Semisynthetic Derivatives of Perovskone: Development of a Promising Class of Antiprotozoal Lead Compounds

Perovskones, intricate triterpenoids with potent antiplasmodial activity, predominantly derive from <i>Salvia hydrangea</i> DC. ex Benth. In this study, ample quantities of the parent compound, perovskone (<b>1</b>), were isolated from the plant. Using perovskone (<b>1</b>) as a feedstock, seven semisynthetic analogues (<b>2</b>-<b>8</b>) were generated via reactions like hydroxylation, elimination, and esterification. Structural characterization was performed by using 1D and 2D NMR, HRMS, and X-ray diffraction experiments. The compounds underwent <i>in vitro</i> antiparasitic testing against <i>Leishmania donovani</i>, <i>Trypanosoma brucei rhodesiense</i>, <i>Plasmodium falciparum</i>, and <i>Trypanosoma cruzi.</i> Cytotoxicity evaluation was performed using rat myoblast (L6) cells. Perovskone (<b>1</b>) demonstrated excellent activity against <i>T. cruzi</i>, showing an IC₅₀ value of 0.89 μM and a selectivity index (SI) of 14.9. Perovskone I (<b>4</b>) and perovskone G (<b>2</b>) exhibited potent activity against <i>P. falciparum</i> (IC₅₀ values of 0.03 and 0.08 μM, respectively), with favorable SIs of 843.0 and 80.0, comparable to those of chloroquine and artemisinin. Perovskone M (<b>8</b>) displayed promising antileishmanial activity (IC₅₀ = 0.44 μM, SI = 22), comparable to the efficacy of miltefosine against <i>L. donovani</i> (IC₅₀ = 0.51 μM). We believe that the current study holds immense potential for the development of promising leads in antiplasmodial drug discovery.