ABSTRACT
The treatment of human leishmaniasis is currently based on few compounds that are highly toxic, expensive and have a high rate of treatment failure. A number of recent studies on new drugs focuses on natural or semi-synthetic compounds. Among them, the endoperoxide artemisinin, extracted from Artemisia annua, and some of its derivatives have shown leishmanicidal activity. In the present work, a series of structurally simple, fully synthetic 1,2-dioxanes were evaluated for in vitro antileishmanial activity against promastigotes of Leishmania donovani; the cytotoxicity for mammalian cells was also assessed. The six most promising compounds in terms of activity and selectivity were further investigated for their antileishmanial activity on the promastigote forms of L. tropica, L. major and L. infantum and against L. donovani amastigotes. The good performance in terms of potency and selectivity makes these six hits promising candidates for a preliminary lead optimization as antileishmanial agents.
Subject(s)
Dioxanes/chemistry , Dioxanes/pharmacology , Leishmania/drug effects , Leishmaniasis/drug therapy , Trypanocidal Agents/chemistry , Trypanocidal Agents/pharmacology , Animals , Chlorocebus aethiops , Dioxanes/chemical synthesis , Drug Design , Humans , Parasitic Sensitivity Tests , Vero CellsABSTRACT
New enantiomerically pure 1,2,4-trioxepanes 10a,b/11a,b were synthesized from D-glucose. Their conformational behavior was studied by low-temperature NMR and substantiated by DFT calculations. On evaluation of in vitro antimalarial activity, the adamantyl derivative 11b showed IC50 values in the low micromolar range, particularly against the W2 chloroquine-resistant Plasmodium falciparum strain (IC50 = 0.15 ± 0.12 µM).
Subject(s)
Adamantane/chemical synthesis , Adamantane/pharmacology , Antimalarials/chemical synthesis , Glucose/chemistry , Oxepins/chemical synthesis , Adamantane/chemistry , Antimalarials/chemistry , Antimalarials/pharmacology , Chloroquine/pharmacology , Dose-Response Relationship, Drug , Molecular Conformation , Molecular Structure , Oxepins/chemistry , Oxepins/pharmacology , Plasmodium falciparum/drug effects , Plasmodium falciparum/genetics , Stereoisomerism , Structure-Activity RelationshipABSTRACT
A continuous bone remodelling takes place throughout life at different turnover speed according to age, physiological and pathological conditions. The evaluation of bone turnover may be of value for a prognostic and therapeutical assessment. Calcium bone exchange may be considered a suitable marker of bone turnover; for this reason 47Ca or 45Ca kinetics may be used; these methods have been employed in the past. Labelled diphosphonates, and in particular 99Technetium-methylene-diphosphonate (99TcmDP) are simpler and safer, because these substances are strongly and almost completely stored in bone and not absorbed by the soft tissue; for this reason they are used at the present time. The evaluation of blood levels and 24 hrs urinary elimination of 99TcmDP is used to measure whole bone diphosphonate retention (WBR). This parameter is positively correlated with other markers of bone turnover such as alkaline phosphatase (AP), osteocalcin (OC), urinary hydroxyproline (HOP). A bicompartmental analysis schedule of 99TcmDP distribution has been proposed some years ago and therefore applied by our group, based on the mathematical evaluation of serum concentration at different times and urinary elimination of the label given intravenously. This method provides the possibility to calculate not only WBR but also total body retention (TBR) and a constant (Kbh) which reflects the influx speed of the tracer in the bone. Kbh probably represents a more sensitive index of bone turnover than WBR. It presents a better correlation with AP and OC values and also shows some (statistically less significant correlations with some indices of bone remodelling obtained by histomorphometry on bone biopsies.(ABSTRACT TRUNCATED AT 250 WORDS)
