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

Author(s)

Lopes, Kheytiany H. S. ; Silva, Virginia C. P. ; Jacinto, Marcos J. ; de Souza, Aline A. ; Padovani, Camila G. D. ; Machado, Mauricio F. M. ; Judice, Wagner A. S. ; Sousa Jr, Paulo T.

• Document type: Journal article
• Source: JOURNAL OF BIOLOGICALLY ACTIVE PRODUCTS FROM NATURE; v. N/A, p. 11-pg., 2023-09-14.

Abstract

The clerodane diterpenoid 2-oxo-5 alpha,8 alpha-cleroda-3,13-dien-16,15-olide (1) isolated from the leaves of A. scaber was identified by IR, H-1 and C-13 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 alpha Ki) 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 mu M) than rCPB2.8 (IC50 = 20 mu M) and rH84Y (IC50 = 75 mu M). From the kinetic mechanisms of inhibitor binding, we found that compound 1 has a higher affinity to rCPB3.0 (K-i = 7.5 mu M and alpha K-i = 7.4 mu M) than rCPB2.8 (K-i = 15.4 mu M, alpha K-i = 14.7 mu M) and rH84Y (K-i = 81.4, and alpha K-i = 27.9 mu M and beta K-i = 41.5 mu M). 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. (AU)

• FAPESP's process: 16/25112-4 - Evaluation of modulators of the activity of proteases involved in pathological processes
• Grantee: Wagner Alves de Souza Júdice
• Support Opportunities: Regular Research Grants
• FAPESP's process: 15/11190-0 - Biochemical characterization of caspase-like involved in a cell cycle of simple eukariotic.
• Grantee: Mauricio Ferreira Marcondes Machado
• Support Opportunities: Regular Research Grants