Complementary Quantitative Structure⁻Activity Relationship Models for the Antitrypanosomal Activity of Sesquiterpene...

Area of Science:

• Medicinal Chemistry
• Computational Chemistry
• Parasitology

Background:

• Human African trypanosomiasis remains a significant health concern, necessitating novel therapeutic agents.
• Sesquiterpene lactones (STLs) are natural products with demonstrated antitrypanosomal activity.
• Previous quantitative structure-activity relationship (QSAR) studies have explored STL activity, but larger, more diverse datasets are needed.

Purpose of the Study:

• To develop robust QSAR models for predicting the antitrypanosomal activity of a large and diverse set of STLs against Trypanosoma brucei rhodesiense (Tbr).
• To identify key molecular descriptors and structural features that govern the antitrypanosomal efficacy of STLs.
• To enhance the understanding of structure-activity relationships for the development of new anti-trypanosomal drugs.

Main Methods:

• Employed three complementary QSAR methodologies: regression modeling using classical molecular descriptors, 3D pharmacophore features, and 2D molecular holograms (HQSAR).
• Developed models for an extended dataset of 130 STLs, including newly isolated compounds and literature data tested under identical conditions.
• Validated the QSAR models using internal (leave-one-out) and external prediction metrics.

Main Results:

• Achieved good predictive ability for all developed QSAR models, with coefficients of determination (R²) ranging from 0.71 to 0.85.
• Demonstrated strong internal validation (Q² values from 0.62 to 0.72) and external validation (P² values from 0.54 to 0.73) across the diverse STL dataset.
• Confirmed that antitrypanosomal activity is significantly influenced by the presence and position of reactive enone groups, as well as hydrophilic/hydrophobic properties and molecular shape.

Conclusions:

• The developed QSAR models provide reliable tools for predicting the antitrypanosomal activity of STLs.
• The findings reinforce the importance of specific structural features, particularly reactive enone groups, for Tbr activity.
• This study contributes to the rational design of novel STL-based compounds for treating human African trypanosomiasis.