Synthesis and Structure–Activity Relationships of Tambjamines and B‑Ring Functionalized Prodiginines as Potent Antimalarials

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.