TY - JOUR
T1 - Sars for the antiparasitic plant metabolite pulchrol. part 2
T2 - B- And c-ring substituents
AU - Terrazas, Paola
AU - Manner, Sophie
AU - Sterner, Olov
AU - Dávila, Marcelo
AU - Giménez, Alberto
AU - Salamanca, Efrain
N1 - Publisher Copyright:
© 2020 by the authors.
PY - 2020/10
Y1 - 2020/10
N2 - Neglected tropical diseases affect most of the underprivileged populations in tropical countries. Among these are chagas and leishmaniasis, present mainly in South and Central America, Africa and East Asia. Current treatments are long and have severe adverse effects, therefore there is a strong need to develop alternatives. In this study, we base our research on the plant metabolite pulchrol, a natural benzochromene which has been shown to possess antiparasitic activity against Trypanosoma and Leishmania species. In a recent study, we investigated how changes in the benzyl alcohol functionality affected the antiparasitic activity, but the importance of B- and C-ring substituents is not understood. Fifteen derivatives of pulchrol with different substituents in positions 1, 2, 3, and 6 while leaving the A-ring intact, were therefore prepared by total synthesis, assayed, and compared with pulchrol and positive controls. The generated series and parental molecule were tested in vitro for antiparasitic activity against Trypanosoma cruzi, Leishmania braziliensis, and L. amazonensis, and cytotoxicity using RAW cells. Substantial differences in the activity of the compounds synthesized were observed, of which some were more potent towards Trypanosoma cruzi than the positive control benznidazole. A general tendency is that alkyl substituents improve the potency, especially when positioned on C-2.
AB - Neglected tropical diseases affect most of the underprivileged populations in tropical countries. Among these are chagas and leishmaniasis, present mainly in South and Central America, Africa and East Asia. Current treatments are long and have severe adverse effects, therefore there is a strong need to develop alternatives. In this study, we base our research on the plant metabolite pulchrol, a natural benzochromene which has been shown to possess antiparasitic activity against Trypanosoma and Leishmania species. In a recent study, we investigated how changes in the benzyl alcohol functionality affected the antiparasitic activity, but the importance of B- and C-ring substituents is not understood. Fifteen derivatives of pulchrol with different substituents in positions 1, 2, 3, and 6 while leaving the A-ring intact, were therefore prepared by total synthesis, assayed, and compared with pulchrol and positive controls. The generated series and parental molecule were tested in vitro for antiparasitic activity against Trypanosoma cruzi, Leishmania braziliensis, and L. amazonensis, and cytotoxicity using RAW cells. Substantial differences in the activity of the compounds synthesized were observed, of which some were more potent towards Trypanosoma cruzi than the positive control benznidazole. A general tendency is that alkyl substituents improve the potency, especially when positioned on C-2.
KW - Benzo[c]chromenes
KW - Leishmania amazonensis
KW - Leishmania braziliensis
KW - Pulchrol
KW - Structure-Activity Relationships (SARs)
KW - Trypanosoma cruzi
UR - http://www.scopus.com/inward/record.url?scp=85092559250&partnerID=8YFLogxK
U2 - 10.3390/molecules25194510
DO - 10.3390/molecules25194510
M3 - Artículo
C2 - 33019678
AN - SCOPUS:85092559250
SN - 1420-3049
VL - 25
JO - Molecules
JF - Molecules
IS - 19
M1 - 4510
ER -