Synthesis and In Vitro Evaluation of Tropane Halogenated-derivatives Against Malaria, Sleeping Sickness, Chagas Disease and Leishmaniasis

Abstract

A series of twelve analogs carrying fluoro, chloro, bromo and iodo halogens on the ortho, meta and para positions of a benzoyloxytropane skeleton were synthesized by a simple acylation of 8-methyl-8-aza-bicyclo[3.2.1]octan- 3α-ol by halogenobenzoyl chlorides. The compounds were evaluated in vitro against Plasmodium falciparum (P. f.), Trypanosoma brucei brucei (T. b. b.), Trypanosoma cruzi (T. c.) and Leishmania infantum (L. i.). This study shows that the presence of a halogenated atom and its position on the aromatic ring are important for in vitro activity. Compounds 4 (IC50 = 3.6 µM), 8 (IC50 = 6.7 µM), 5 (IC50 = 8.1 µM) and 7 (IC50 = 9.5 µM) were found the most active against P. f., whereas compounds 12 (IC50 = 5.1 µM), 11 (IC50 = 5.6 µM) and 9 (IC50 = 5.8 µM) exhibited the most pronounced activity against T. b. b. This series of compounds can be considered as non-toxic to the human cell line MRC-5.

4-Chlorothymol Exerts Antiplasmodial Activity Impeding Redox Defense System in Plasmodium falciparum

“…In the present study, among eight derivatives of thymol, 4chlorothymol was found to be the most active against chloroquine sensitive (NF-54) as well as resistant strains (K1) of P. falciparum. In a previous study, among different halogenated tropane 3α-(2′-chlorobenzoyloxy) derivatives with chloro group it was found to be the most active (Cretton et al, 2014). Chloro group is also known to increase the lipophilicity of molecules that improve membrane permeability (Gerebtzoff et al, 2004).…”

Discovering a mitochondrion-localized BAHD acyltransferase involved in calystegine biosynthesis and engineering the production of 3β-tigloyloxytropane

“…The synthetic methods used were described previously. The acids were converted to acyl chloride derivatives and then reacted with 3 β -tropanol to prepare 3 β -tropanol esters 71 , 72 . Tigloyl-CoA thioesters were synthesized from CoA and free acid via the catalysis of PyBOP 73 .…”

Two New Hygroline and Tropane Alkaloids Isolated from Schizanthus Hookeri and S. Tricolor (Solanaceae)

“…Previous results [5] reporting on the antiplasmodial activity of the aerial parts of S. tricolor (IC 50 = 10 μg/mL) prompted us to evaluate the antiparasitic activity of the alkaloid extract of S. hookeri and of the isolated alkaloids. They were tested against Plasmodium falciparum, Leishmania infantum, Trypanosoma brucei brucei and Trypanosoma cruzi, and their cytotoxicity was determined following the same assay described previously [27]. The alkaloid extract of S. tricolor was inactive (IC 50 > 64 μg/mL) against L. infantum, but moderately active against T. b. brucei (IC 50 = 32 μg/mL) and T. cruzi (IC 50 = 31 μg/mL), whereas S. hookeri was moderately active against T. b. brucei (IC 50 = 32 μg/mL), L. infantum (IC 50 = 32 μg/mL), and T. cruzi (IC 50 = 26 μg/mL) and active against P. falciparum (IC 50 = 5 μg/mL) (Table 1).…”

“…HRESIMS: m/z [M + H] + calcd for C 13 H 22 NO 4 : 256.1549; found: 256.1544 GC-EI-MS (IPT 2403) 70eV: m/z 255 [M] + . (8), 238 (8), 226 (15), 172 (47), 156 (15), 138 (5), 129 (20), 112 (25), 94 (40), 82 (100), 57 (52), 42 (45).Antiparasitic and cytotoxicity assays:The in vitro activities against P. falciparum, L. infantum, T. b. brucei and T. cruzi, as well as the cytotoxicity assessment in MRC-5 cells, were determined as reported elsewhere[27]. The following strains and parasite forms were used: P. falciparum K1 (chloroquine, pyrimethamine and cycloguanil resistant); L. infantum MHOM/MA(BE)/67, amastigote form; T. b. brucei, Squib 427 (suramin-sensitive), trypomastigote Cretton et al form; T. cruzi, Tulahuen LacZ C4 (nifurtimox-sensitive), amastigotes maintained on MRC-5 SV2 cells, human lung fibroblasts.…”