A Clerodane Diterpene from Aquarius scaber (Rataj) Christenh. & Byng Leaves as Inhibitor of Leishmania mexicana Trypanosomatid Enzymes

Abstract The clerodane diterpenoid 2-oxo-5α,8α-cleroda-3,13-dien-16,15-olide (1) isolated from the leaves of A. scaber was identified by IR, 1H and 13C NMR (1D and 2D) and HRESIMS spectrometric analysis. This is the first report of this diterpene in the Aquarius genus. The inhibitory potential of 1 has been determined against cysteine proteases from Leishmania mexicana rCPB2.8, rCPB3.0 and rH84Y. The inhibitory constants (Ki and αKi) as well as the mechanism of action were also investigated. Compound 1 was 7- and 18-fold more potent in the inhibition of rCPB3.0 (IC50 = 4.2 µM) than rCPB2.8 (IC50 = 20 µM) and rH84Y (IC50 = 75 µM). From the kinetic mechanisms of inhibitor binding, we found that compound 1 has a higher affinity to rCPB3.0 (K i = 7.5 µM and αK i = 7.4 µM) than rCPB2.8 (K i = 15.4 µM, αK i = 14.7 µM) and rH84Y (K i = 81.4, and αK i = 27.9 μM and βKi = 41.5 µM). Compound 1 also presented a non-competitive linear simple inhibition mechanism at both enzymes rCPB3.0 and rCPB2.8. On the other hand, 1 presented a positive cooperativity mechanism of inhibition at rH84Y. GRAPHICAL ABSTRACT