ABSTRACT
The antiplasmodial active extract of Xanthium cavanillesii contains 3,4-dicaffeoyl quinic acid (3,4-DCQA), 3,5-dicaffeoyl quinic acid (3,5-DCQA) and 1,3,5-tricaffeoyl quinic acid (1,3,5-TCQA). These results inspired us to investigate the interaction of these molecules with a promising validated target of Plasmodium, PfATP6 orthologue of mammalian Ca+2-ATPase. Models of this receptor were obtained through comparative modelling. Afterwards, molecular docking studies were used to identify possible interaction modes of these caffeoyl quinic derivatives on the binding site. The 1,3,5-TCQA had the best energy, but all of these had better energy than thapsigargin, a non-competitive inhibitor of the sarco/endoplasmatic reticulum Ca+2-ATPase (SERCA).
Subject(s)
Antimalarials/pharmacology , Fruit/chemistry , Plant Extracts/pharmacology , Quinic Acid/analogs & derivatives , Xanthium/chemistry , Animals , Antimalarials/chemistry , Calcium-Transporting ATPases/antagonists & inhibitors , Enzyme Inhibitors/pharmacology , Models, Molecular , Molecular Docking Simulation , Plant Extracts/chemistry , Plasmodium/drug effects , Quinic Acid/chemistry , Quinic Acid/pharmacology , Thapsigargin/pharmacologyABSTRACT
A useful concept for the rational design of antiparasitic drug candidates is the complexation of bioactive ligands with transition metals. In view of this, an investigation was conducted into a new set of metal complexes as potential antiplasmodium and antiamoebic agents, in order to examine the importance of metallic atoms, as well as the kind of sphere of co-ordination, in these biological properties. Four functionalized furyl-thiosemicarbazones (NT1-4) treated with divalent metals (Cu, Co, Pt, and Pd) to form the mononuclear metallic complexes of formula [M(L)2Cl2] or [M(L)Cl2] were examined. The pharmacological characterization, including assays against Plasmodium falciparum and Entamoeba histolytica, cytotoxicity to mammalian cells, and interaction with pBR 322 plasmid DNA was performed. Structure-activity relationship data revealed that the metallic complexation plays an essential role in antiprotozoal activity, rather than the simple presence of the ligand or metal alone. Important steps towards identification of novel antiplasmodium (NT1Cu, IC50 of 4.6 microM) and antiamoebic (NT2Pd, IC50 of 0.6 microM) drug prototypes were achieved. Of particular relevance to this work, these prototypes were able to reduce the proliferation of these parasites at concentrations that are not cytotoxic to mammalian cells.
Subject(s)
Amebicides/chemistry , Antimalarials/chemistry , Coordination Complexes/chemistry , Metals/chemistry , Thiosemicarbazones/chemistry , Amebicides/chemical synthesis , Amebicides/toxicity , Animals , Antimalarials/chemical synthesis , Antimalarials/toxicity , Coordination Complexes/chemical synthesis , Coordination Complexes/toxicity , Entamoeba histolytica/drug effects , Mice , Mice, Inbred BALB C , Plasmodium falciparum/drug effects , Spleen/cytology , Spleen/drug effects , Structure-Activity Relationship , Thiosemicarbazones/chemical synthesis , Thiosemicarbazones/toxicityABSTRACT
Malaria is one of the most important tropical diseases and mainly affects populations living in developing countries. Reduced sensitivity of Plasmodium sp. to formerly recommended antimalarial drugs places an increasing burden on malaria control programs as well as on national health systems in endemic countries. The present study aims to evaluate the antimalarial activity of betulinic acid and its derivative compounds, betulonic acid, betulinic acid acetate, betulinic acid methyl ester, and betulinic acid methyl ester acetate. These substances showed antiplasmodial activity against chloroquine-resistant Plasmodium falciparum parasites in vitro, with IC(50) values of 9.89, 10.01, 5.99, 51.58, and 45.79 microM, respectively. Mice infected with Plasmodium berghei and treated with betulinic acid acetate had a dose-dependent reduction of parasitemia. Our results indicate that betulinic acid and its derivative compounds are candidates for the development of new antimalarial drugs.
Subject(s)
Antimalarials/pharmacology , Antimalarials/therapeutic use , Malaria/drug therapy , Plasmodium berghei/drug effects , Plasmodium falciparum/drug effects , Triterpenes/pharmacology , Triterpenes/therapeutic use , Animals , Dose-Response Relationship, Drug , Humans , Inhibitory Concentration 50 , Mice , Mice, Inbred BALB C , Parasitemia/drug therapy , Pentacyclic Triterpenes , Survival Analysis , Betulinic AcidABSTRACT
Despite many advances made in disease mechanisms knowledge and drug discovery and development processes, the election of promising lead compounds continues to be a challenge. Efficient techniques are required for lead selection of hit compounds selected through in vitro pharmacological studies, in order to generate precise low cost throughput data with minimal amount of compound to support the right decision making. In this context, the selection of lead compounds with physicochemical parameters that will benefit orally bioavailable drugs are crucial for patients compliance and cost effectiveness, as well as for successful pharmacology. A concept based in Lipinski's rules point out the importance of analyzing these informations in early stages. A hepatocyte screening system may provide data on many processes such as drug-drug interaction, metabolite formation, drug toxicity and ADME profile of a hit. Drug-induced liver injury is the most frequent reason for the withdrawal of an approved drug from the market and hepatocytes have a central role in the metabolism of xenobiotics. Cytotoxicity screening assays can also give some information about toxicity early drug discovery process. A set of goals in lead compound selection must be shared between all areas involved so the chances of success can be improved in translational research.
