Pulchrol, a natural compound isolated from the roots of the vegetal specie Bourreria pulchra has been shown to possess potential antiparasitic activity toward Trypanosomatids, particularly against Trypanosoma cruzi, which causes the Chagas disease; and moderately against Leishmania species, responsible for Leishmaniasis. In this investigation, several pulchrol analogues were prepared and assayed toward T. cruzi epimastigotes, and L. braziliensis and L. amazonensis promastigotes, to develop structure activity relationship studies (SARs).
Analogues with transformations in the three rings of the pulchrol’s scaffold were prepared. Initially, compounds with transformations at the benzylic position in the A-ring were assayed to evaluate the role of the benzylic alcohol in pulchrol. The results showed that an hydrogen bond acceptor group is important for the antitrypanosomatid activity and that ester groups with bulky alkyl substituents increase the potency toward all parasites. Analogues with transformations in the B- and C-rings, were focused on the variation of lipophilicity. In the B-ring, the methyl substituents placed at position 6 in pulchrol were replaced for two hydrogen atoms, just one methyl substituent, or two longer alkyl substituents. The biological activity results showed that longer chains with less than four carbon atoms are benefitial for the activity. A methoxy subtituent is placed at position 2 in pulchrol’s C-ring, in this study, analogues with the methoxy subtituent placed in different positions or replaced with alkyl subtituents were prepared, the results showed that compounds with hydrophobic groups in the C-ring incresed the potency.
Several analogues with more than one modification in different rings were also prepared. The combination of carbonyl groups in the A-ring with bulky alkyl groups in the C-ring was the most benefitial for the activity. In contrast, esters subtituted with a hydrophobic group in the A-ring and bulky alkyl groups in the C-ring hampered the activity. A hydrogen bond acceptor at the benzylic position in the A-ring, as well as an additional hydroxyl group at position 1 in the C-ring (as in cannabinol) appeared to be important for the activity. The combination of different functionalities also seemed to have and effect in the orientation of the molecule inside the target protein.
Our results showed that differences between the active sites for the different parasites may exist, however, preliminary pharmacophore hypotheses based on our biological results showed that the main pharmacophoric features are two hydrogen bond acceptor groups (one at the benzylic position and one on the B-ring’s oxigen) and three hydrophobic features (two in the B-ring at position 6, and one in the C-ring at position 2 or 3).
A qualitative evaluation of ADMET-descriptors calculated in silico, showed that most of the molecules have potential as orally administered substances, however, further studies focused on the development of compounds with more potency and focused on the optimization of the ADME characteristics are recommended.
- Sterner, Olov, Supervisor
- Manner, Sophie, Assistant supervisor
- Dávila, Marcelo , Assistant supervisor, External person
|Place of Publication||Lund|
|ISBN (electronic) ||978-91-7422-817-5|
|Publication status||Published - 2021 May 7|
Place: Kemiska institutionen, Lecture hall C. Join via zoom: https://lu-se.zoom.us/j/67827628774?pwd=R2xTcFRkbFZJV1g5NjZWeEI3T3FIQT09
Name: Blum, Zoltan
Affiliation: Faculty of Health and Society, Department of Biomedical Science, Malmö University
- Leishmania braziliensis
- Leishmania amazonensis
- Trypanozoma cruzi
- Bourreria pulchra
- Chagas disease