ABSTRACT
As part of a program to develop new drugs for the treatment of neglected diseases, new dialkylphosphorylhydrazones were synthesized and evaluated against the trypanosomatid parasites Leishmania braziliensis and Leishmania amazonensis. The synthesis of these compounds proved satisfactory with yields ranging from moderate to good. The most active compounds against L. braziliensis presented IC50 values in the 10(-2) µM range, similar to that of the reference drug pentamidine. Two compounds, 4m and 4n, showed a significant dose dependent decrease in the infection index of L. amazonensis infected macrophages and caused a complete healing of nodules and ulcers when tested in vivo against L. amazonensis-infected mice, but the control of parasite burden at the inoculation site was statistically significant only in the case of treatment with 4n. A target fishing (reverse docking) approach using molecular docking with 15 enzymes of L. braziliensis indicated that the probable target of the active compounds was hexokinase, the first enzyme of the glycolytic pathway.
Subject(s)
Hydrazones/chemistry , Hydrazones/pharmacology , Leishmania/drug effects , Trypanocidal Agents/chemical synthesis , Trypanocidal Agents/pharmacology , Animals , Dose-Response Relationship, Drug , Hexokinase/metabolism , Hydrazones/chemical synthesis , Leishmania/enzymology , Leishmania/metabolism , Macrophages/drug effects , Macrophages/parasitology , Mice , Molecular Docking Simulation , Molecular Structure , Parasitic Sensitivity Tests , Structure-Activity Relationship , Trypanocidal Agents/chemistryABSTRACT
A series of new compounds, N,N'-bis(dialkylphosphoryl)diamines and S,S'-bis(dialkylphosphoryl)-1,3-propanedithiols were prepared by a Todd-Atherton like reaction of dialkylphosphites with symmetrical diamines and 1,3-propanedithiols in a biphasic system [F.R. Athertoon, H.T. Howard, A.R. Todd, J. Chem. Soc. (1948) 1106-1111; F.R. Athertoon, H.T. Openshaw, A.R. Todd, J. Chem. Soc. (1945) 660-663]. The structures were characterized by IR, 1H NMR, 13C NMR and mass spectrometry. Compounds with butoxy, isobutoxy and isopropoxy groups linked in the phosphorus atom showed the lowest LD50 values when tested against Musca domestica and Stomoxys calcitrans. The pharmacological and toxicological evaluation of N,N'-bis(diisobutylphosphoryl)-1,3-propylenediamine and S,S'-bis(diisobutylphosphoryl)-1,3-propanedithiol, which were very active against M. domestica and S. calcitrans, demonstrated that these compounds present no toxicological effects against mice in a concentration of 200mg/kg. An explanation for the observed activity profile is presented based on results obtained in a molecular modeling study with insect and mammalian acetylcholinesterase models.
Subject(s)
Acetylcholinesterase/chemistry , Cholinesterase Inhibitors/chemistry , Insecticides/chemistry , Organophosphorus Compounds/chemistry , Animals , Cholinesterase Inhibitors/pharmacology , Cholinesterase Inhibitors/toxicity , Computational Biology , Female , Houseflies/drug effects , Hydrogen Bonding , Hydrophobic and Hydrophilic Interactions , Insecta/drug effects , Insecta/enzymology , Insecticides/pharmacology , Insecticides/toxicity , Lethal Dose 50 , Male , Mice , Mice, Inbred Strains , Models, Molecular , Molecular Structure , Muscidae/drug effects , Organophosphorus Compounds/pharmacology , Organophosphorus Compounds/toxicity , Thermodynamics , Toxicity Tests/methodsABSTRACT
This work describes the results of an investigation on the structure-activity relationships of a series of acronine (CAS 7008-42-6) analogues which possess cytotoxic and antitumor activity. The results were obtained employing a commercially available software, which correlates structure and activity through calculations with different descriptors. The best results, obtained with electrostatic descriptors, led to propose new structures which present higher calculated activity than that of acronine.
