Mapping the Electronic Topography of Crotofolane Diterpenoids: CDFT Study on Bioactivity, Ambiphilic Collapse, and Steric Quenching
TL;DR
The reactive profile and its correlation with biological efficacy against human rhinovirus type‐2 (HRV‐2) and Plasmodium falciparum Dd2 are characterized by integrating the RIJCOSX‐DEF2/J approximation and the CPCM solvation model (water).
Abstract
The electronic topography of crotofolane diterpenoids M1 – M6 was systematically investigated using conceptual DFT (CDFT) at the B3LYP‐D4/def2‐TZVP level. By integrating the RIJCOSX‐DEF2/J approximation and the CPCM solvation model (water), this study characterizes the reactive profile and its correlation with biological efficacy against human rhinovirus type‐2 (HRV‐2) and Plasmodium falciparum Dd2. Global reactivity descriptors reveal that antiplasmodial potency is confined to a specific chemical hardness ( η ) window (5.30–5.45 eV). In the bioactive series ( M1 – M3 ), local analysis identifies a spatially resolved O40–O10 functional axis as the primary pharmacophoric determinant, where the exocyclic O40 acts as the primary nucleophilic site ( = 1.000) and the lactone O10 as the primary electrophilic locus ( = 1.000). Conversely, the inactivity of M4 is driven by an “ambiphilic collapse” at the C14 site, which simultaneously concentrates the absolute primary dominance for both nucleophilic and electrophilic attacks ( = = 1.000), disrupting the polarized topography required for specific binding. For M5 , angular strain induces an ambiphilic transition at O40 ( = = 1.000) with the maximum radical susceptibility ( = 0.2248), shifting selectivity toward a modest antiviral profile potentially governed by single electron transfer (SET) mechanisms. Finally, in M6 , the transformation of the exocyclic carbonyl into a bulky propionyl ester eliminates the primary reactive site, trapping reactive density within the α,β‐unsaturated γ‐lactone. These findings provide a quantitative roadmap for the rational design of diterpenoid‐based agents.