Antiparasitic hybrids of Cinchona alkaloids and bile acids

Structure-activity relationship of hybrids of Cinchona alkaloids and bile acids with in vitro antiplasmodial and antitrypanosomal activities

“…In this sense, bile acids are of great interest in drug discovery because of their efficient transport system and their properties as adsorption enhancers [14]. All these observations led to the preparation of a new series of antiparasitic hybrids of Cinchona alkaloids and bile acids [15]. The strategy was to combine the antiparasitic properties of the natural Cinchona alkaloids, which are currently used to treat severe cases of malaria [16], with the known properties of the bile acids as drug transporters, especially taking into account that some bile acids also have mild antiparasitic activity [17,18].…”

“…In these compounds C-4 0 of the quinoline core is substituted, leaving C-2 0 as the only available position for a nucleophilic attack. From a biological point of view, the incorporation of a norcholane moiety to Cinchona alkaloids (quinine, quinidine, cinchonine and cinchonidine), had a positive effect on their in vitro antiparasitic activity against Plasmodium falciparum and Trypanosoma brucei [15]. In the first group of synthesized hybrids, the degree of oxidation of the bile acid moiety had a marked influence on the activity, since the compounds derived from chenodeoxycholic acid were more active than those prepared from lithocholic acid.…”

“…The cytotoxicities of all these compounds against the WI-38 cell line (human non cancer fibroblast) were also determined. Based on previous disappointing results [15], the activity of the new hybrids against Leishmania mexicana mexicana was not tested. In this work, the antiparasitic activity results of the complete series of 48 hybrids are discussed, and some structure-activity relationships can now be established.…”

“…In the present work, 32 new hybrids were synthesised ( Fig. 1) to add to the series of the 16 previous derivatives prepared from lithocholic and chenodeoxycholic acids [15]. The in vitro antiparasitic activities of the hybrids 1e12aed, the four parent alkaloids (QN ¼ quinine, QND ¼ quinidine, CN ¼ cinchonine, CND ¼ cinchonidine) and the bile acids 1e12 were also evaluated against P. falciparum and T. brucei brucei.…”

Quinoline-based antimalarial hybrid compounds

“…Although none of the conjugates 89 were more active in vitro than the corresponding Cinchona alkaloids, they all exhibited activities with IC 50 < 6 µg/mL, most of them even < 1 µg/mL. Moreover, hybrids 89 showed good selectivity indices 168. …”