Synthesis and Structure−Activity Relationships of Tambjamines and B‑Ring Functionalized Prodiginines as Potent Antimalarials
This work was supported by a grant from the National Institutes of Health (Grant GM077147).
Journal of Medicinal Chemistry
Pyrroles -- Synthesis, Tambjamines -- Antimalarial activity of, Ring formation (Chemistry), Chemical preparations industry
Synthesis and antimalarial activity of 94 novel bipyrrole tambjamines (TAs) and a library of B-ring functionalized tripyrrole prodiginines (PGs) against a panel of Plasmodium falciparum strains are described. The activity and structure–activity relationships demonstrate that the ring-C of PGs can be replaced by an alkylamine, providing for TAs with retained/enhanced potency. Furthermore, ring-B of PGs/TAs can be substituted with short alkyl substitutions at either 4-position (replacement of OMe) or 3- and 4-positions without impacting potency. Eight representative TAs and two PGs have been evaluated for antimalarial activity against multidrug-resistant P. yoelii in mice in the dose range of 5–100 mg/kg × 4 days by oral administration. The KAR425 TA offered greater efficacy than previously observed for any PG, providing 100% protection to malaria-infected mice until day 28 at doses of 25 and 50 mg/kg × 4 days, and was also curative in this model in a single oral dose (80 mg/kg). This study presents the first account of antimalarial activity in tambjamines.
Kancharla, P., Kelly, J. X., & Reynolds, K. A. (2015). Synthesis and Structure–Activity Relationships of Tambjamines and B-Ring Functionalized Prodiginines as Potent Antimalarials. Journal of Medicinal Chemistry, 58(18), 7286–7309.
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