Rapid Dereplication of Trunk Bark Constituents of Croton sylvaticus and Molecular Docking of Terpenoids from Three Congolese Croton Species

Abstract

Phytochemical investigation and bioactivity evaluation of terpenoids from the <i>Croton</i> species were conducted. The chemical composition of <i>C. sylvaticus</i> was explored using chemical phytochemical screening techniques and dereplication of ¹³C NMR data using MixONat software (v. 1.0.1). Natural products with diverse structural features were identified in the dichloromethane extract of trunk bark. These include monoterpenoids, sesquiterpenoids, diterpenoids, triterpenoids, along with other minor metabolites, such as steroids, saponins, and fatty acids. Further purification of this extract led to the isolation of three major secondary metabolites, acetyl aleuritolic acid, caryophyllene oxide, and phytol. These secondary metabolites were reported for the first time in <i>C. sylvaticus</i>. The isolated compounds were structurally compared to known anticancer terpenoids previously identified in two other Congolese <i>Croton</i> species. Through molecular docking studies, the predicted binding affinities of the identified compounds were assessed, and possible structure-activity relationships (SAR) were proposed. Two structurally characterized receptors-the human androgen receptor (HAR, PDB ID: 1E3G) and hypoxia-inducible factor 1-alpha (HIF-1α, PDB ID: 3KCX), known for their involvement in cancer-related pathways, were used for molecular docking investigations. Among the tested compounds, <b>1</b>, <b>2</b>, <b>3</b>, and <b>12</b> were identified as having strong-to-moderate predicted binding affinities to both protein targets, along with favorable drug-like properties according to the ADMET analysis. This investigation could justify the use of <i>Croton</i> plants in traditional medicine. In addition, our study highlights the potential of the Congolese <i>Croton</i> species as sources of bioactive secondary metabolites.