ABSTRACT
A series of novel thioetherhydroxyethylsulfonamide derivatives has been synthesized from the coupling of intermediates 3-amino-4-phenyl-1-thioetherazine-butan-2-oles 6,7 with arenesulfonyl chlorides in good yields. Characterizations of products were achieved by NMR techniques and specifically for compound 8e by X-ray crystallography. Preliminary results of antimalarial activity in vitro against the Plasmodium falciparum W2 clone (chloroquine resistant and mefloquine sensitive) showed moderate activity for hydroxyethylsulfonamide 8f. In addition, none of the compounds tested showed cytotoxicity at high concentration tested against HepG2 and BGM cell lines.
Subject(s)
Aspartic Acid Proteases/antagonists & inhibitors , Chemistry Techniques, Synthetic , Sulfonamides/chemical synthesis , Sulfonamides/pharmacology , Antimalarials/chemical synthesis , Antimalarials/chemistry , Antimalarials/pharmacology , Antimalarials/toxicity , Hep G2 Cells , Humans , Inhibitory Concentration 50 , Models, Molecular , Molecular Conformation , Plasmodium falciparum/drug effects , Protease Inhibitors/chemical synthesis , Protease Inhibitors/chemistry , Protease Inhibitors/pharmacology , Protease Inhibitors/toxicity , Sulfonamides/chemistry , Sulfonamides/toxicityABSTRACT
The antimalarial acitivity of hydroxyethylamines, synthesized from the reaction of intermediated hydroxyethypiperazines with benzenesulfonyl chlorides or benzoyl chlorides, has been evaluated in vitro against a W2 Plasmodium falciparum clone. Some of the nineteen tested derivatives showed a significant activity in vitro, thus turning into a promising new class of antimalarials. In addition, a molecular modeling study of the most active derivative (5l) was performed and its most probable binding modes within plasmepsin II enzyme were identified.
Subject(s)
Antimalarials/chemistry , Antimalarials/pharmacology , Ethanolamines/chemical synthesis , Ethanolamines/pharmacology , Malaria, Falciparum/drug therapy , Plasmodium falciparum/drug effects , Animals , Antimalarials/chemical synthesis , Antimalarials/toxicity , Aspartic Acid Endopeptidases/metabolism , Cell Line , Erythrocytes/parasitology , Ethanolamines/chemistry , Ethanolamines/toxicity , Humans , Macrophages/cytology , Macrophages/drug effects , Models, Molecular , Monocytes/cytology , Monocytes/drug effects , Murinae , Plasmodium falciparum/enzymology , Protein Binding , Protozoan Proteins/metabolismABSTRACT
The search for new antimalarials, which in the past relied on animal models, is now usually performed with cultures of Plasmodium falciparum (PF) blood parasites by evaluation of parasite growth inhibition. Field isolates of PF human malaria parasite, parasite strains and clones, well characterized for their susceptibility to chloroquine and other standard antimalarials are available for the in vitro tests. The simplest method to evaluate parasite growth is the determination of parasitemias in Giemsa stained blood smears through light microscopy. Other methodologies have proven to be more precise and allow mass screening of new compounds against PF blood stages, such as: (i) measuring the incorporation of radioactive hypoxanthine by the parasites; (ii) indirect colorimetric assays in which specific parasite enzyme activities, and histidine-rich protein II (HRP2) production are measured with the help of monoclonal antibodies; (iii) the beta-haematin formation, and; (iv) assays using green fluorescent protein (GFP) in gene-expressing parasites. The advantages and disadvantages of the different in vitro screening methods, as well as the different in vivo models for antimalarial tests, are described in this review. Such tests can be used for the evaluation of medicinal plants, synthetic and hybrid molecules or drug combinations.