SARs for the Antiparasitic Plant Metabolite Pulchrol



Pulchrol, a natural compound isolated from the roots of the plant Bourreria pulchra showed 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. 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 and 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. The biological activity results showed that longer chains with less than four carbon atoms are benefitial for the activity in the B-ring and 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.

Populärvetenskaplig beskrivning

Leishmaniasis and Chagas are neglected diseases caused by trypanosomatid parasites from the genus Leishmania and Trypanosoma, respectively. These diseases occur primarily in tropical and subtropical regions, affecting mainly people from underdeveloped countries that live in distant rural places with insufficient access to medical care. The development of appropriate treatments has been overlooked by the big pharmaceutical companies, and current treatments mostly come from repurpose drug studies, presenting several disadvantages such as unwanted side effects, and the need for parenteral administration that may require hospitalization in some cases.
The complex life cycles of the Leishmania and Trypanosoma parasites makes it difficult to understand their infection mechanisms, making the development of new drugs challenging. However, empirical knowledge obtained from traditional medicine, may contribute to the isolation and identification of new natural products with potential antiparasitic activity. Such is the case of natural product pulchrol, isolated from the roots of the vegetal specie Bourreria pulchra, traditionally used to treat cutaneous diseases, infections and fevers in Yucatan, Mexico. After its isolation, pulchrol has been shown to possess interesting activity toward T. cruzi, and several Leishmania species.
In this investigation, several pulchrol analogues systematically modified were prepared to be used in structure-activity relationship studies. The effects that transformations of pulchrol’s substituents produced in the antiparasitic activity were evaluated. A hydrogen bond acceptor at the benzylic position in pulchrol’s A-ring, ethyl substituents in the B-ring, and isopropyl substituents in the C-ring were found to be important for the activity. A pharmacophore hypothesis developed for T. cruzi agreed with the observations made during the SAR studies.
The absorption, distribution, metabolism, excretion and toxicity (ADMET) potential of pulchrol’s derivatives was evaluated qualitatively. Most of them were able to be absorbed orally, and therefore had potential as orally administered drugs.
Gällande start-/slutdatum2014/04/012021/06/17