Structure-activity relationship of (-) mammea A/BB derivatives against Leishmania amazonensis.
To study the structure-activity relationship of coumarin (-) mammea A/BB isolated from the CH(2)Cl(2) extract of Calophyllum brasiliense leaves, we evaluated the antileishmanial activity of natural, synthetic and derivatives of this coumarin, against promastigote and intracellular amastigote forms of Leishmania amazonensis, and their cytotoxicity to J774G8 murine macrophages. The derivatives were obtained by hydrogenation and methoxylation reactions. The compound structures were elucidated on the basis of spectroscopic data. The compounds 5,7-dihydroxy-8-(2-methylbutanoyl)-6-(3-methylbutyl)-4-phenyl-chroman-2-one (3), 7-hydroxy-5-methoxy-8-(2-methylbutanoyl)-6-(3-methylbut-2-en-1-yl)-4-phenylcoumarin (4) and 5,7-dimethoxy-8-(1-methoxy-2-methylbutyl)-6-(3-methylbut-2-en-1-yl)-4 phenylcoumarin (6) were more biologically active than the compound (-) mammea A/BB (1) (7.4 microM), with IC(50) values from 0.9, 2.4 and 1.9 microM respectively; compound (3) displayed the highest activity. The compounds mammea B/BB (2), 5,7-dimethoxy-8-(2-methylbutanoyl)-6-(3-methylbut-2-en-1-yl)-4-phenylcoumarin (5) and 5,7-dihydroxy-4-phenylcoumarin (7) were less active than (-) mammea A/BB (1), with IC(50) of 30.1, 15.1 and 60.2 microM respectively; compound (7) showed the lowest antileishmanial activity of all. Compounds (1), (3), (4) and (6) were active not only against promastigote forms of L. amazonensis, but also against intracellular amastigote forms with IC(50) of 14.3, 0.6, 34.0 and 22.2 microM, respectively. Interestingly, compound (3) showed the most antileishmanial activity of all. This study demonstrated that several aspects of the structure were important for antileishmanial activity.
Pós Graduação em Ciências Farmacêuticas, Departamento de Farmácia e Farmacologia, Universidade Estadual de Maringá, Av. Colombo 5790, 87020-900 Maringá, PR, Brazil.
Mislaine Adriana
MA
Brenzan
Celso Vataru
CV
Nakamura
Benedito Prado
BP
Dias Filho
Tânia
T
Ueda-Nakamura
Maria Claudia M
MC
Young
Arlene Gonçalves
AG
Côrrea
Joel
J
Alvim
Adriana Oliveira
AO
dos Santos
Diógenes Aparício Garcia
DA
Cortez
D000818:Animals; D029759:Calophyllum; D002460:Cell Line; D003374:Coumarins / Q000737:chemistry / Q000494:pharmacology* / Q000633:toxicity; D007891:Leishmania / Q000187:drug effects*; D008264:Macrophages / Q000187:drug effects; D051379:Mice; D013329:Structure-Activity Relationship; D014344:Trypanocidal Agents / Q000737:chemistry / Q000494:pharmacology* / Q000633:toxicity
D003374:Coumarins; D014344:Trypanocidal Agents