Low Molecular Weight Non-Peptidyl Antimalarial Leads: Lichen Metabolite, Usnic Acid and Its Analogues

The search for newer antimicrobial agents is a developing and continuing process. With an aim to discover new antimalarial leads from natural sources, a unique lichen-derived metabolite namely, usnic acid (USA) and their
analogues were screened against a chloroquine-sensitive Plasmodium falciparum 3D7 line using an in vitro parasite growth inhibition assay. A bioguided fractionation of USA, the molecule of interest, derived from the ether extract of the lichen, Usnea undulata, reported to exhibit significant
protease enzyme inhibitory activity, was used as a natural product scaffold and was chemically modified to yield three hydrazine, viz usnic acid anhydro phenyl hydrazone (S1), usnic acid anhydro 4-nitro phenyl hydrazone (S2), usnic acid anhydro 2,4-dinitro phenyl hydrazone (S3) and two amino
compounds namely usnic acid anhydro o-phenylene diamine derivative (S5) and usnic acid anhydro piperazine derivative (S6) respectively. These low molecular weight non-peptidyl newer chemical entities (USA, S1, S2, S3, S5 and S6) were tested in vitro against the malaria parasite, Plasmodium falciparum and among all, the hydrazine moiety, usnic acid
anhydro 4-nitro phenyl hydrazone (S2) was shown to the most active compound with an IC50 of 1.4105 M when compared to the parent pharmacophore, USA with an IC50 of 6.5105 M. The results reveal that lichen metabolite; USA offers a large scaffold for combinatorial outputs in developing lead candidates with potent antimalarial activity.