ABSTRACT
We describe the synthesis and protozoocidal evaluation of a series of diazabicycles based on benzotropolone ethers. Several of the compounds, which can be obtained through a high-yielding hetero Diels-Alder reaction using simple and readily available starting materials, have in vitro activities against Trypanosoma cruzi and Leishmania donovani that are comparable to, and in some cases better than, those of currently used chemotherapies.
Subject(s)
Antiprotozoal Agents/chemical synthesis , Antiprotozoal Agents/pharmacology , Biflavonoids/chemical synthesis , Biflavonoids/pharmacology , Catechin/analogs & derivatives , Leishmania donovani/drug effects , Trypanosoma cruzi/drug effects , Animals , Aza Compounds/chemistry , Bridged Bicyclo Compounds/chemistry , Catechin/chemical synthesis , Catechin/pharmacologyABSTRACT
In this article, the design and synthesis of some novel azasterols is described, followed by their evaluation against Trypanosoma brucei rhodesiense, T. cruzi, Leishmania donovani, and Plasmodium falciparum, the causative agents of human African trypanosomiasis, Chagas disease, leishmaniasis, and malaria, respectively. Some of the compounds showed anti-parasitic activity. In particular, a number of compounds appeared to very potently inhibit the growth of the blood stream form T. b. rhodesiense, with one compound giving an IC50 value of 12 nM. Clear structure activity relationships could be discerned. These compounds represent important leads for further optimization. Azasterols have previously been shown to inhibit sterol biosynthesis in T. cruzi and L. donovani by the inhibition of the enzyme sterol 24-methyltransferase. However, in this case, none of the compounds showed inhibition of the enzyme. Therefore, these compounds have an unknown mode of action.
Subject(s)
Antimalarials/chemical synthesis , Azasteroids/chemical synthesis , Sterols/chemical synthesis , Trypanocidal Agents/chemical synthesis , Animals , Antimalarials/chemistry , Antimalarials/pharmacology , Azasteroids/chemistry , Azasteroids/pharmacology , Leishmania donovani/drug effects , Methyltransferases/antagonists & inhibitors , Plasmodium falciparum/drug effects , Stereoisomerism , Sterols/chemistry , Sterols/pharmacology , Structure-Activity Relationship , Trypanocidal Agents/chemistry , Trypanocidal Agents/pharmacology , Trypanosoma brucei rhodesiense/drug effects , Trypanosoma cruzi/drug effectsABSTRACT
The effect of several alkyl-linked bis tetrahydro-(2H)-1,3,5-thiadiazine-2-thione (bis-THTT) on Leishmania donovani, Trypanosoma brucei rhodesiense, and Plasmodium falciparum is reported. Most of the compounds exhibited a potent activity against the three parasitic strains but the best in vitro activity profiles were found against T. b. rhodesiense with IC(50) values ranging between 0.3 and 4 microM for the most active compounds.
