“Comprehensive in Silico Modeling, QSAR Analysis, and Drug-Likeness Evaluation of Triazolopyrazine Derivatives as Potential Inhibitors of Plasmodium falciparum”

Abstract

Background: Malaria, caused by the protozoan parasite Plasmodium falciparum, remains a major global health challenge, particularly in tropical and subtropical regions. The emergence of drug-resistant strains has necessitated the discovery of new antimalarial agents. Triazolopyrazine derivatives have recently gained attention due to their potential inhibitory activity against P. falciparum. Quantitative Structure–Activity Relationship (QSAR) modeling serves as an effective computational approach to correlate molecular properties with biological activity and to guide the design of novel compounds.

Methods: A QSAR study was carried out on a series of triazolopyrazine derivatives to evaluate their inhibitory activity against P. falciparum. Experimentally reported inhibition constants (KI) were collected from the literature and transformed into logarithmic activity values using the equation:

A = log(c / KI)

Minimum-energy conformations of the compounds were generated using the MMFF94s force field and further optimized with the semi-empirical PM6 method. A diverse set of molecular descriptors was calculated and used to construct QSAR models. A prediction set of twelve novel triazolopyrazine derivatives was designed using BROOD software. Drug-likeness and oral bioavailability were assessed using Lipinski’s rule of five and related filters, incorporating parameters such as molecular weight (MW), lipophilicity, hydrogen bond donors and acceptors, topological polar surface area (TPSA), and molecular flexibility.

Results: The QSAR analysis demonstrated a significant correlation between molecular descriptors and inhibitory activity. Several compounds from the calibration set, particularly a2, a5, a8, and a13, exhibited strong inhibitory potency. Among the twelve newly designed compounds, p1, p6, and p11 showed the highest predicted activities, indicating their potential as promising antimalarial candidates. Drug-likeness evaluation revealed that most compounds satisfied Lipinski’s criteria, suggesting favourable oral bioavailability and pharmacokinetic profiles.

Conclusion: The study highlights the effectiveness of QSAR modeling in predicting the antimalarial activity of triazolopyrazine derivatives. The identified lead compounds, especially p1, p6, and p11, demonstrate promising inhibitory potential against Plasmodium falciparum and warrant further experimental validation. Overall, triazolopyrazine derivatives represent a valuable scaffold for the development of new antimalarial drugs.