability. Derivatives of compounds 1 and 2 were synthesized. In these derivatives the functionality at the C-1 amine position or the C-4 position was substituted with groups with various hydrophilicities to determine if a direct relation existed between water solubility and overall activity. The chlorinated precursors of these derivatives were also examined and were found to be less active in the C. parvum assays, a result in direct contrast to earlier work with Leishmania. Enhanced water solubility alone did not overcome the drug availability problem; however, several candidates with similar activities but with toxicities lower than those of the lead compounds were produced.
Subject(s)
Cryptosporidium parvum/drug effects , Dinitrobenzenes/chemical synthesis , Dinitrobenzenes/pharmacokinetics , Sulfanilamides , Trifluralin/chemical synthesis , Trifluralin/pharmacokinetics , Animals , Cells, Cultured , Coccidiostats/therapeutic use , Cryptosporidiosis/drug therapy , Cryptosporidiosis/parasitology , Cryptosporidium parvum/growth & development , Dinitrobenzenes/therapeutic use , Dogs , Structure-Activity Relationship , Trifluralin/therapeutic useABSTRACT
3H-Trifluralin was synthesized by condensation of 3H-4-chloro-3,5-dinitro-alpha, alpha, alpha-trifluorotoluene with di-n-propylamine. After incubation of trifluralin with Aspergillus carneus, Fusarium oxysporum and Trichoderma viride for 10 days, a small percentage (less than 10%) of unchanged herbicide was recovered in the extractable fraction. This indicates a fairly rapid degradation of the herbicide by the fungal species. Other than trifluralin, the culture medium contained at least five labelled products: 2,6-dinitro-N-n-propyl-alpha, alpha, alpha-trifluoro-p-toluidine; 2,6-dinitro-alpha, alpha, alpha-trifluoro-p-toluidine; 2-amino-6-nitro-alpha, alpha, alpha-trifluoro-p-toluidine, 2,6-dinitro-4-trifluoromethyl phenol and a major polar product which constituted more than 50% of the total extractable transformation products. A pathway, which simulates that of aerobic degradation of the herbicide in soil, is suggested for the microbiological degradation of trifluralin.
